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Creatine transport and pathological changes in creatine transporter deficient mice. Journal of inherited metabolic disease Wawro, A. M., Gajera, C. R., Baker, S. A., Nirschl, J. J., Vogel, H., Montine, T. J. 2021
Abstract

The severe impact on brain function and lack of effective therapy for patients with creatine (Cr) transporter deficiency motivated the generation of three ubiquitous Slc6a8 deficient mice (-/y). While each mouse knock-out line has similar behavioral effects at 2 to 3 months of age, other features critical to the efficient use of these mice in drug discovery are unclear or lacking: the concentration of Cr in brain and heart differ widely between mouse lines, there are limited data on histopathologic changes, and no data on Cr uptake. Here, we determined survival, measured endogenous Cr and uptake of its deuterium-labeled analogue Cr-d3 using a liquid chromatography coupled with tandem mass spectrometry assay, and performed comprehensive histopathologic examination on the Slc6a8-/y mouse developed by Skelton et. al. Our results show that Slc6a8-/y mice have widely varying organ-specific uptake of Cr-d3, significantly diminished growth with the exception of brain, progressive vacuolar myopathy, and markedly shortened lifespan. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/jimd.12358

View details for PubMedID 33389772
Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia. Nature neuroscience Zhu, X., Zhou, B., Pattni, R., Gleason, K., Tan, C., Kalinowski, A., Sloan, S., Fiston-Lavier, A. S., Mariani, J., Petrov, D., Barres, B. A., Duncan, L., Abyzov, A., Vogel, H., Moran, J. V., Vaccarino, F. M., Tamminga, C. A., Levinson, D. F., Urban, A. E. 2021
Abstract

Retrotransposons can cause somatic genome variation in the human nervous system, which is hypothesized to have relevance to brain development and neuropsychiatric disease. However, the detection of individual somatic mobile element insertions presents a difficult signal-to-noise problem. Using a machine-learning method (RetroSom) and deep whole-genome sequencing, we analyzed L1 and Alu retrotransposition in sorted neurons and glia from human brains. We characterized two brain-specific L1 insertions in neurons and glia from a donor with schizophrenia. There was anatomical distribution of the L1 insertions in neurons and glia across both hemispheres, indicating retrotransposition occurred during early embryogenesis. Both insertions were within the introns of genes (CNNM2 and FRMD4A) inside genomic loci associated with neuropsychiatric disorders. Proof-of-principle experiments revealed these L1 insertions significantly reduced gene expression. These results demonstrate that RetroSom has broad applications for studies of brain development and may provide insight into the possible pathological effects of somatic retrotransposition.

View details for DOI 10.1038/s41593-020-00767-4

View details for PubMedID 33432196
FIRST-IN-HUMAN FLUORESCENCE GUIDED SURGERY OF HIGH-GRADE GLIOMAS USING PANITUMUMAB-IRDYE800 Zhou, Q., van den Berg, N., Nishio, N., Lu, G., Chirita, S., Raymundo, R., Yi, G., Vogel, H., Cayrol, R., Rosenthal, E., Li, G. OXFORD UNIV PRESS INC. 2020: 52
View details for Web of Science ID 000590061300209
MALIGNANT GLIOMAS REMODEL FUNCTIONAL NEURAL CIRCUITS THROUGH PARACRINE SIGNALING WHICH CONFERS A NEGATIVE PROGNOSIS Krishna, S., Choudhury, A., Ni, L., Seo, K., Kakaizada, S., Findlay, A., Lee, A., Sudharshan, R., Cao, C., Venkatesh, H., Vogel, H., Phillips, J., Almeida, N., Nagarajan, S., Berger, M., Raleigh, D., Brang, D., Monje, M., Hervey-Jumper, S. OXFORD UNIV PRESS INC. 2020: 217?18
View details for Web of Science ID 000590061300911
Quality-control mechanisms targeting translationally stalled and C-terminally extended poly(GR) associated with ALS/FTD. Proceedings of the National Academy of Sciences of the United States of America Li, S., Wu, Z., Tantray, I., Li, Y., Chen, S., Dong, J., Glynn, S., Vogel, H., Snyder, M., Lu, B. 2020
Abstract

Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing-like activity in metazoans remain unclear. Here we show that CAT-tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated GGGGCC (G4C2) repeat expansion in C9ORF72, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to be cotranslationally imported into mitochondria. However, poly(GR) translation on mitochondrial surface is frequently stalled, triggering RQC and CAT-tailing-like C-terminal extension (CTE). CTE promotes poly(GR) stabilization, aggregation, and toxicity. Our genetic studies in Drosophila uncovered an important role of the mitochondrial protease YME1L in clearing poly(GR), revealing mitochondria as major sites of poly(GR) metabolism. Moreover, the mitochondria-associated noncanonical Notch signaling pathway impinges on the RQC machinery to restrain poly(GR) accumulation, at least in part through the AKT/VCP axis. The conserved actions of YME1L and noncanonical Notch signaling in animal models and patient cells support their fundamental involvement in ALS/FTD.

View details for DOI 10.1073/pnas.2005506117

View details for PubMedID 32958650
Leptomeningeal spread with spinal involvement of pineal glioblastoma at initial presentation: A case report INTERDISCIPLINARY NEUROSURGERY-ADVANCED TECHNIQUES AND CASE MANAGEMENT Yerneni, K., Fatemi, P., Vogel, H., Li, G., Zygourakis, C. C. 2020; 21
View details for DOI 10.1016/j.inat.2019.100658

View details for Web of Science ID 000541501300019
Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor. Acta neuropathologica communications Lucas, C. G., Gupta, R., Doo, P., Lee, J. C., Cadwell, C. R., Ramani, B., Hofmann, J. W., Sloan, E. A., Kleinschmidt-DeMasters, B. K., Lee, H. S., Wood, M. D., Grafe, M., Born, D., Vogel, H., Salamat, S., Puccetti, D., Scharnhorst, D., Samuel, D., Cooney, T., Cham, E., Jin, L., Khatib, Z., Maher, O., Chamyan, G., Brathwaite, C., Bannykh, S., Mueller, S., Kline, C. N., Banerjee, A., Reddy, A., Taylor, J. W., Clarke, J. L., Oberheim Bush, N. A., Butowski, N., Gupta, N., Auguste, K. I., Sun, P. P., Roland, J. L., Raffel, C., Aghi, M. K., Theodosopoulos, P., Chang, E., Hervey-Jumper, S., Phillips, J. J., Pekmezci, M., Bollen, A. W., Tihan, T., Chang, S., Berger, M. S., Perry, A., Solomon, D. A. 2020; 8 (1): 151
Abstract

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

View details for DOI 10.1186/s40478-020-01027-z

View details for PubMedID 32859279
Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD. Cell reports Li, S., Wu, Z., Li, Y., Tantray, I., De Stefani, D., Mattarei, A., Krishnan, G., Gao, F., Vogel, H., Lu, B. 2020; 32 (5): 107989
Abstract

Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to motor neurons, the contribution of the other cell types to the ALS phenotypes is understudied. G4C2 repeat expansion in C9ORF72 is the most common genetic cause of ALS along with frontotemporal dementia (C9-ALS/FTD), with increasing evidence supporting repeat-encoded poly(GR) in disease pathogenesis. Here, we show in Drosophila muscle that poly(GR) enters mitochondria and interacts with components of the Mitochondrial Contact Site and Cristae Organizing System (MICOS), altering MICOS dynamics and intra-subunit interactions. This impairs mitochondrial inner membrane structure, ion homeostasis, mitochondrial metabolism, and muscle integrity. Similar mitochondrial defects are observed in patient fibroblasts. Genetic manipulation of MICOS components or pharmacological restoration of ion homeostasis with nigericin effectively rescue the mitochondrial pathology and disease phenotypes in both systems. These results implicate MICOS-regulated ion homeostasis in C9-ALS pathogenesis and suggest potential new therapeutic strategies.

View details for DOI 10.1016/j.celrep.2020.107989

View details for PubMedID 32755582
Deconstructing the origins of PDAC development. Flowers, B., Xu, H., Hanson, K., Curtis, C., Vogel, H., Wood, L., Attardi., L. D. AMER ASSOC CANCER RESEARCH. 2020: 19
View details for Web of Science ID 000537844900012
TREM1-PET imaging of pro-inflammatory myeloid cells distinguishes active disease from remission in Multiple Sclerosis Chaney, A., Wilson, E., Jain, P., Cropper, H., Swarovski, M., Lucot, K., Vogel, H., Andreasson, K., James, M. L. SOC NUCLEAR MEDICINE INC. 2020
View details for Web of Science ID 000568290500179
Generation of Functional Human 3D Cortico-Motor Assembloids. Cell Andersen, J., Revah, O., Miura, Y., Thom, N., Amin, N. D., Kelley, K. W., Singh, M., Chen, X., Thete, M. V., Walczak, E. M., Vogel, H., Fan, H. C., Pa?ca, S. P. 2020
Abstract

Neurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this pathway have been previously generated and studied in�vitro, the assembly of this multi-synaptic circuit has not yet been achieved with human cells. Here, we derive organoids resembling the cerebral cortex or the hindbrain/spinal cord and assemble them with human skeletal muscle spheroids to generate 3D cortico-motor assembloids. Using rabies tracing, calcium imaging, and patch-clamp recordings, we show that corticofugal neurons project and connect with spinal spheroids, while spinal-derived motor neurons connect with muscle. Glutamate uncaging or optogenetic stimulation of cortical spheroids triggers robust contraction of 3D muscle, and assembloids are morphologically and functionally intact for up to 10�weeks post-fusion. Together, this system highlights the remarkable self-assembly capacity of 3D cultures to form functional circuits that could be used to understand development and disease.

View details for DOI 10.1016/j.cell.2020.11.017

View details for PubMedID 33333020
MACHINE LEARNING REVEALS BILATERAL DISTRIBUTION OF SOMATIC L1 INSERTIONS IN HUMAN NEURONS AND GLIA Zhu, X., Zhou, B., Pattni, R., Gleason, K., Tan, C., Kalinowski, A., Sloan, S., Fiston-Lavier, A., Mariani, J., Vogel, H., Moran, J., Vaccarino, F., Tamminga, C., Levinson, D., Urban, A. ELSEVIER. 2019: S68
View details for DOI 10.1016/j.euroneuro.2019.07.158

View details for Web of Science ID 000488216600131
Electrical and synaptic integration of glioma into neural circuits. Nature Venkatesh, H. S., Morishita, W., Geraghty, A. C., Silverbush, D., Gillespie, S. M., Arzt, M., Tam, L. T., Espenel, C., Ponnuswami, A., Ni, L., Woo, P. J., Taylor, K. R., Agarwal, A., Regev, A., Brang, D., Vogel, H., Hervey-Jumper, S., Bergles, D. E., Suva, M. L., Malenka, R. C., Monje, M. 2019
Abstract

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.

View details for DOI 10.1038/s41586-019-1563-y

View details for PubMedID 31534222
Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons. Neuron Marro, S. G., Chanda, S., Yang, N., Janas, J. A., Valperga, G., Trotter, J., Zhou, B., Merrill, S., Yousif, I., Shelby, H., Vogel, H., Kalani, M. Y., Sudhof, T. C., Wernig, M. 2019
Abstract

The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.

View details for DOI 10.1016/j.neuron.2019.05.043

View details for PubMedID 31257103
Rosette-Forming Glioneuronal Tumor is Defined by FGFR1 Activating Alterations with Frequent Accompanying PI3K and MAPK Pathway Mutations Lucas, C., Lee, J., Sloan, E., Hofmann, J., Van Ziffle, J., Onodera, C., Grenert, J., Bastian, B., Kline, C., Banerjee, A., Clarke, J., Taylor, J., Bush, N., Buerki, R., Butowski, N., Chang, S., McDermott, M., Aghi, M., Hervey-Jumper, S., Berger, M., Raffel, C., Gupta, N., Kleinschmidt-DeMasters, B., Wood, M., Grafe, M., Guo, H., Sun, P., Torkildson, J., Cooney, T., Fata, C., Scharnhorst, D., Samuel, D., Bannykh, S., Khatib, Z., Maher, O., Chamyan, G., Pelaez, L., Braithwaite, C., Jin, L., Lechpammer, M., Born, D., Vogel, H., Lee, H., Phillips, J., Pekmezci, M., Bollen, A., Tihan, T., Perry, A., Solomon, D. OXFORD UNIV PRESS INC. 2019: 554
View details for Web of Science ID 000472806000141
Neuropathologic Findings in a Patient with CAR T-Cell-Associated Inflammatory Cytokine Release Syndrome Lavezo, J., Mount, C., Monje, M., Miklos, D., Vogel, H. OXFORD UNIV PRESS INC. 2019: 575
View details for Web of Science ID 000472806000227
Validation and Clinical Use of Whole Slide Digital Imaging at Stanford Neuropathology Lavezo, J., Born, D., Lummus, S., Young, A., Montine, T., Vogel, H. OXFORD UNIV PRESS INC. 2019: 576
View details for Web of Science ID 000472806000230
Clustered Cytochrome-oxidase Negative Myofibers in Muscular Dystrophies: A Novel Finding Cayrol, R., Klotz, J., Vogel, H. OXFORD UNIV PRESS INC. 2019: 543
View details for Web of Science ID 000472806000098
ELECTRICAL INTEGRATION OF GLIOMA INTO NEURAL CIRCUITRY Venkatesh, H., Morishita, W., Geraghty, A., Silverbush, D., Arzt, M., Tam, L., Ponnuswami, A., Gillespie, S., Agarwal, A., Regev, A., Vogel, H., Bergles, D., Suva, M., Malenka, R., Monje, M. OXFORD UNIV PRESS INC. 2019: 73
View details for DOI 10.1093/neuonc/noz036.042

View details for Web of Science ID 000473243700043
Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment CELL Gibson, E. M., Nagaraja, S., Ocampo, A., Tam, L. T., Wood, L. S., Pallegar, P. N., Greene, J. J., Geraghty, A. C., Goldstein, A. K., Ni, L., Woo, P. J., Barres, B. A., Liddelow, S., Vogel, H., Monje, M. 2019; 176 (1-2): 43-+
View details for DOI 10.1016/j.cell.2018.10.049

View details for Web of Science ID 000455410800007
Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature Dulken, B. W., Buckley, M. T., Navarro Negredo, P., Saligrama, N., Cayrol, R., Leeman, D. S., George, B. M., Boutet, S. C., Hebestreit, K., Pluvinage, J. V., Wyss-Coray, T., Weissman, I. L., Vogel, H., Davis, M. M., Brunet, A. 2019
Abstract

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-?, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-?. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.

View details for DOI 10.1038/s41586-019-1362-5

View details for PubMedID 31270459
E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family. Nature communications Hsu, J., Arand, J., Chaikovsky, A., Mooney, N. A., Demeter, J., Brison, C. M., Oliverio, R., Vogel, H., Rubin, S. M., Jackson, P. K., Sage, J. 2019; 10 (1): 2939
Abstract

E2F transcription factors are central regulators of cell division and cell fate decisions. E2F4 often represents the predominant E2F activity in cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. This role for E2F4 is independent of the RB family. Furthermore, E2F4 functionally interacts with chromatin regulators associated with gene activation and we observed decreased histone acetylation at the promoters of cell cycle genes and E2F targets upon loss of E2F4 in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that provide insights into the biology of rapidly dividing cells.

View details for DOI 10.1038/s41467-019-10901-x

View details for PubMedID 31270324
Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Thomas, R. P., Nagpal, S., Iv, M., Soltys, S. G., Bertrand, S., Pelpola, J. S., Ball, R. L., Yang, J., Sundaram, V., Lavezo, J. L., Born, D. E., Vogel, H., Brown, J. M., Recht, L. 2019
Abstract

Preclinical studies have demonstrated that post-irradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in newly diagnosed glioblastoma patients.We enrolled 9 patients to the phase I study and an additional 20 patients to phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via PICC line for four consecutive weeks beginning at day 35 of conventional treatment with concurrent chemo-radiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 �g/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months (95% Confidence Interval (CI) 15.9, NA) with a progression-free survival of 14.5 months (95% CI 11.8, NA). MRI and histopathology support the mechanism of action to inhibit post-irradiation tumor revascularization.Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemo-irradiation in newly diagnosed GBM patients and improves local control of tumor recurrences.

View details for DOI 10.1158/1078-0432.CCR-19-1421

View details for PubMedID 31537527
Anti-GD2 chimeric antigen receptor T cells as a potent immunotherapy regimen in xenograft models of histone 3 K27M mutant diffuse midline glioma Mount, C. W., Majzner, R., Sundaresh, S., Arnold, E. P., Kadapakkam, M., Haile, S., Labanieh, L., Woo, P., Rietberg, S. P., Vogel, H., Monje, M., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2018
View details for DOI 10.1158/1538-7445.AM2018-958

View details for Web of Science ID 000468818902457
ANTI-GD2 CHIMERIC ANTIGEN RECEPTOR T CELLS AS A POTENT IMMUNOTHERAPY REGIMEN IN XENOGRAFT MODELS OF HISTONE 3 K27M MUTANT DIFFUSE MIDLINE GLIOMA Mount, C., Majzner, R., Sundaresh, S., Arnold, E., Kadapakkam, M., Haile, S., Labanieh, L., Woo, P., Rietberg, S., Vogel, H., Monje, M., Mackall, C. OXFORD UNIV PRESS INC. 2018: 56
View details for Web of Science ID 000438339000131
Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect MOLECULAR GENETICS AND METABOLISM Wang, J., Kim, E., Dai, H., Stefans, V., Vogel, H., Al Jasmi, F., Vergano, S., Castro, D., Bernes, S., Bhambhani, V., Long, C., El-Hattab, A. W., Wong, L. 2018; 124 (2): 124?30
Abstract

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.

View details for PubMedID 29735374
Long-term liver disease in methylmalonic and propionic acidemias MOLECULAR GENETICS AND METABOLISM Imbard, A., Segarra, N., Tardieu, M., Broue, P., Bouchereau, J., Pichard, S., de Baulny, H., Slama, A., Mussini, C., Touati, G., Danjoux, M., Gaignard, P., Vogel, H., Labarthe, F., Schiff, M., Benoist, J. 2018; 123 (4): 433?40
Abstract

Patients affected with methylmalonic acidemia (MMA) and propionic acidemia (PA) exhibit diverse long-term complications and poor outcome. Liver disease is not a reported complication. The aim of this study was to characterize and extensively evaluate long-term liver involvement in MMA and PA patients.We first describe four patients who had severe liver involvement during the course of their disease. Histology showed fibrosis and/or cirrhosis in 3 patients. Such liver involvement led us to retrospectively collect liver (clinical, laboratory and ultrasound) data of MMA (N?=?12) or PA patients (N?=?16) from 2003 to 2016.Alpha-fetoprotein (?FP) levels were increased in 8/16 and 3/12 PA and MMA patients, respectively, and tended to increase with age. Moderate and recurrent increase of GGT was observed in 4/16 PA patients and 4/12 MMA patients. Abnormal liver ultrasound with either hepatomegaly and/or hyperechoic liver was observed in 7/9 PA patients and 3/9 MMA patients.These data demonstrate that approximately half of the patients affected by MMA or PA had signs of liver abnormalities. The increase of ?FP with age suggests progressive toxicity, which might be due to the metabolites accumulated in PA and MMA. These metabolites (e.g., methylmalonic acid and propionic acid derivatives) have previously been reported to have mitochondrial toxicity; this toxicity is confirmed by the results of histological and biochemical mitochondrial analyses of the liver in two of our MMA patients. In contrast to the moderate clinical, laboratory or ultrasound expression, severe pathological expression was found for three of the 4 patients who underwent liver biopsy, ranging from fibrosis to cirrhosis. These results emphasize the need for detailed liver function evaluation in organic aciduria patients, including liver biopsy when liver disease is suspected.MMA and PA patients exhibit long-term liver abnormalities.

View details for PubMedID 29433791
CORRELATION OF VASARI-BASED MRI PHENOTYPES WITH MGMT AND IDH STATUS ACROSS GLIOMA GRADES: A STATISTICAL ANALYSIS IN 372 PATIENTS Das, D., Yoon, B., Golden, L., Samghabadi, P., Vogel, H., Yeom, K., Iv, M., Massoud, T. OXFORD UNIV PRESS INC. 2017: 150
View details for Web of Science ID 000415152502222
Cerebral Segmental Arterial Mediolysis In A Pediatric Patient: A Novel Case Report Samghabadi, P., Vogel, H. OXFORD UNIV PRESS INC. 2017: 544
View details for Web of Science ID 000404906900222
Cortical Mimic of Pilocytic Astrocytoma in Infantile Alexander Disease: A Case Report Lummus, S., Antony, R., Jin, L., Vogel, H. OXFORD UNIV PRESS INC. 2017: 527
View details for Web of Science ID 000404906900150
Giant Prolactinoma Presenting with Neck Pain and Structural Compromise of the Occipital Condyles. Journal of neurological surgery reports Yecies, D., Ajlan, A., Ratliff, J., Ziskin, J., Hwang, P., Vogel, H., Katznelson, L., Harsh, G. 2015; 76 (2): e297-301
Abstract

Prolactinomas are the most common form of endocrinologically active pituitary adenoma; they account for ? 45% of pituitary adenomas encountered in clinical practice. Giant adenomas are those?>?4 cm in diameter. Less than 0.5% of pituitary adenomas encountered in neurosurgical practice are giant prolactinomas. Patients with giant prolactinomas typically present with highly elevated prolactin levels, endocrinologic disturbances, and neurologic symptoms from mass-induced pressure. Described here is an unusual case of a giant prolactinoma presenting with neck pain and structural compromise of the occipital condyles. Transnasal biopsy of the nasopharyngeal portion of the mass obtained tissue consistent with an atypical prolactinoma with p53 reactivity and a high Ki-67 index of 5%. Despite the size and invasiveness of the tumor, the patient had resolution of his clinical symptoms, dramatic reduction of his hyperprolactinemia, and near-complete disappearance of his tumor following medical treatment.

View details for DOI 10.1055/s-0035-1566124

View details for PubMedID 26623246
Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease NEUROBIOLOGY OF AGING Zeineh, M. M., Chen, Y., Kitzler, H. H., Hammond, R., Vogel, H., Rutt, B. K. 2015; 36 (9): 2483-2500
Abstract

Although amyloid plaques and neurofibrillary pathology play important roles in Alzheimer disease (AD), our understanding of AD is incomplete, and the contribution of microglia and iron to neurodegeneration is unknown. High-field magnetic resonance imaging (MRI) is exquisitely sensitive to microscopic iron. To explore iron-associated neuroinflammatory AD pathology, we studied AD and control human brain specimens by (1) performing ultra-high resolution ex vivo 7 Tesla MRI, (2) coregistering the MRI with successive histologic staining for iron, microglia, amyloid beta, and tau, and (3) quantifying the relationship between magnetic resonance signal intensity and histological staining. In AD, we identified numerous small MR hypointensities primarily within the subiculum that were best explained by the combination of microscopic iron and activated microglia (p = 0.025), in contradistinction to the relatively lesser contribution of tau or amyloid. Neuropathologically, this suggests that microglial-mediated neurodegeneration may occur in the hippocampal formation in AD and is detectable by ultra-high resolution MRI.

View details for DOI 10.1016/j.neurobiolaging.2015.05.022

View details for Web of Science ID 000358803400005
Pilomyxoid Astrocytoma (PMA) Shows Significant Differences in Gene Expression vs. Pilocytic Astrocytoma (PA) and Variable Tendency Toward Maturation to PA BRAIN PATHOLOGY Kleinschmidt-DeMasters, B. K., Donson, A. M., Vogel, H., Foreman, N. K. 2015; 25 (4): 429-440
Abstract

Pilomyxoid astrocytomas (PMAs) manifest a more aggressive clinical course than pilocytic astrocytomas (PAs). Development of effective therapies demands a better biological understanding of PMA. We first conducted gene expression microarray analysis of 9 PMA and 13 PA from infra- and supratentorial sites. Unsupervised hierarchical clustering analysis demonstrated that tumors are grouped according to anatomic site, not diagnosis. Gene expression profiles were then contrasted between eight PMAs and six PAs, all supratentorial/hypothalamic/chiasmal. Clinical outcome of PMAs varied, with four out of four patients with diencephalic syndrome succumbing to disease, one of whom showed bulky metastatic leptomeningeal spread at autopsy, with bimodal maturation to PA in some areas and de-differentiation to glioblastoma in others. A surviving child has undergone multiple surgical debulking, with progressive maturation to PA over time. Ontology-enrichment analysis identified overexpression in PMAs of extracellular matrix and mitosis-related genes. Genes overexpressed in PMA vs. PA, ranked according to fold-change, included developmental genes H19, DACT2, extracellular matrix collagens (COL2A1; COL1A1) and IGF2BP3 (IMP3), the latter previously identified as an adverse prognostic factor in PMA and PA.

View details for DOI 10.1111/bpa.12239

View details for PubMedID 25521223
Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion CELL Venkatesh, H. S., Johung, T. B., Caretti, V., Noll, A., Tang, Y., Nagaraja, S., Gibson, E. M., Mount, C. W., Polepalli, J., Mitra, S. S., Woo, P. J., Malenka, R. C., Vogel, H., Bredel, M., Mallick, P., Monje, M. 2015; 161 (4): 803-816
Abstract

Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

View details for DOI 10.1016/j.cell.2015.04.012

View details for PubMedID 25913192
Atypical and Rare Variants of Central Neurocytomas NEUROSURGERY CLINICS OF NORTH AMERICA Choudhri, O., Razavi, S., Vogel, H., Li, G. 2015; 26 (1): 91-?
Abstract

This article reviews the variation in imaging, histopathology, clinical course, and management seen with central neurocytomas (CNs). CNs have often been misdiagnosed as oligodendrogliomas and ependymomas; however, synaptophysin positivity can correctly diagnose these neurocytic neoplasms. Atypical CNs, an important variant first described in 1997, are marked by increased proliferative potential and associated with worse clinical outcomes in terms of long-term survival and local tumor control. Complete surgical resection is the cornerstone of therapy, and postoperative radiation is recommended in the setting of residual disease. Other less aggressive variants of central neurocytomas, including liponeurocytomas, ganglioneurocytomas, and pigmented neurocytomas, are also discussed.

View details for DOI 10.1016/j.nec.2014.09.003

View details for Web of Science ID 000346620900012

View details for PubMedID 25432187
Inappropriate p53 activation during development induces features of CHARGE syndrome NATURE Van Nostrand, J. L., Brady, C. A., Jung, H., Fuentes, D. R., Kozak, M. M., Johnson, T. M., Lin, C., Lin, C., Swiderski, D. L., Vogel, H., Bernstein, J. A., Attie-Bitach, T., Chang, C., Wysocka, J., Martin, D. M., Attardi, L. D. 2014; 514 (7521): 228-?
Abstract

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

View details for DOI 10.1038/nature13585

View details for Web of Science ID 000342663100042
Evidence that Meningeal Mast Cells Can Worsen Stroke Pathology in Mice AMERICAN JOURNAL OF PATHOLOGY Arac, A., Grimbaldeston, M. A., Nepomuceno, A. R., Olayiwola, O., Pereira, M. P., Nishiyama, Y., Tsykin, A., Goodall, G. J., Schlecht, U., Vogel, H., Tsai, M., Galli, S. J., Bliss, T. M., Steinbergtt, G. K. 2014; 184 (9): 2493-2504
Abstract

Stroke is the leading cause of adult disability and the fourth most common cause of death in the United States. Inflammation is thought to play an important role in stroke pathology, but the factors that promote inflammation in this setting remain to be fully defined. An understudied but important factor is the role of meningeal-located immune cells in modulating brain pathology. Although different immune cells traffic through meningeal vessels en route to the brain, mature mast cells do not circulate but are resident in the meninges. With the use of genetic and cell transfer approaches in mice, we identified evidence that meningeal mast cells can importantly contribute to the key features of stroke pathology, including infiltration of granulocytes and activated macrophages, brain swelling, and infarct size. We also obtained evidence that two mast cell-derived products, interleukin-6 and, to a lesser extent, chemokine (C-C motif) ligand 7, can contribute to stroke pathology. These findings indicate a novel role for mast cells in�the meninges, the membranes that envelop the brain, as potential gatekeepers for�modulating brain inflammation and pathology after stroke.

View details for DOI 10.1016/j.ajpath.2014.06.003

View details for PubMedID 25134760
Congenital muscular dystrophy and generalized epilepsy caused by GMPPB mutations. Brain research Raphael, A. R., Couthouis, J., Sakamuri, S., Siskind, C., Vogel, H., Day, J. W., Gitler, A. D. 2014; 1575: 66-71
Abstract

The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (?-DG). Alpha-dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutations were recently linked to eight cases of alpha-dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. This article is part of a Special Issue entitled RNA Metabolism 2013.

View details for DOI 10.1016/j.brainres.2014.04.028

View details for PubMedID 24780531
Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression JOURNAL OF CLINICAL INVESTIGATION Ferrarese, R., Harsh, G. R., Yadav, A. K., Bug, E., Maticzka, D., Reichardt, W., Dombrowski, S. M., Miller, T. E., Masilamani, A. P., Dai, F., Kim, H., Hadler, M., Scholtens, D. M., Yu, I. L., Beck, J., Srinivasasainagendra, V., Costa, F., Baxan, N., Pfeifer, D., von Elverfeldt, D., Backofen, R., Weyerbrock, A., Duarte, C. W., He, X., Prinz, M., Chandler, J. P., Vogel, H., Chakravarti, A., Rich, J. N., Carro, M. S., Bredel, M. 2014; 124 (7): 2861-2876
Abstract

Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

View details for DOI 10.1172/JCI68836

View details for Web of Science ID 000338688400015

View details for PubMedCentralID PMC4071411
Human pontine glioma cells can induce murine tumors. Acta neuropathologica Caretti, V., Sewing, A. C., Lagerweij, T., Schellen, P., Bugiani, M., Jansen, M. H., van Vuurden, D. G., Navis, A. C., Horsman, I., Vandertop, W. P., Noske, D. P., Wesseling, P., Kaspers, G. J., Nazarian, J., Vogel, H., Hulleman, E., Monje, M., Wurdinger, T. 2014; 127 (6): 897-909
Abstract

Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9�months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.

View details for DOI 10.1007/s00401-014-1272-4

View details for PubMedID 24777482
Neuronal Activity Promotes Oligodendrogenesis and Adaptive Myelination in the Mammalian Brain SCIENCE Gibson, E. M., Purger, D., Mount, C. W., Goldstein, A. K., Lin, G. L., Wood, L. S., Inema, I., Miller, S. E., Bieri, G., Zuchero, J. B., Barres, B. A., Woo, P. J., Vogel, H., Monje, M. 2014; 344 (6183): 487-?
Abstract

Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.

View details for DOI 10.1126/science.1252304

View details for Web of Science ID 000335157700034

View details for PubMedCentralID PMC4096908
Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science Gibson, E. M., Purger, D., Mount, C. W., Goldstein, A. K., Lin, G. L., Wood, L. S., Inema, I., Miller, S. E., Bieri, G., Zuchero, J. B., Barres, B. A., Woo, P. J., Vogel, H., Monje, M. 2014; 344 (6183): 1252304-?
Abstract

Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.

View details for DOI 10.1126/science.1252304

View details for PubMedID 24727982
Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscular disorders Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., Gitler, A. D. 2014; 24 (5): 431-435
Abstract

Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the "limb-girdle" muscles), although it is a heterogeneous disorder that can present with varying symptoms. There is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D.

View details for DOI 10.1016/j.nmd.2014.01.014

View details for PubMedID 24594375
A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression GENES & DEVELOPMENT Okada, N., Lin, C., Ribeiro, M. C., Biton, A., Lai, G., He, X., Bu, P., Vogel, H., Jablons, D. M., Keller, A. C., Wilkinson, J. E., He, B., Speed, T. P., He, L. 2014; 28 (5): 438-450
Abstract

As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 3' untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.

View details for DOI 10.1101/gad.233585.113

View details for Web of Science ID 000332475600003

View details for PubMedID 24532687

View details for PubMedCentralID PMC3950342
Composite pleomorphic xanthoastrocytoma-epithelioid glioneuronal tumor with BRAF V600E mutation - report of three cases CLINICAL NEUROPATHOLOGY Aisner, D. L., Newell, K. L., Pollack, A. G., Kleinschmidt-Demasters, B. K., Steinberg, G. K., Smyth, L. T., Vogel, H. 2014; 33 (2): 112-121
Abstract

We report three examples of a composite pleomorphic xanthoastrocytoma-epithelioid glioneuronal tumor (PXAEGT) occurring in an adolescent male and two young women. All were superficial and two were located in proximity to the optic nerves. Previously reported composite PXA-gangliogliomas (PXA-GG), have been considered "collision tumors" since little intermingling of the two elements has been present. In contrast, we hypothesized that the two elements of the PXA-EGT might instead derive from a common origin. To test this, we sampled the separate regions of these biphasic tumors and assessed each component for the BRAF V600E mutation, a genetic feature seen in two-thirds of pure PXAs. The BRAF mutation was found in both tumor areas in all cases, suggesting a common origin for the components, rather than a collision tumor. These biphasic PXA-EGT cases represent a new histomorphological combination of neuroepithelial neoplastic elements. These cases further expand the range of glial neoplasia in which epithelioid morphology is encountered, and add to the growing list of biphasic tumors harboring the BRAF V600E mutation.

View details for DOI 10.5414/NP300679

View details for Web of Science ID 000333860500003

View details for PubMedID 24321241
Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III. Cancer research Emlet, D. R., Gupta, P., Holgado-Madruga, M., Del Vecchio, C. A., Mitra, S. S., Han, S., Li, G., Jensen, K. C., Vogel, H., Xu, L. W., Skirboll, S. S., Wong, A. J. 2014; 74 (4): 1238-1249
Abstract

The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII- cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.

View details for DOI 10.1158/0008-5472.CAN-13-1407

View details for PubMedID 24366881
Relapse patterns in pediatric embryonal central nervous system tumors JOURNAL OF NEURO-ONCOLOGY Perreault, S., Lober, R. M., Carret, A., Zhang, G., Hershon, L., Decarie, J., Yeom, K., Vogel, H., Fisher, P. G., Partap, S. 2013; 115 (2): 209-215
Abstract

Embryonal tumors of the central nervous system (CNS) share histological features and were therefore initially grouped as primitive neuroectodermal tumors (PNET) and treated similarly. We sought to determine the relapse patterns of specific embryonal CNS tumors. We conducted a historical cohort study of children diagnosed with CNS embryonal tumors from January 2000 to December 2011 in two pediatric neuro-oncology centers. Patients of 21�years of age or younger at time of presentation with a diagnosis of medulloblastoma, supratentorial PNET, pineoblastoma or atypical teratoid/rhabdoid tumor (ATRT) and at least one surveillance MRI were included. A total of 133 patients met inclusion criteria and 49 (37�%) patients relapsed during the observation period. The majority (79�%) of sPNET relapses were local, whereas all (100�%) PB relapses were associated with diffuse leptomeningeal disease. Relapse patterns for MB were more diverse with local recurrence in 27�%, distant recurrence in 35�% and diffuse leptomeningeal disease in 38�%. The frequency of relapses involving the spine differed (p�<�0.001) between tumor types (MB 28/55 [51�%], sPNET 3/33 [9�%], ATRT 3/7 [43�%] and PB 12/12 [100�%]). No sPNET patients had isolated spinal relapse (0/14). Embryonal tumors were found to have divergent patterns of recurrence. While medulloblastoma has variable relapse presentations, sPNET relapses locally and pineoblastoma recurs with diffuse leptomeningeal disease involving the spine. These results point toward possibly new upfront treatment stratification among embryonal tumors in accordance with relapse pattern.

View details for DOI 10.1007/s11060-013-1213-4

View details for PubMedID 23921420
A Mutation in TGFB3 Associated With a Syndrome of Low Muscle Mass, Growth Retardation, Distal Arthrogryposis and Clinical Features Overlapping With Marfan and Loeys-Dietz Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Rienhoff, H. Y., Yeo, C., Morissette, R., Khrebtukova, I., Melnick, J., Luo, S., Leng, N., Kim, Y., Schroth, G., Westwick, J., Vogel, H., McDonnell, N., Hall, J. G., Whitman, M. 2013; 161 (8): 2040-2046
Abstract

The transforming growth factor ? (TGF-?) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys-Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-? signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth.

View details for DOI 10.1002/ajmg.a.36056

View details for Web of Science ID 000327789600031

View details for PubMedCentralID PMC3885154
AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Penchala, S. C., Connelly, S., Wang, Y., Park, M. S., Zhao, L., Baranczak, A., Rappley, I., Vogel, H., Liedtke, M., Witteles, R. M., Powers, E. T., Reixach, N., Chan, W. K., Wilson, I. A., Kelly, J. W., Graef, I. A., Alhamadsheh, M. M. 2013; 110 (24): 9992-9997
Abstract

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

View details for DOI 10.1073/pnas.1300761110

View details for Web of Science ID 000320930100085

View details for PubMedID 23716704
Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis JOURNAL OF NEUROSURGERY-PEDIATRICS Selden, N. R., Al-Uzri, A., Huhn, S. L., Koch, T. K., Sikora, D. M., Nguyen-Driver, M. D., Guillaume, D. J., Koh, J. L., Gultekin, S. H., Anderson, J. C., Vogel, H., Sutcliffe, T. L., Jacobs, Y., Steiner, R. D. 2013; 11 (6): 643-652
Abstract

Infantile and late-infantile neuronal ceroid lipofuscinoses (NCLs) are invariably fatal lysosomal storage diseases associated with defects in lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP1) activity. Previous preclinical studies have demonstrated that human CNS stem cells (HuCNS-SCs) produce both PPT-1 and TPP1 and result in donor cell engraftment and reduced accumulation of storage material in the brain when tested in an NCL mouse model.HuCNS-SC transplantation was tested in an open-label dose-escalation Phase I clinical trial as a potential treatment for infantile and late-infantile NCL. Study design included direct neurosurgical transplantation of allogeneic HuCNS-SCs into the cerebral hemispheres and lateral ventricles accompanied by 12 months of immunosuppression.Six children with either the infantile or late-infantile forms of NCL underwent low- (3 patients) and high- (3 patients) dose transplantation of HuCNS-SCs followed by immunosuppression. The surgery, immunosuppression, and cell transplantation were well tolerated. Adverse events following transplantation were consistent with the underlying disease, and none were directly attributed to the donor cells. Observations regarding efficacy of the intervention were limited by the enrollment criteria requiring that patients be in advanced stages of disease.This study represents the first-in-human clinical trial involving transplantation of a purified population of human neural stem cells for a neurodegenerative disorder. The feasibility of this approach and absence of transplantation-related serious adverse events support further exploration of HuCNS-SC transplantation as a potential treatment for select subtypes of NCL, and possibly for other neurodegenerative disorders.

View details for DOI 10.3171/2013.3.PEDS12397

View details for PubMedID 23581634
EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene Del Vecchio, C. A., Giacomini, C. P., Vogel, H., Jensen, K. C., Florio, T., Merlo, A., Pollack, J. R., Wong, A. J. 2013; 32 (21): 2670-2681
Abstract

Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in glioblastoma multiforme (GBM). The most common variant is EGFR variant III (EGFRvIII). Research suggests that EGFRvIII could be a marker for a cancer stem cell or tumor-initiating population. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved throughout the tumor. However, in primary GBM, EGFRvIII expression is focal and sporadic. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression, suggesting that mechanisms exist to modulate EGFRvIII expression even in the presence of high gene amplification. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII. EGFRvIII expression was heterogeneous, with both positive and negative populations maintaining the genetic alterations, akin to primary tumors. Furthermore, EGFRvIII defined a hierarchy where EGFRvIII-positive cells gave rise to additional positive and negative cells. Only cells that had recently lost EGFRvIII expression could re-express EGFRvIII, providing an important buffer for maintaining EGFRvIII-positive cell numbers. Epigenetic mechanisms had a role in maintaining heterogeneous EGFRvIII expression. Demethylation induced a 20-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII. Surprisingly, inhibition of histone deacetylation resulted in a 50-80% reduction in EGFRvIII expression. Collectively, this data demonstrates that EGFR amplification and rearrangement are early events in tumorigenesis and EGFRvIII follows a model of hierarchical expression. Furthermore, EGFRvIII expression is restricted by epigenetic mechanisms, suggesting that drugs that modulate the epigenome might be used successfully in glioblastoma tumors.

View details for DOI 10.1038/onc.2012.280

View details for PubMedID 22797070
Diffusion-weighted MRI: distinction of skull base chordoma from chondrosarcoma. AJNR. American journal of neuroradiology Yeom, K. W., Lober, R. M., Mobley, B. C., Harsh, G., Vogel, H., Allagio, R., Pearson, M., Edwards, M. S., Fischbein, N. J. 2013; 34 (5): 1056-?
Abstract

Chordoma and chondrosarcoma of the skull base are rare tumors with overlapping presentations and anatomic imaging features but different prognoses. We hypothesized that these tumors might be distinguished by using diffusion-weighted MR imaging.We retrospectively reviewed 19 patients with pathologically confirmed chordoma or chondrosarcoma who underwent both conventional and diffusion-weighted MR imaging. Differences in distributions of ADC were assessed by the Kruskal-Wallis test. Associations between histopathologic diagnosis and conventional MR imaging features (T2 signal intensity, contrast enhancement, and tumor location) were assessed with the Fisher exact test.Chondrosarcoma was associated with the highest mean ADC value (2051 � 261 � 10(-6) mm(2)/s) and was significantly different from classic chordoma (1474 � 117 � 10(-6) mm(2)/s) and poorly differentiated chordoma (875 � 100 � 10(-6) mm(2)/s) (P < .001). Poorly differentiated chordoma was characterized by low T2 signal intensity (P = .001), but other conventional MR imaging features of enhancement and/or lesion location did not reliably distinguish these tumor types.Diffusion-weighted MR imaging may be useful in assessing clival tumors, particularly in differentiating chordoma from chondrosarcoma. A prospective study of a larger cohort will be required to determine the value of ADC in predicting histopathologic diagnosis.

View details for DOI 10.3174/ajnr.A3333

View details for PubMedID 23124635
Chd5 requires PHD-mediated histone 3 binding for tumor suppression. Cell reports Paul, S., Kuo, A., Schalch, T., Vogel, H., Joshua-Tor, L., McCombie, W. R., Gozani, O., Hammell, M., Mills, A. A. 2013; 3 (1): 92-102
Abstract

Chromodomain Helicase DNA binding protein 5 (CHD5) is a tumor suppressor mapping to 1p36, a genomic region that is frequently deleted in human cancer. Although CHD5 belongs to the CHD family of chromatin-remodeling proteins, whether its tumor-suppressive role involves an interaction with chromatin is unknown. Here we report that Chd5 binds the unmodified N terminus of H3 through its tandem plant homeodomains (PHDs). Genome-wide chromatin immunoprecipitation studies reveal preferential binding of Chd5 to loci lacking the active mark H3K4me3 and also identify Chd5 targets implicated in cancer. Chd5 mutations that abrogate H3 binding are unable to inhibit proliferation or transcriptionally modulate target genes, which leads to tumorigenesis in vivo. Unlike wild-type Chd5, Chd5-PHD mutants are unable to induce differentiation or efficiently suppress the growth of human neuroblastoma in vivo. Our work defines Chd5 as an N-terminally unmodified H3-binding protein and provides functional evidence that this interaction orchestrates chromatin-mediated transcriptional programs critical for tumor suppression.

View details for DOI 10.1016/j.celrep.2012.12.009

View details for PubMedID 23318260

View details for PubMedCentralID PMC3575599
Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma ANNALS OF DIAGNOSTIC PATHOLOGY Raghunathan, A., Olar, A., Vogel, H., Parker, J. R., Coventry, S. C., Debski, R., Albarracin, C. T., Aldape, K. D., Cahill, D. P., Powell, S. Z., Fuller, G. N. 2012; 16 (4): 255-259
Abstract

Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild-type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG may help further distinguish this unique neoplasm from diffuse glioma.

View details for DOI 10.1016/j.anndiagpath.2011.11.003

View details for Web of Science ID 000306628200004

View details for PubMedID 22445362
Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Horev, G., Ellegood, J., Lerch, J. P., Son, Y. E., Muthuswamy, L., Vogel, H., Krieger, A. M., Buja, A., Henkelman, R. M., Wigler, M., Mills, A. A. 2011; 108 (41): 17076-17081
Abstract

Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.

View details for DOI 10.1073/pnas.1114042108

View details for Web of Science ID 000295973800043

View details for PubMedID 21969575

View details for PubMedCentralID PMC3193230
Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Monje, M., Mitra, S. S., Freret, M. E., Raveh, T. B., Kim, J., Masek, M., Attema, J. L., Li, G., Haddix, T., Edwards, M. S., Fisher, P. G., Weissman, I. L., Rowitch, D. H., Vogel, H., Wong, A. J., Beachy, P. A. 2011; 108 (11): 4453-4458
Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.

View details for DOI 10.1073/pnas.1101657108

View details for PubMedID 21368213
NFKBIA Deletion in Glioblastomas. NEW ENGLAND JOURNAL OF MEDICINE Bredel, M., Scholtens, D. M., Yadav, A. K., Alvarez, A. A., Renfrow, J. J., Chandler, J. P., Yu, I. L., Carro, M. S., Dai, F., Tagge, M. J., Ferrarese, R., Bredel, C., Phillips, H. S., Lukac, P. J., Robe, P. A., Weyerbrock, A., Vogel, H., Dubner, S., Mobley, B., He, X., Scheck, A. C., Sikic, B. I., Aldape, K. D., Chakravarti, A., Harsh, G. R. 2011; 364 (7): 627-637
Abstract

Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of ?-light polypeptide gene enhancer in B-cells inhibitor-?), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR.We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons.NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease.Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.

View details for DOI 10.1056/NEJMoa1006312

View details for Web of Science ID 000287406000008

View details for PubMedID 21175304

View details for PubMedCentralID PMC3652611
Loss of SMARCB1/INI1 expression in poorly differentiated chordomas ACTA NEUROPATHOLOGICA Mobley, B. C., McKenney, J. K., Bangs, C. D., Callahan, K., Yeom, K. W., Schneppenheim, R., Hayden, M. G., Cherry, A. M., Gokden, M., Edwards, M. S., Fisher, P. G., Vogel, H. 2010; 120 (6): 745-753
Abstract

Chordomas are malignant neoplasms that typically arise in the axial spine and primarily affect adults. When chordomas arise in pediatric patients they are more likely to display unusual histological features and aggressive behavior. We noted the absence of SMARCB1/INI1 expression by immunohistochemistry in an index case of poorly differentiated chordoma of the sacrum, leading us to further examine SMARCB1/INI1 expression as well as that of brachyury, a highly specific marker of notochordal differentiation, in 3 additional poorly differentiated chordomas of the clivus, 10 typical chordomas, and 8 atypical teratoid/rhabdoid tumors (AT/RTs). All 4 poorly differentiated chordomas and all AT/RTs lacked nuclear expression of SMARCB1/INI1, while the 10 typical chordomas maintained strong nuclear SMARCB1/INI1 immunoreactivity. All 10 typical and 4 poorly differentiated chordomas expressed brachyury; all 8 AT/RTs were brachyury immunonegative. Cytogenetic evaluation utilizing FISH probes near the SMARCB1/INI1 locus on chromosome 22q was also performed in all of the poorly differentiated chordomas in this series. Three of the four poorly differentiated chordomas had evidence for deletion of this region by FISH. Analysis of the SMARCB1/INI1 gene sequence was performed using formalin-fixed paraffin-embedded tissue in all cases and no point mutations were observed. In summary, all poorly differentiated chordomas in this series showed the absence of SMARCB1/INI1 expression, and were reliably distinguished from AT/RTs, clinically by their characteristic primary sites of origin and pathologically by strong nuclear brachyury expression. Our findings reveal a likely role for SMARCB1/INI1 in a subset of chordomas with aggressive features.

View details for DOI 10.1007/s00401-010-0767-x

View details for PubMedID 21057957
G1 arrest and differentiation can occur independently of Rb family function JOURNAL OF CELL BIOLOGY Wirt, S. E., Adler, A. S., Gebala, V., Weimann, J. M., Schaffer, B. E., Saddic, L. A., Viatour, P., Vogel, H., Chang, H. Y., Meissner, A., Sage, J. 2010; 191 (4): 809-825
Abstract

The ability of progenitor cells to exit the cell cycle is essential for proper embryonic development and homeostasis, but the mechanisms governing cell cycle exit are still not fully understood. Here, we tested the requirement for the retinoblastoma (Rb) protein and its family members p107 and p130 in G0/G1 arrest and differentiation in mammalian cells. We found that Rb family triple knockout (TKO) mouse embryos survive until days 9-11 of gestation. Strikingly, some TKO cells, including in epithelial and neural lineages, are able to exit the cell cycle in G0/G1 and differentiate in teratomas and in culture. This ability of TKO cells to arrest in G0/G1 is associated with the repression of key E2F target genes. Thus, G1 arrest is not always dependent on Rb family members, which illustrates the robustness of cell cycle regulatory networks during differentiation and allows for the identification of candidate pathways to inhibit the expansion of cancer cells with mutations in the Rb pathway.

View details for DOI 10.1083/jcb.201003048

View details for Web of Science ID 000284737200014

View details for PubMedID 21059851

View details for PubMedCentralID PMC2983066
End-Stage Cardiac Disease as an Initial Presentation of Systemic Myopathies: Case Series and Literature Review JOURNAL OF CHILD NEUROLOGY Katzberg, H., Karamchandani, J., So, Y. T., Vogel, H., Wang, C. H. 2010; 25 (11): 1382-1388
Abstract

Life-threatening cardiomyopathy is associated with certain systemic myopathies and usually presents as an end-stage progression of the disease. However, cardiac symptoms can sometimes precede muscle weakness. The authors reviewed medical records from 2003 to 2008 on patients attending their neuromuscular clinic and identified patients who initially presented with an end-stage cardiomyopathy and were later diagnosed with a specific muscle disease through muscle biopsy. They report 5 cases of children who initially presented with cardiomyopathies without neuromuscular symptoms. The cardiac symptoms were so severe that 4 of them required cardiac transplantation and 1 died prior to transplantation. Review of muscle pathology confirmed the diagnoses of Becker muscular dystrophy, myofibrillar myopathy, mitochondrial myopathy with cytochrome oxidase deficiency, Danon disease, and glycogen storage disease. The authors conclude that cardiomyopathy can be the initial presentation of a wide spectrum of systemic myopathies. Careful evaluation of neuromuscular systems should be carried out in patients presenting with end-stage cardiomyopathies.

View details for DOI 10.1177/0883073810367683

View details for PubMedID 20445193
TAp63 induces senescence and suppresses tumorigenesis in vivo NATURE CELL BIOLOGY Guo, X., Keyes, W. M., Papazoglu, C., Zuber, J., Li, W., Lowe, S. W., Vogel, H., Mills, A. A. 2009; 11 (12): 1451-U150
Abstract

p63 is distinct from its homologue p53 in that its role as a tumour suppressor is controversial, an issue complicated by the existence of two classes of p63 isoforms. Here we show that TAp63 isoforms are robust mediators of senescence that inhibit tumorigenesis in vivo. Whereas gain of TAp63 induces senescence, loss of p63 enhances sarcoma development in mice lacking p53. Using a new TAp63-specific conditional mouse model, we demonstrate that TAp63 isoforms are essential for Ras-induced senescence, and that TAp63 deficiency increases proliferation and enhances Ras-mediated oncogenesis in the context of p53 deficiency in vivo. TAp63 induces senescence independently of p53, p19(Arf) and p16(Ink4a), but requires p21(Waf/Cip1) and Rb. TAp63-mediated senescence overrides Ras-driven transformation of p53-deficient cells, preventing tumour initiation, and doxycycline-regulated expression of TAp63 activates p21(Waf/Cip1), induces senescence and inhibits progression of established tumours in vivo. Our findings demonstrate that TAp63 isoforms function as tumour suppressors by regulating senescence through p53-independent pathways. The ability of TAp63 to trigger senescence and halt tumorigenesis irrespective of p53 status identifies TAp63 as a potential target of anti-cancer therapy for human malignancies with compromised p53.

View details for DOI 10.1038/ncb1988

View details for Web of Science ID 000272251300012

View details for PubMedID 19898465

View details for PubMedCentralID PMC2920298
Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Yadav, A. K., Renfrow, J. J., Scholtens, D. M., Xie, H., Duran, G. E., Bredel, C., Vogel, H., Chandler, J. P., Chakravarti, A., Robe, P. A., Das, S., Scheck, A. C., Kessler, J. A., Soares, M. B., Sikic, B. I., Harsh, G. R., Bredel, M. 2009; 302 (3): 276-289
Abstract

Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood.To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1-q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas.Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006-2008; and unpublished, tumors collected 2001-2008). Functional analyses using LN229 and U87 glioblastoma cells.Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis.Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P = 1 x 10(-15); linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P = .004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%-744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in approximately 75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (approximately 6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P = .008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493-0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P = .00003; HR, 0.476; 95% CI, 0.333-0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P = .042; HR, 0.686; 95% CI, 0.476-0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion).Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene.

View details for Web of Science ID 000267948100021

View details for PubMedID 19602687

View details for PubMedCentralID PMC3089898
A Network Model of a Cooperative Genetic Landscape in Brain Tumors JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bredel, M., Scholtens, D. M., Harsh, G. R., Bredel, C., Chandler, J. P., Renfrow, J. J., Yadav, A. K., Vogel, H., Scheck, A. C., Tibshirani, R., Sikic, B. I. 2009; 302 (3): 261-275
Abstract

Gliomas, particularly glioblastomas, are among the deadliest of human tumors. Gliomas emerge through the accumulation of recurrent chromosomal alterations, some of which target yet-to-be-discovered cancer genes. A persistent question concerns the biological basis for the coselection of these alterations during gliomagenesis.To describe a network model of a cooperative genetic landscape in gliomas and to evaluate its clinical relevance.Multidimensional genomic profiles and clinical profiles of 501 patients with gliomas (45 tumors in an initial discovery set collected between 2001 and 2004 and 456 tumors in validation sets made public between 2006 and 2008) from multiple academic centers in the United States and The Cancer Genome Atlas Pilot Project (TCGA).Identification of genes with coincident genetic alterations, correlated gene dosage and gene expression, and multiple functional interactions; association between those genes and patient survival.Gliomas select for a nonrandom genetic landscape-a consistent pattern of chromosomal alterations-that involves altered regions ("territories") on chromosomes 1p, 7, 8q, 9p, 10, 12q, 13q, 19q, 20, and 22q (false-discovery rate-corrected P<.05). A network model shows that these territories harbor genes with putative synergistic, tumor-promoting relationships. The coalteration of the most interactive of these genes in glioblastoma is associated with unfavorable patient survival. A multigene risk scoring model based on 7 landscape genes (POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7, and PDCD4) is associated with the duration of overall survival in 189 glioblastoma samples from TCGA (global log-rank P = .02 comparing 3 survival curves for patients with 0-2, 3-4, and 5-7 dosage-altered genes). Groups of patients with 0 to 2 (low-risk group) and 5 to 7 (high-risk group) dosage-altered genes experienced 49.24 and 79.56 deaths per 100 person-years (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.10-2.40; Cox regression model P = .02), respectively. These associations with survival are validated using gene expression data in 3 independent glioma studies, comprising 76 (global log-rank P = .003; 47.89 vs 15.13 deaths per 100 person-years for high risk vs low risk; Cox model HR, 3.04; 95% CI, 1.49-6.20; P = .002) and 70 (global log-rank P = .008; 83.43 vs 16.14 deaths per 100 person-years for high risk vs low risk; HR, 3.86; 95% CI, 1.59-9.35; P = .003) high-grade gliomas and 191 glioblastomas (global log-rank P = .002; 83.23 vs 34.16 deaths per 100 person-years for high risk vs low risk; HR, 2.27; 95% CI, 1.44-3.58; P<.001).The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape during gliomagenesis, are associated with patient prognosis.

View details for Web of Science ID 000267948100020

View details for PubMedID 19602686
Impaired human hippocampal neurogenesis after treatment for central nervous system ANNALS OF NEUROLOGY Monje, M. L., Vogel, H., Masek, M., Ligon, K. L., Fisher, P. G., Palmer, T. D. 2007; 62 (5): 515-520
Abstract

The effects of cancer treatments such as cranial radiation and chemotherapy on human hippocampal neurogenesis remain unknown. In this study, we examine neuropathological markers of neurogenesis and inflammation in the human hippocampus after treatment for acute myelogenous leukemia or medulloblastoma. We demonstrate a persistent radiation-induced microglial inflammation that is accompanied by nearly complete inhibition of neurogenesis after cancer treatment. These findings are consistent with preclinical animal studies and suggest potential therapeutic strategies.

View details for DOI 10.1002/ana.21214

View details for Web of Science ID 000251383300012

View details for PubMedID 17786983
Recurrence of cavernous malformations after surgery in childhood. Journal of neurosurgery. Pediatrics Prolo, L. M., Jin, M. C., Loven, T., Vogel, H., Edwards, M. S., Steinberg, G. K., Grant, G. A. 2020: 1?10
Abstract

Cavernous malformations (CMs) are commonly treated cerebrovascular anomalies in the pediatric population; however, the data on radiographic recurrence of pediatric CMs after surgery are limited. The authors aimed to study the clinical presentation, outcomes, and recurrence rate following surgery for a large cohort of CMs in children.Pediatric patients (? 18 years old) who had a CM resected at a single institution were identified and retrospectively reviewed. Fisher's exact test of independence was used to assess differences in categorical variables. Survival curves were evaluated using the Mantel-Cox method.Fifty-three patients aged 3 months to 18 years underwent resection of 74 symptomatic CMs between 1996 and 2018 at a single institution. The median length of follow-up was 5.65 years. Patients most commonly presented with seizures (45.3%, n = 24) and the majority of CMs were cortical (58.0%, n = 43). Acute radiographic hemorrhage was common at presentation (64.2%, n = 34). Forty-two percent (n = 22) of patients presented with multiple CMs, and they were more likely to develop de novo lesions (71%) compared to patients presenting with a single CM (3.4%). Both radiographic hemorrhage and multiple CMs were independently prognostic for a higher risk of the patient requiring subsequent surgery. Fifty percent (n = 6) of the 12 patients with both risk factors required additional surgery within 2.5 years of initial surgery compared to none of the patients with neither risk factor (n = 9).Patients with either acute radiographic hemorrhage or multiple CMs are at higher risk for subsequent surgery and require long-term MRI surveillance. In contrast, patients with a single CM are unlikely to require additional surgery and may require less frequent routine imaging.

View details for DOI 10.3171/2020.2.PEDS19543

View details for PubMedID 32357336
Whole slide images reflect DNA methylation patterns of human tumors. NPJ genomic medicine Zheng, H., Momeni, A., Cedoz, P. L., Vogel, H., Gevaert, O. 2020; 5: 11
Abstract

DNA methylation is an important epigenetic mechanism regulating gene expression and its role in carcinogenesis has been extensively studied. High-throughput DNA methylation assays have been used broadly in cancer research. Histopathology images are commonly obtained in cancer treatment, given that tissue sampling remains the clinical gold-standard for diagnosis. In this work, we investigate the interaction between cancer histopathology images and DNA methylation profiles to provide a better understanding of tumor pathobiology at the epigenetic level. We demonstrate that classical machine learning algorithms can associate the DNA methylation profiles of cancer samples with morphometric features extracted from whole slide images. Furthermore, grouping the genes into methylation clusters greatly improves the performance of the models. The well-predicted genes are enriched in key pathways in carcinogenesis including hypoxia in glioma and angiogenesis in renal cell carcinoma. Our results provide new insights into the link between histopathological and molecular data.

View details for DOI 10.1038/s41525-020-0120-9

View details for PubMedID 32194984

View details for PubMedCentralID PMC7064513
Deciphering the origins of PDAC development Flowers, B., Xu, H., Hanson, K., Curtis, C., Vogel, H., Wood, L. D., Attardi, L. D. AMER ASSOC CANCER RESEARCH. 2019
View details for DOI 10.1158/1538-7445.PANCA19-I15

View details for Web of Science ID 000526416300153
Elucidating the role of p53 in the cellular origins of pancreatic cancer development Flowers, B. M., Xu, H., Hanson, K., Curtis, C., Vogel, H., Wood, L. D., Attardi, L. D. AMER ASSOC CANCER RESEARCH. 2019
View details for DOI 10.1158/1538-7445.PANCA19-A15

View details for Web of Science ID 000526416300013
ELECTRICAL CIRCUIT INTEGRATION OF GLIOMA THROUGH NEURON-GLIOMA SYNAPSES AND POTASSIUM CURRENTS Venkatesh, H., Morishita, W., Geraghty, A., Silverbush, D., Gillespie, S., Arzt, M., Tam, L., Ponnuswami, A., Ni, L., Woo, P., Taylor, K., Agarwal, A., Regev, A., Brang, D., Vogel, H., Hervey-Jumper, S., Bergles, D., Suva, M., Malenka, R., Monje, M. OXFORD UNIV PRESS INC. 2019: 251
View details for Web of Science ID 000509478706064
ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS Calixto-Hope, L., Lee, J., Sloan, E., Hofmann, J., Van Ziffle, J., Onodera, C., Grenert, J., Devine, P., Kline, C., Banerjee, A., Clarke, J., Taylor, J., Oberheim-Bush, N., Buerki, R., Butowski, N., Chang, S., McDermott, M., Aghi, M., Theodosopoulos, P., Hervey-Jumper, S., Berger, M., Raffel, C., Gupta, N., Kleinschmidt-DeMasters, B., Wood, M., Grafe, M., Guo, H., Sun, P., Torkildson, J., Cooney, T., Fata, C., Scharnhorst, D., Samuel, D., Bannykh, S., Khatib, Z., Maher, O., Chamyan, G., Pelaez, L., Brathwaite, C., Jin, L., Lechpammer, M., Born, D., Vogel, H., Lee, H., Phillips, J., Pekmezci, M., Bollen, A., Tihan, T., Perry, A., Solomon, D. OXFORD UNIV PRESS INC. 2019: 151?52
View details for Web of Science ID 000509478703106
A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis JOURNAL OF GENERAL INTERNAL MEDICINE Hom, J., Marwaha, S., Postolova, A., Kittle, J., Vasquez, R., Davidson, J., Kohler, J., Dries, A., Fernandez-Betancourt, L., Majcherska, M., Dearlove, J., Raghavan, S., Vogel, H., Bernstein, J. A., Fisher, P., Ashley, E., Sampson, J., Wheeler, M., Undiagnosed Dis Network 2019; 34 (6): 1058?62
View details for DOI 10.1007/s11606-019-04931-w

View details for Web of Science ID 000469884700059
Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study RADIOLOGY Iv, M., Samghabadi, P., Holdsworth, S., Gentles, A., Rezaii, P., Harsh, G., Li, G., Thomas, R., Moseley, M., Daldrup-Link, H. E., Vogel, H., Wintermark, M., Cheshier, S., Yeom, K. W. 2019; 290 (1): 198?206
View details for DOI 10.1148/radiol.2018181204

View details for Web of Science ID 000453784400037
MACHINE LEARNING ANALYSIS OF ULTRA-DEEP WHOLE-GENOME SEQUENCING IN HUMAN BRAIN REVEALS SOMATIC GENOMIC RETROTRANSPOSITION IN GLIA AS WELL AS IN NEURONS Urban, A., Zhu, X., Zhou, B., Sloan, S., Pattni, R., Fiston-Lavier, A., Snyder, M., Petrov, D., Abyzov, A., Vaccarino, F., Barres, B., Vogel, H., Tamminga, C., Levinson, D. ELSEVIER. 2019: 1240
View details for DOI 10.1016/j.euroneuro.2018.08.316

View details for Web of Science ID 000477708400398
EXCITATORY SYNAPSES BETWEEN PRESYNAPTIC NEURONS AND POSTSYNAPTIC GLIOMA CELLS PROMOTE GLIOMA PROGRESSION Venkatesh, H., Morishita, W., Geraghty, A., Tam, L., Silverbush, D., Regev, A., Vogel, H., Suva, M., Malenka, R., Monje, M. OXFORD UNIV PRESS INC. 2018: 257?58
View details for Web of Science ID 000460646301422
First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800 JOURNAL OF NEURO-ONCOLOGY Miller, S. E., Tummers, W. S., Teraphongphom, N., van den Berg, N. S., Hasan, A., Ertsey, R. D., Nagpal, S., Recht, L. D., Plowey, E. D., Vogel, H., Harsh, G. R., Grant, G. A., Li, G. H., Rosenthal, E. L. 2018; 139 (1): 135?43
View details for DOI 10.1007/s11060-018-2854-0

View details for Web of Science ID 000437255200015
Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma. Acta neuropathologica communications Lin, G. L., Nagaraja, S., Filbin, M. G., Suva, M. L., Vogel, H., Monje, M. 2018; 6 (1): 51
Abstract

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM). We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b+macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments.

View details for PubMedID 29954445
Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma ACTA NEUROPATHOLOGICA COMMUNICATIONS Lin, G. L., Nagaraja, S., Filbin, M. G., Suva, M. L., Vogel, H., Monje, M. 2018; 6
View details for DOI 10.1186/s40478-018-0553-x

View details for Web of Science ID 000436975700001
Clinical and Immunohistochemical Analysis of Clinically Non-functional Pituitary Neuroendocrine Tumors Lavezo, J., Frankel, M., Balliu, B., Pan, J., Hoffman, A., Dodd, R., Harsh, G., Katznelson, L., Vogel, H. OXFORD UNIV PRESS INC. 2018: 518
View details for Web of Science ID 000434064400162
Plurihormonal pituitary neuroendocrine tumor with Pit1 and SF-1 coexpression: A novel entity Jonathan, L., Forgo, E., Katznelson, L., Harsh, G., Vogel, H. OXFORD UNIV PRESS INC. 2018: 523
View details for Web of Science ID 000434064400181
EXCITATORY SYNAPSES BETWEEN PRESYNAPTIC NEURONS AND POSTSYNAPTIC GLIOMA CELLS PROMOTE DIPG PROGRESSION Venkatesh, H., Geraghty, A., Morishita, W., Tam, L., Tirosh, I., Regev, A., Vogel, H., Suva, M., Malenka, R., Monje, M. OXFORD UNIV PRESS INC. 2018: 49
View details for Web of Science ID 000438339000099
Inhibitory Interneurons in Hemimegalencephaly: A Survey of 9 Cases Lummus, S., Andersen, J., Pasca, S., Kleinschmidt-DeMasters, B., Vogel, H. OXFORD UNIV PRESS INC. 2018: 501
View details for Web of Science ID 000434064400092
Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas NATURE MEDICINE Mount, C. W., Majzner, R. G., Sundaresh, S., Arnold, E. P., Kadapakkam, M., Haile, S., Labanieh, L., Hulleman, E., Woo, P. J., Rietberg, S. P., Vogel, H., Monje, M., Mackall, C. L. 2018; 24 (5): 572-+
View details for DOI 10.1038/s41591-018-0006-x

View details for Web of Science ID 000432126800013
Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell Gibson, E. M., Nagaraja, S., Ocampo, A., Tam, L. T., Wood, L. S., Pallegar, P. N., Greene, J. J., Geraghty, A. C., Goldstein, A. K., Ni, L., Woo, P. J., Barres, B. A., Liddelow, S., Vogel, H., Monje, M. 2018
Abstract

Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter�dysfunction are thought to contribute to this�debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a�mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is�dependent on inflammatory microglia. Microglial�depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a�therapeutic target to abrogate chemotherapy-related cognitive impairment.

View details for PubMedID 30528430
Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO molecular medicine Joshi, A. U., Saw, N. L., Vogel, H., Cunnigham, A. D., Shamloo, M., Mochly-Rosen, D. 2018
Abstract

Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient-derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients.

View details for PubMedID 29335339
Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study. Radiology Iv, M., Samghabadi, P., Holdsworth, S., Gentles, A., Rezaii, P., Harsh, G., Li, G., Thomas, R., Moseley, M., Daldrup-Link, H. E., Vogel, H., Wintermark, M., Cheshier, S., Yeom, K. W. 2018: 181204
Abstract

Purpose To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. Materials and Methods In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400� magnification high-power fields with iron-containing macrophages. Results Ten adults (four male participants [mean age, 65 years � 9 {standard deviation}; age range, 57-74 years] and six female participants [mean age, 53 years � 12 years; age range, 32-65 years]; mean age of all participants, 58 years � 12 [age range, 32-74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2' and the number of high-power fields with CD163-positive (r range, 0.64-0.71; P < .01) and CD68-positive (r range, 0.55-0.57; P value range, .01-.02) iron-containing macrophages. No significant correlation was found between R2 and CD163-positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron-containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein-positive tumor cells. Conclusion MRI measurements of susceptibility, R2*, and R2' (R2* - R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. � RSNA, 2018 Online supplemental material is available for this article.

View details for PubMedID 30398435
First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. Journal of neuro-oncology Miller, S. E., Tummers, W. S., Teraphongphom, N., van den Berg, N. S., Hasan, A., Ertsey, R. D., Nagpal, S., Recht, L. D., Plowey, E. D., Vogel, H., Harsh, G. R., Grant, G. A., Li, G. H., Rosenthal, E. L. 2018
Abstract

Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2�days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0?�?0.5) compared to non-CE tumors (1.2?�?0.3; p?=?0.02). The TBR was higher at a 100�mg dose than at 50�mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70�mg with 50�mg of dye and 10�mg with 100�mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50�mg dose, 98.2% for 100�mg dose) and specific (66.3% for 50�mg dose, 69.8% for 100�mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.

View details for PubMedID 29623552
Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nature medicine Mount, C. W., Majzner, R. G., Sundaresh, S., Arnold, E. P., Kadapakkam, M., Haile, S., Labanieh, L., Hulleman, E., Woo, P. J., Rietberg, S. P., Vogel, H., Monje, M., Mackall, C. L. 2018
Abstract

Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.

View details for PubMedID 29662203
Utility of Pit-1 Immunostaining in Distinguishing Pituitary Adenomas of Primitive Differentiation from Null Cell Adenomas ENDOCRINE PATHOLOGY Lee, J. C., Pekmezci, M., Lavezo, J. L., Vogel, H., Katznelson, L., Fraenkel, M., Harsh, G., Dulai, M., Perry, A., Tihan, T. 2017; 28 (4): 287?92
Abstract

Pit-1 immunostaining is not routinely used in the characterization of pituitary adenomas, and its utility in distinguishing adenomas dedicated towards the lactotroph, somatotroph, and thyrotroph lineage from null cell adenomas warrants further evaluation. Pituitary adenomas that were negative for expression of a basic panel of hormonal markers (ACTH, prolactin, and growth hormone) were further evaluated for TSH, SF-1, and Pit-1 expression using a tissue microarray. Among the 147 identified pituitary adenomas that were negative for ACTH, prolactin, growth hormone, and TSH, expression of SF-1 was present in 68 cases (46%). Of the remaining 72 cases with sufficient tissue for further analysis, four were Pit-1 positive (6% of the adenomas negative for ACTH, prolactin, growth hormone, TSH, and SF-1); the remaining 68 were potentially null cell adenomas. Two of the Pit-1-positive adenomas displayed a paranuclear CAM 5.2 staining pattern suggestive of a sparsely granulated somatotroph adenoma; however, only one case contained fibrous bodies within a majority of the adenoma cells. Our data suggests that Pit-1 can be utilized as a second tier immunostain in cases of clinically non-functioning adenomas that are immunonegative for ACTH, prolactin, growth hormone, TSH, and SF-1 in order to further segregate rare cases of Pit-1-positive adenomas from null cell adenomas. Pit-1 immunostaining can recognize rare cases of sparsely granulated somatotroph adenomas that appear immunonegative for growth hormone, as well as rare cases of other Pit-1-positive adenomas that are negative for Pit-1 lineage hormones. Overall, pituitary adenomas of the Pit-1 lineage that do not produce prolactin, growth hormone, or TSH are rare, with only four cases identified in the current study.

View details for PubMedID 28994039
THE EFFECT OF PATIENT AGE AT GLIOMA PRESENTATION ON MRI PHENOTYPE: A COMPREHENSIVE ANALYSIS OF VASARI-BASED FEATURE-SET CRITERIA IN 711 PATIENTS Das, D., Yoon, B., Golden, L., Samghabadi, P., Vogel, H., Yeom, K., Iv, M., Massoud, T. OXFORD UNIV PRESS INC. 2017: 158
View details for Web of Science ID 000415152503005
A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma JOURNAL OF NEURO-ONCOLOGY Connolly, I., Li, Y., Pan, W., Johnson, E., You, L., Vogel, H., Ratliff, J., Gephart, M. 2017; 135 (1): 29?36
Abstract

Cerebrospinal fluid (CSF) represents a promising source of cell-free DNA (cfDNA) for tumors of the central nervous system. A CSF-based liquid biopsy may obviate the need for riskier tissue biopsies and serve as a means for monitoring tumor recurrence or response to therapy. Spinal ependymomas most commonly occur in adults, and aggressive resection must be delicately balanced with the risk of injury to adjacent normal tissue. In patients with subtotal resection, recurrence commonly occurs. A CSF-based liquid biopsy matched to the patient's spinal ependymoma mutation profile has potential to be more sensitive then surveillance MRI, but the utility has not been well characterized for tumors of the spinal cord. In this study, we collected matched blood, tumor, and CSF samples from three adult patients with WHO grade II intramedullary spinal ependymoma. We performed whole exome sequencing on matched tumor and normal DNA to design Droplet Digital? PCR (ddPCR) probes for tumor and wild-type mutations. We then interrogated CSF samples for tumor-derived cfDNA by performing ddPCR on extracted cfDNA. Tumor cfDNA was not reliably detected in the CSF of our cohort. Anatomic sequestration and low grade�of intramedullary spinal cord tumors likely limits the role of CSF liquid biopsy.

View details for PubMedID 28900844
Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings JOURNAL OF CHILD NEUROLOGY Song, H., Haeri, S., Vogel, H., van der Knaap, M., Van Haren, K. 2017; 32 (10): 867?70
Abstract

We describe 2 male siblings with a severe, prenatal phenotype of vanishing white matter disease and the impact of whole exome sequencing on their diagnosis and clinical care.The 2 children underwent detailed clinical characterization, through clinical and laboratory testing, as well as prenatal and postnatal imaging. Biobanked blood from the 2 siblings was submitted for whole exome sequencing at Baylor Laboratories.Both male children had abnormal prenatal neuroimaging and suffered precipitous, fatal neurologic decline. Neuropathologic findings included subependymal pseudocysts, microcalcifications, and profound lack of brain myelin and sparing of peripheral nerve myelin. A novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) was found in both children; both parents were heterozygous carriers. The family subsequently conceived a healthy child via in vitro fertilization with preimplantation mutation screening.These histories expand the prenatal phenotype of eIF2b-related disorders and poignantly illustrate the impact that unbiased genomic sequencing can have on the diagnosis and medical decision making for families affected by childhood neurodegenerative disorders.

View details for PubMedID 28597716
The Unusual Presentation of a Myxoma Within the Sphenoid Sinus: Case Report and Review of the Literature WORLD NEUROSURGERY Clarke, J. V., Mandpe, A. H., Weber, P. B., Vogel, H., Leng, L. Z. 2017; 103: 951.e5?951.e12
Abstract

We describe a rare case of a sphenoid sinus myxoma that was resected via an endoscopic endonasal skull base approach. We review the literature regarding these rare tumors of the paranasal sinuses.A 72-year-old woman was diagnosed with an incidental sphenoid sinus tumor and left sphenoid wing meningioma during a workup for left-sided proptosis and diplopia. Biopsies of the sphenoid wing and sphenoid sinus tumors were obtained. After undergoing surgical resection of the meningioma, the patient then underwent definitive resection of the sphenoid sinus myxoma via endoscopic endonasal skull base approach. Postoperative imaging demonstrated a gross total resection. The patient suffered postoperative thromboembolic complications due to underlying hypercoagulable state but made a complete recovery and returned to her neurologic baseline. There has been no evidence of recurrent myxoma in the sphenoid sinus 24 months after surgery.Myxomas are benign tumors derived from primitive mesenchyme. Myxomas very rarely present in the paranasal or skull base location. Complete surgical resection is the primary treatment for these tumors. The endoscopic endonasal approach is an effective technique for resecting various benign and more aggressive extradural skull base tumors.Myxomas of the sphenoid sinus are rare. The endoscopic endonasal skull base approach is an effective and minimal access technique for resection of this rare tumor of the sphenoid sinus.

View details for PubMedID 28433840
NEURAL PRECURSOR CELL: GLIOMA INTERACTIONS MEDIATE TUMOR COLONIZATION OF THE SUBVENTRICULAR ZONE BY DIPG Qin, E. Y., Cooper, D., Abbott, K., MacKay, A., Jones, C., Vogel, H., Jackson, P., Monje, M. OXFORD UNIV PRESS INC. 2017: 7
View details for Web of Science ID 000402766800028
Anti-PD-1-associated inflammatory-demyelinating lesions in patients with brain metastases Samghabadi, P., Makar, S., Thomas, R., Pelpola, J., Reddy, S., Tranvinh, E., Spence, A., Vogel, H., Born, D., Sobel, R. OXFORD UNIV PRESS INC. 2017: 500?501
View details for Web of Science ID 000404906900045
Lymphoplasmacytic Lymphoma Presenting As Giant Cell Arteritis: A Novel Case Report Samghabadi, P., Berry, G., Natkunam, Y., Vogel, H., Shoor, S., Born, D. OXFORD UNIV PRESS INC. 2017: 545
View details for Web of Science ID 000404906900225
Unifying mechanism for different fibrotic diseases PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wernig, G., Chen, S., Cui, L., Van Neste, C., Tsai, J. M., Kambham, N., Vogel, H., Natkunam, Y., Gilliland, D. G., Nolan, G., Weissman, I. L. 2017; 114 (18): 4757-4762
Abstract

Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts. Expression of the related AP1 transcription factor FRA2 was restricted to pulmonary artery hypertension. Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple organs and steatohepatosis, which was dependent on sustained c-Jun expression. Single cell mass cytometry revealed that c-Jun activates multiple signaling pathways in mice, including pAkt and CD47, which were also induced in human disease. ?CD47 antibody treatment and VEGF or PI3K inhibition reversed various organ c-Jun-mediated fibroses in vivo. These data suggest that c-JUN is a central molecular mediator of most fibrotic conditions.

View details for DOI 10.1073/pnas.1621375114

View details for PubMedID 28424250
Disrupting the CD47-SIRP alpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors SCIENCE TRANSLATIONAL MEDICINE Gholamin, S., Mitra, S. S., Feroze, A. H., Liu, J., Kahn, S. A., Zhang, M., Esparza, R., Richard, C., Ramaswamy, V., Remke, M., Volkmer, A. K., Willingham, S., Ponnuswami, A., McCarty, A., Lovelace, P., Storm, T. A., Schubert, S., Hutter, G., Narayanan, C., Chu, P., Raabe, E. H., Harsh, G., Taylor, M. D., Monje, M., Cho, Y., Majeti, R., Volkmer, J. P., Fisher, P. G., Grant, G., Steinberg, G. K., Vogel, H., Edwards, M., Weissman, I. L., Cheshier, S. H. 2017; 9 (381)
Abstract

Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRP? interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

View details for DOI 10.1126/scitranslmed.aaf2968

View details for PubMedID 28298418
The p53 family members have distinct roles during mammalian embryonic development. Cell death and differentiation Van Nostrand, J. L., Bowen, M. E., Vogel, H., Barna, M., Attardi, L. D. 2017
Abstract

The p53 tumor suppressor is a member of a multi-protein family, including the p63 and p73 transcription factors. These proteins can bind to the same consensus sites in DNA and activate the same target genes, suggesting that there could be functional redundancy between them. Indeed, double mutant mice heterozygous for any two family member-encoding genes display enhanced cancer phenotypes relative to single heterozygous mutants. However, whether the family members play redundant roles during embryonic development has remained largely unexplored. Although p53(-/-); p73(-/-) mice are born and manifest phenotypes characteristic of each of the single mutants, the consequences of combined deficiency of p63 and either p53 or p73 have not been elucidated. To examine the functional overlap of p53 family members during development, we bred and analyzed compound mutant embryo phenotypes. We discovered that double knockout embryos and five allele knockout embryos only displayed obvious defects accounted for by loss of single p53 family members. Surprisingly, at mid-gestation (E11), we identified a single viable triple knockout embryo that appeared grossly normal. Together, these results suggest that the p53 family is not absolutely required for early embryogenesis and that p53 family members are largely non-redundant during early development.

View details for DOI 10.1038/cdd.2016.128

View details for PubMedID 28211873
Immunohistochemical Assessment of 23 Immature Ovarian Teratomas Charville, G., Longacre, T., Vogel, H., Ulbright, T. M., Kao, C. NATURE PUBLISHING GROUP. 2017: 279A?280A
View details for Web of Science ID 000394467301400
Immunohistochemical Assessment of 23 Immature Ovarian Teratomas Charville, G., Longacre, T., Vogel, H., Ulbright, T. M., Kao, C. NATURE PUBLISHING GROUP. 2017: 279A?280A
View details for Web of Science ID 000393724401400
Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma. Cell Qin, E. Y., Cooper, D. D., Abbott, K. L., Lennon, J., Nagaraja, S., Mackay, A., Jones, C., Vogel, H., Jackson, P. K., Monje, M. 2017; 170 (5): 845?59.e19
Abstract

The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular�mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP.

View details for PubMedID 28823557
Neat1 is a p53-inducible lincRNA essential for transformation suppression. Genes & development Mello, S. S., Sinow, C., Raj, N., Mazur, P. K., Bieging-Rolett, K., Broz, D. K., Imam, J. F., Vogel, H., Wood, L. D., Sage, J., Hirose, T., Nakagawa, S., Rinn, J., Attardi, L. D. 2017; 31 (11): 1095?1108
Abstract

The p53 gene is mutated in over half of all cancers, reflecting its critical role as a tumor suppressor. Although p53 is a transcriptional activator that induces myriad target genes, those p53-inducible genes most critical for tumor suppression remain elusive. Here, we leveraged p53 ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) and RNA-seq (RNA sequencing) data sets to identify new p53 target genes, focusing on the noncoding genome. We identify Neat1, a noncoding RNA (ncRNA) constituent of paraspeckles, as a p53 target gene broadly induced by mouse and human p53 in different cell types and by diverse stress signals. Using fibroblasts derived from Neat1(-/-) mice, we examined the functional role of Neat1 in the p53 pathway. We found that Neat1 is dispensable for cell cycle arrest and apoptosis in response to genotoxic stress. In sharp contrast, Neat1 plays a crucial role in suppressing transformation in response to oncogenic signals. Neat1 deficiency enhances transformation in oncogene-expressing fibroblasts and promotes the development of premalignant pancreatic intraepithelial neoplasias (PanINs) and cystic lesions in Kras(G12D)-expressing mice. Neat1 loss provokes global changes in gene expression, suggesting a mechanism by which its deficiency promotes neoplasia. Collectively, these findings identify Neat1 as a p53-regulated large intergenic ncRNA (lincRNA) with a key role in suppressing transformation and cancer initiation, providing fundamental new insight into p53-mediated tumor suppression.

View details for PubMedID 28698299
Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease. Scientific reports Hsueh, B., Burns, V. M., Pauerstein, P., Holzem, K., Ye, L., Engberg, K., Wang, A. C., Gu, X., Chakravarthy, H., Arda, H. E., Charville, G., Vogel, H., Efimov, I. R., Kim, S., Deisseroth, K. 2017; 7 (1): 5899
Abstract

Three-dimensional tissue-structural relationships are not well captured by typical thin-section histology, posing challenges for the study of tissue physiology and pathology. Moreover, while recent progress has been made with intact methods for clearing, labeling, and imaging whole organs such as the mature brain, these approaches are generally unsuitable for soft, irregular, and heterogeneous tissues that account for the vast majority of clinical samples and biopsies. Here we develop a biphasic hydrogel methodology, which along with automated analysis, provides for high-throughput quantitative volumetric interrogation of spatially-irregular and friable tissue structures. We validate and apply this approach in the examination of a variety of developing and diseased tissues, with specific focus on the dynamics of normal and pathological pancreatic innervation and development, including in clinical samples. Quantitative advantages of the intact-tissue approach were demonstrated compared to conventional thin-section histology, pointing to broad applications in both research and clinical settings.

View details for PubMedID 28724969
A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer. Cancer cell Mello, S. S., Valente, L. J., Raj, N., Seoane, J. A., Flowers, B. M., McClendon, J., Bieging-Rolett, K. T., Lee, J., Ivanochko, D., Kozak, M. M., Chang, D. T., Longacre, T. A., Koong, A. C., Arrowsmith, C. H., Kim, S. K., Vogel, H., Wood, L. D., Hruban, R. H., Curtis, C., Attardi, L. D. 2017; 32 (4): 460?73.e6
Abstract

The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

View details for PubMedID 29017057
Response of metastatic glioma to vemurafenib NEURO-ONCOLOGY PRACTICE Leaver, K., Zhang, N., Ziskin, J. L., Vogel, H., Recht, L., Thomas, R. P. 2016; 3 (4): 268?71
View details for DOI 10.1093/nop/npv054

View details for Web of Science ID 000439199800007
Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy ONCOTARGET Renier, C., Do, J., Reyna-Neyra, A., Foster, D., De, A., Vogel, H., Jeffrey, S. S., Tse, V., Carrasco, N., Wapnir, I. 2016; 7 (34): 54811-54824
Abstract

Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I- symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (131I-). We show impressive enhancement of tumor response by combining131I- with gemcitabine (GEM), a cytotoxic radiosensitizer. Nude mice mammary fat-pad (MFP) tumors and BCBMs were generated with braintropic MDA-MB-231Br cells transduced with bicistronically-linked NIS and firefly luciferase cDNAs. Response was monitored in vivo via bioluminescent imaging and NIS tumor expression.131I-/GEM therapy inhibited MFP tumor growth more effectively than either agent alone. BCBMs were treated with: high or low-dose GEM (58 or 14.5 mg/Kg�4); 131I- (1mCi or 2�0.5 mCi 7 days apart); and 131I-/GEM therapy. By post-injection day (PID) 25, 82-86% of controls and 78-83% of 131I--treated BCBM grew, whereas 17% low-dose and 36% high-dose GEM regressed. The latter tumors were smaller than the controls with comparable NIS expression (~20% of cells). High and low-dose 131I-/ GEM combinations caused 89% and 57% tumor regression, respectively. High-dose GEM/131I- delayed tumor growth: tumors increased 5-fold in size by PID45 (controls by PID18). Although fewer than 25% of cells expressed NIS, GEM/131I- caused dramatic tumor regression in NIS-transduced BCBMs. This effect was synergistic, and supports the hypothesis that GEM radiosensitizes cells to 131I-.

View details for DOI 10.18632/oncotarget.10238

View details for Web of Science ID 000385435000059
Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types CELL Loh, K. M., Chen, A., Koh, P. W., Deng, T. Z., Sinha, R., Tsai, J. M., Barkal, A. A., Shen, K. Y., Jain, R., Morganti, R. M., Shyh-Chang, N., Fernhoff, N. B., George, B. M., Wernig, G., Salomon, R. E., Chen, Z., Vogel, H., Epstein, J. A., Kundaje, A., Talbot, W. S., Beachy, P. A., Ang, L. T., Weissman, I. L. 2016; 166 (2): 451-467
Abstract

Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in�vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. VIDEO ABSTRACT.

View details for DOI 10.1016/j.cell.2016.06.011

View details for PubMedID 27419872
CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer JOURNAL OF CLINICAL INVESTIGATION Weiskopf, K., Jahchan, N. S., Schnorr, P. J., Cristea, S., Ring, A. M., Maute, R. L., Volkmer, A. K., Volkmer, J., Liu, J., Lim, J. S., Yang, D., Seitz, G., Thuyen Nguyen, T., Wu, D., Jude, K., Guerston, H., Barkal, A., Trapani, F., George, J., Poirier, J. T., Gardner, E. E., Miles, L. A., de Stanchina, E., Lofgren, S. M., Vogel, H., Winslow, M. M., Dive, C., Thomas, R. K., Rudin, C. M., van de Rijn, M., Majeti, R., Garcia, K. C., Weissman, I. L., Sage, J. 2016; 126 (7): 2610-2620
Abstract

Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRP?), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRP? using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture. In a murine model, administration of CD47-blocking antibodies or targeted inactivation of the Cd47 gene markedly inhibited SCLC tumor growth. Furthermore, using comprehensive antibody arrays, we identified several possible therapeutic targets on the surface of SCLC cells. Antibodies to these targets, including CD56/neural cell adhesion molecule (NCAM), promoted phagocytosis in human SCLC cell lines that was enhanced when combined with CD47-blocking therapies. In light of recent clinical trials for CD47-blocking therapies in cancer treatment, these findings identify disruption of the CD47/SIRP? axis as a potential immunotherapeutic strategy for SCLC. This approach could enable personalized immunotherapeutic regimens in patients with SCLC and other cancers.

View details for DOI 10.1172/JCI81603

View details for Web of Science ID 000379094800024

View details for PubMedID 27294525

View details for PubMedCentralID PMC4922696
Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis ACTA NEUROPATHOLOGICA Hasselblatt, M., Thomas, C., Hovestadt, V., Schrimpf, D., Johann, P., Bens, S., Oyen, F., Peetz-Dienhart, S., Crede, Y., Wefers, A., Vogel, H., Riemenschneider, M. J., Antonelli, M., Giangaspero, F., Bernardo, M., Giannini, C., Din, N., Perry, A., Keyvani, K., van Landeghem, F., Sumerauer, D., Hauser, P., Capper, D., Korshunov, A., Jones, D. W., Pfister, S. M., Schneppenheim, R., Siebert, R., Fruehwald, M. C., Kool, M. 2016; 132 (1): 149?51
View details for PubMedID 27067307
Transcriptome sequencing analysis of four psammomatous meningiomas Samghabadi, P., Forgo, E., West, R., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2016: 575
View details for Web of Science ID 000377665000038
ATYPICAL TERATOID RHABDOID TUMORS AND POORLY DIFFERENTIATED CHORDOMAS: DISTINCT MOLECULAR ENTITIES WITH SMARCB1/INI1 LOSS AND DISMAL PROGNOSIS Thomas, C., Hovestadt, V., Schrimpf, D., Johann, P., Bens, S., Oyen, F., Vogel, H., Giangaspero, F., Antonelli, M., Riemenschneider, M., Christine Bernardo, M., Giannini, C., Din, N., Perry, A., Keyvani, K., van Landeghem, F., Sumerauer, D., Hauser, P., Capper, D., Korshunov, A., Jones, D. W., Pfister, S., Schneppenheim, R., Siebert, R., Fruehwald, M. C., Kool, M., Hasselblatt, M. OXFORD UNIV PRESS INC. 2016: 3
View details for Web of Science ID 000379749000010
NOTCH1 PROMOTES GROUP 3 MEDULLOBLASTOMA METASTASIS, INITIATION AND SELF-RENEWAL Kahn, S., Wang, X., Nitta, R., Gholamin, S., Ramaswamy, V., Azad, T., Sahoo, D., Esparza, R., Chu, P., Fisher, P., Vogel, H., Li, G., Cho, Y., Taylor, M., Mitra, S., Weissman, I., Cheshier, S. OXFORD UNIV PRESS INC. 2016: 100
View details for Web of Science ID 000379749000394
A Novel Intronic Mutation in TK2 Affects mRNA Expression and Causes Adult-Onset Mitochondrial Depletion Syndrome Lopez-Gomez, C., Garone, C., Karch, C., Vogel, H., Ralph, J., Hirano, M. LIPPINCOTT WILLIAMS & WILKINS. 2016
View details for Web of Science ID 000411328605153
Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse NEURON Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S., Li, G., Duncan, J. A., Cheshier, S. H., Shuer, L. M., Chang, E. F., Grant, G. A., Gephart, M. G., Barres, B. A. 2016; 89 (1): 37-53
Abstract

The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and�engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.

View details for DOI 10.1016/j.neuron.2015.11.013

View details for PubMedID 26687838
Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy. Oncotarget Renier, C., Do, J., Reyna-Neyra, A., Foster, D., De, A., Vogel, H., Jeffrey, S. S., Tse, V., Carrasco, N., Wapnir, I. 2016
Abstract

Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I- symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (131I-). We show impressive enhancement of tumor response by combining131I- with gemcitabine (GEM), a cytotoxic radiosensitizer. Nude mice mammary fat-pad (MFP) tumors and BCBMs were generated with braintropic MDA-MB-231Br cells transduced with bicistronically-linked NIS and firefly luciferase cDNAs. Response was monitored in vivo via bioluminescent imaging and NIS tumor expression.131I-/GEM therapy inhibited MFP tumor growth more effectively than either agent alone. BCBMs were treated with: high or low-dose GEM (58 or 14.5 mg/Kg�4); 131I- (1mCi or 2�0.5 mCi 7 days apart); and 131I-/GEM therapy. By post-injection day (PID) 25, 82-86% of controls and 78-83% of 131I--treated BCBM grew, whereas 17% low-dose and 36% high-dose GEM regressed. The latter tumors were smaller than the controls with comparable NIS expression (~20% of cells). High and low-dose 131I-/ GEM combinations caused 89% and 57% tumor regression, respectively. High-dose GEM/131I- delayed tumor growth: tumors increased 5-fold in size by PID45 (controls by PID18). Although fewer than 25% of cells expressed NIS, GEM/131I- caused dramatic tumor regression in NIS-transduced BCBMs. This effect was synergistic, and supports the hypothesis that GEM radiosensitizes cells to 131I-.

View details for PubMedID 27363025
Response of metastatic glioma to vemurafenib. Neuro-oncology practice Leaver, K. E., Zhang, N., Ziskin, J. L., Vogel, H., Recht, L., Thomas, R. P. 2016; 3 (4): 268?71
Abstract

Extraneural metastatic disease of glioma is rare and poses unique therapeutic challenges. Increasingly, the ability to sequence genetic alterations in tumors has allowed for the identification of common oncogenic signatures such as the activating BRAFV600E mutation and may be useful in therapeutic decision making. We report two patients with widespread aggressive gliomas whose tumors were found to express the BRAFV600E mutation and then responded robustly albeit transiently when exposed to vemurafenib. Although both patients succumbed to their disease, our results suggest that targeting BRAF might be appropriate for patients with aggressive gliomas that express this mutation.

View details for DOI 10.1093/nop/npv054

View details for PubMedID 31386052

View details for PubMedCentralID PMC6657395
Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiology of aging Zeineh, M. M., Chen, Y., Kitzler, H. H., Hammond, R., Vogel, H., Rutt, B. K. 2015; 36 (9): 2483-2500
Abstract

Although amyloid plaques and neurofibrillary pathology play important roles in Alzheimer disease (AD), our understanding of AD is incomplete, and the contribution of microglia and iron to neurodegeneration is unknown. High-field magnetic resonance imaging (MRI) is exquisitely sensitive to microscopic iron. To explore iron-associated neuroinflammatory AD pathology, we studied AD and control human brain specimens by (1) performing ultra-high resolution ex vivo 7 Tesla MRI, (2) coregistering the MRI with successive histologic staining for iron, microglia, amyloid beta, and tau, and (3) quantifying the relationship between magnetic resonance signal intensity and histological staining. In AD, we identified numerous small MR hypointensities primarily within the subiculum that were best explained by the combination of microscopic iron and activated microglia (p = 0.025), in contradistinction to the relatively lesser contribution of tau or amyloid. Neuropathologically, this suggests that microglial-mediated neurodegeneration may occur in the hippocampal formation in AD and is detectable by ultra-high resolution MRI.

View details for DOI 10.1016/j.neurobiolaging.2015.05.022

View details for PubMedID 26190634
DISTINCT BRAIN LINEAGE AND STROMAL GENE EXPRESSION PATTERNS IN WNT, SHH, GROUP 3 AND GROUP 4 MOLECULAR SUBGROUPS OF PEDIATRIC MEDULLOBLASTOMA Achrol, A., Liu, T., Vogel, H., Chang, S., Edwards, M., Harsh, G., Sahoo, D. OXFORD UNIV PRESS INC. 2015: 30
View details for Web of Science ID 000361304800122
NEURONAL ACTIVITY-REGULATED SECRETION OF NEUROLIGIN-3 PROMOTES GLIOMA GROWTH Venkatesh, H., Johung, T., Caretti, V., Noll, A., Vogel, H., Bredel, M., Mallick, P., Monje, M. OXFORD UNIV PRESS INC. 2015: 11
View details for Web of Science ID 000361304800042
IMPACT OF MOLECULAR SUB-TYPE AND CRANIOSPINAL IRRADIATION (CSI) DOSE ON RELAPSE OF MEDULLOBLASTOMA Wang, A., Partap, S., Yeom, K., Martinez, M., Vogel, H., Donaldson, S., Fisher, P., Perreault, S., Cho, Y., Gibbs, I. OXFORD UNIV PRESS INC. 2015: 22
View details for Web of Science ID 000361304800088
CDKN2A Loss Is Associated With Shortened Overall Survival in Lower-Grade (World Health Organization Grades II-III) Astrocytomas JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Reis, G. F., Pekmezci, M., Hansen, H. M., Rice, T., Marshall, R. E., Molinaro, A. M., Phillips, J. J., Vogel, H., Wiencke, J. K., Wrensch, M. R., Walsh, K. M., Perry, A. 2015; 74 (5): 442-452
Abstract

Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.

View details for DOI 10.1097/NEN.0000000000000188

View details for PubMedID 25853694
Atypical and rare variants of central neurocytomas. Neurosurgery clinics of North America Choudhri, O., Razavi, S., Vogel, H., Li, G. 2015; 26 (1): 91-98
Abstract

This article reviews the variation in imaging, histopathology, clinical course, and management seen with central neurocytomas (CNs). CNs have often been misdiagnosed as oligodendrogliomas and ependymomas; however, synaptophysin positivity can correctly diagnose these neurocytic neoplasms. Atypical CNs, an important variant first described in 1997, are marked by increased proliferative potential and associated with worse clinical outcomes in terms of long-term survival and local tumor control. Complete surgical resection is the cornerstone of therapy, and postoperative radiation is recommended in the setting of residual disease. Other less aggressive variants of central neurocytomas, including liponeurocytomas, ganglioneurocytomas, and pigmented neurocytomas, are also discussed.

View details for DOI 10.1016/j.nec.2014.09.003

View details for PubMedID 25432187
SUBVENTRICULAR SPREAD OF DIFFUSE INTRINSIC PONTINE GLIOMA Caretti, V., Bugiani, M., Freret, M., Schellen, P., Jansen, M., van Vuurden, D., Kaspers, G., Fisher, P. G., Hulleman, E., Wesseling, P., Vogel, H., Monje, M. OXFORD UNIV PRESS INC. 2014
View details for DOI 10.1093/neuonc/nou261.3

View details for Web of Science ID 000350452200480
Endoscopic resection of a giant intradural retroclival ecchordosis physaliphora: surgical technique and literature review. World neurosurgery Choudhri, O., Feroze, A., Hwang, P., Vogel, H., Ajlan, A., Harsh, G. 2014; 82 (5): 912 e21-6
View details for DOI 10.1016/j.wneu.2014.06.019

View details for PubMedID 24937599
Endoscopic resection of a giant intradural retroclival ecchordosis physaliphora: surgical technique and literature review. World neurosurgery Choudhri, O., Feroze, A., Hwang, P., Vogel, H., Ajlan, A., Harsh, G. 2014; 82 (5): 912 e21-6
Abstract

To report the first complete resection of a giant ecchordosis physaliphora using an endoscopic transclival approach and to provide a current review of the literature.This rare benign lesion, originating from embryonic notochordal remnants, was located in the prepontine cistern of a 63-year-old man presenting with progressive tremor and imbalance. Preoperative imaging demonstrated a 2.1-cm intradural lesion abutting the pons and basilar artery and extending through the dura mater.A gross total resection was successfully achieved endoscopically without neurovascular compromise or additional complications. Postoperative histopathologic examination was consistent with a diagnosis of giant ecchordosis physaliphora.An endoscopic endonasal transclival approach provided a direct, minimally invasive route for safe and complete resection of this rare prepontine tumor, as it has for similarly located skull base chordomas. Our experience highlights the utility of endoscopy in visualization of both pathologic entities and nearby critical neurovascular structures in the management of ecchordosis physaliphora and other cranial base neoplasms.

View details for DOI 10.1016/j.wneu.2014.06.019

View details for PubMedID 24937599
Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature Van Nostrand, J. L., Brady, C. A., Jung, H., Fuentes, D. R., Kozak, M. M., Johnson, T. M., Lin, C., Lin, C., Swiderski, D. L., Vogel, H., Bernstein, J. A., Atti�-Bitach, T., Chang, C., Wysocka, J., Martin, D. M., Attardi, L. D. 2014; 514 (7521): 228-232
Abstract

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

View details for DOI 10.1038/nature13585

View details for PubMedID 25119037
Abnormal Hepatocellular Mitochondria in Methylmalonic Acidemia ULTRASTRUCTURAL PATHOLOGY Wilnai, Y., Enns, G. M., Niemi, A., Higgins, J., Vogel, H. 2014; 38 (5): 309-314
Abstract

Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.

View details for DOI 10.3109/01913123.2014.921657

View details for Web of Science ID 000345348700003
Abnormal hepatocellular mitochondria in methylmalonic acidemia. Ultrastructural pathology Wilnai, Y., Enns, G. M., Niemi, A., Higgins, J., Vogel, H. 2014; 38 (5): 309-314
Abstract

Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.

View details for DOI 10.3109/01913123.2014.921657

View details for PubMedID 24933007
MRI surrogates for molecular subgroups of medulloblastoma. AJNR. American journal of neuroradiology Perreault, S., Ramaswamy, V., Achrol, A. S., Chao, K., Liu, T. T., Shih, D., Remke, M., Schubert, S., Bouffet, E., Fisher, P. G., Partap, S., Vogel, H., Taylor, M. D., Cho, Y. J., Yeom, K. W. 2014; 35 (7): 1263-1269
Abstract

Recently identified molecular subgroups of medulloblastoma have shown potential for improved risk stratification. We hypothesized that distinct MR imaging features can predict these subgroups.All patients with a diagnosis of medulloblastoma at one institution, with both pretherapy MR imaging and surgical tissue, served as the discovery cohort (n = 47). MR imaging features were assessed by 3 blinded neuroradiologists. NanoString-based assay of tumor tissues was conducted to classify the tumors into the 4 established molecular subgroups (wingless, sonic hedgehog, group 3, and group 4). A second pediatric medulloblastoma cohort (n = 52) from an independent institution was used for validation of the MR imaging features predictive of the molecular subtypes.Logistic regression analysis within the discovery cohort revealed tumor location (P < .001) and enhancement pattern (P = .001) to be significant predictors of medulloblastoma subgroups. Stereospecific computational analyses confirmed that group 3 and 4 tumors predominated within the midline fourth ventricle (100%, P = .007), wingless tumors were localized to the cerebellar peduncle/cerebellopontine angle cistern with a positive predictive value of 100% (95% CI, 30%-100%), and sonic hedgehog tumors arose in the cerebellar hemispheres with a positive predictive value of 100% (95% CI, 59%-100%). Midline group 4 tumors presented with minimal/no enhancement with a positive predictive value of 91% (95% CI, 59%-98%). When we used the MR imaging feature-based regression model, 66% of medulloblastomas were correctly predicted in the discovery cohort, and 65%, in the validation cohort.Tumor location and enhancement pattern were predictive of molecular subgroups of pediatric medulloblastoma and may potentially serve as a surrogate for genomic testing.

View details for DOI 10.3174/ajnr.A3990

View details for PubMedID 24831600
UNRAVELING THE TALE OF MEDULLOBLASTOMA: IMPACT OF MOLECULAR SUB-TYPE AND CRANIOSPINAL IRRADIATION (CSI) DOSE ON RELAPSE Gibbs, I. C., Partap, S., Yeom, K., Martinez, M., Vogel, H., Donaldson, S. S., Fisher, P., Perreault, S., Cho, Y. OXFORD UNIV PRESS INC. 2014: 82?83
View details for Web of Science ID 000337924200313
Cerebral Biopsies in Posterior "Irreversible'' Encephalopathy Syndrome (PIES) Vogel, H., Ziskin, J., Moes, G. LIPPINCOTT WILLIAMS & WILKINS. 2014: 611
View details for Web of Science ID 000336732100109
Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma. Journal of neuro-oncology Lober, R. M., Cho, Y., Tang, Y., Barnes, P. D., Edwards, M. S., Vogel, H., Fisher, P. G., Monje, M., Yeom, K. W. 2014; 117 (1): 175-182
Abstract

While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-na�ve DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295�נ10(-6)�mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13�months, respectively (log-rank p�<�0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG.

View details for DOI 10.1007/s11060-014-1375-8

View details for PubMedID 24522717
Tectal pineal cyst in a 1-year-old girl. Human pathology Plowey, E. D., Vogel, H., Yeom, K. W., Jung, H., Chao, K., Edwards, M. S. 2014; 45 (3): 653-656
Abstract

Glial cysts of the pineal gland can frequently be found in adults and children, but only rarely do they enlarge to become clinically relevant. We report a unique presentation of a pineal cyst in the midbrain tectum of a 16-month-old girl who initially presented with ptosis and strabismus. Preoperative imaging studies and intraoperative findings revealed no continuity between the tectal cyst and the pineal gland proper. We surmise that this tectal pineal cyst may have arisen from duplicated pineal gland tissue.

View details for DOI 10.1016/j.humpath.2013.10.002

View details for PubMedID 24411061
Pilocytic astrocytoma with IDH1 mutation in the cerebellum of an elderly patient. Clinical neuropathology Medress, Z. A., Xu, L. W., Ziskin, J. L., Lefterova, M., Vogel, H., Li, G. 2014
View details for DOI 10.5414/NP300810

View details for PubMedID 25295857
Atypical teratoid/rhabdoid tumor with ganglioglioma-like differentiation: case report and review of the literature HUMAN PATHOLOGY Krishnan, C., Vogel, H., Perry, A. 2014; 45 (1): 185?88
Abstract

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive embryonal tumor of the central nervous system, which typically affects young children. A characteristic feature of AT/RT is a polyphenotypic immunoprofile and ultrastructural diversity. The morphologic and antigenic heterogeneity of AT/RT give it the potential to mimic other embryonal central nervous system tumors, epithelial neoplasms or mesenchymal tumors. Alternatively, "collision-type" tumors have been published, in which AT/RT coexists with a separate low-grade central nervous system tumor. Here, we report a case of AT/RT with morphologic and immunohistochemical evidence of extensive ganglioglioma-like differentiation with only a small focal primitive component and minimal rhabdoid cytology. Fluorescence in situ hybridization and immunohistochemistry demonstrated INI1/BAF47 gene/protein losses in both histologic components. To the best of our knowledge, this is the first reported case of AT/RT with extensive ganglioglioma-like differentiation. This unique case supports the notion that routine application of INI1 stains/in situ hybridization can capture AT/RT with unexpected patterns of differentiation.

View details for DOI 10.1016/j.humpath.2013.07.039

View details for Web of Science ID 000328800700026

View details for PubMedID 24034858
Endoscopic Resection of a Giant Intradural Retroclival Ecchordosis Physaliphora: Surgical Technique and Literature Review World Neurosurgery Choudhri, O., Feroze, A., Hwang, P., Vogel, H., Ajlan, A., Harsh IV, G. 2014: 912.e21?6
Abstract

To report the first complete resection of a giant ecchordosis physaliphora using an endoscopic transclival approach and to provide a current review of the literature.This rare benign lesion, originating from embryonic notochordal remnants, was located in the prepontine cistern of a 63-year-old man presenting with progressive tremor and imbalance. Preoperative imaging demonstrated a 2.1-cm intradural lesion abutting the pons and basilar artery and extending through the dura mater.A gross total resection was successfully achieved endoscopically without neurovascular compromise or additional complications. Postoperative histopathologic examination was consistent with a diagnosis of giant ecchordosis physaliphora.An endoscopic endonasal transclival approach provided a direct, minimally invasive route for safe and complete resection of this rare prepontine tumor, as it has for similarly located skull base chordomas. Our experience highlights the utility of endoscopy in visualization of both pathologic entities and nearby critical neurovascular structures in the management of ecchordosis physaliphora and other cranial base neoplasms.

View details for DOI 10.1016/j.wneu.2014.06.019
Subventricular spread of diffuse intrinsic pontine glioma. Acta neuropathologica Caretti, V., Bugiani, M., Freret, M., Schellen, P., Jansen, M., van Vuurden, D., Kaspers, G., Fisher, P. G., Hulleman, E., Wesseling, P., Vogel, H., Monje, M. 2014
View details for PubMedID 24929912
MEDULLOBLASTOMA IN THE OPERATIVE THEATER: ARE THEY PLAYING ACCORDING TO THEIR SUBTYPES? Perreault, S., Chao, K., Ramaswamy, V., Shih, D., Remke, M., Luu, B., Schubert, S., Fisher, P., Partap, S., Vogel, H., Taylor, M., Goumnerova, L., Cho, Y. OXFORD UNIV PRESS INC. 2013: 168
View details for Web of Science ID 000327456200666
A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. American journal of medical genetics. Part A Rienhoff, H. Y., Yeo, C., Morissette, R., Khrebtukova, I., Melnick, J., Luo, S., Leng, N., Kim, Y., Schroth, G., Westwick, J., Vogel, H., McDonnell, N., Hall, J. G., Whitman, M. 2013; 161A (8): 2040-2046
Abstract

The transforming growth factor ? (TGF-?) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys-Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-? signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth.

View details for DOI 10.1002/ajmg.a.36056

View details for PubMedID 23824657
Highly proliferative sellar chordoma with unusually rapid recurrence NEUROPATHOLOGY Karamchandani, J., Wu, M., Das, S., Vogel, H., Muller, P., Cusimano, M., Montanera, W., Kovacs, K. 2013; 33 (4): 424?30
Abstract

Chordomas are tumors of notochordal differentiation of low to intermediate grade malignancy. These tumors are typically slow growing, with an indolent but progressive clinical course. We present a case of a highly proliferative chordoma arising in a 73-year-old woman with unusually rapid clinical growth and aggressive histologic and immunohistochemical features. This patient had an unusually brief preclinical course and within 1 month of developing headaches presented to medical attention with diplopia. The resected chordoma showed uncommonly elevated mitotic activity, without the histologic hallmarks of de-differentiation. This proliferative activity correlated with elevated Ki67 staining (60%), B-cell leukemia/lymphoma1 (BCL1) expression (100%), and topoisomerase II? staining (>95%). E-cadherin expression was also lost throughout the majority of the tumor. Other markers of epithelial mesenchymal transition (EMT) including vimentin, N-cadherin, Slug and Twist, were also strongly expressed in this aggressive tumor. The sellar component of the tumor recurred within a 2-month interval. The evaluation of the additional biomarkers, including makers of EMT studied in this, case may allow for identification of aggressive chordomas in which the tempo of disease is significantly more rapid than in typical cases of chordoma.

View details for DOI 10.1111/j.1440-1789.2012.01360.x

View details for Web of Science ID 000322597800006

View details for PubMedID 23082799
Cytochrome Oxidase-Deficient Myofibers as a Function of Age and Disease in 1000 Muscle Biopsies Tanboon, J., Kantipudi, A., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2013: 588?89
View details for Web of Science ID 000319454400187
Siblings with a Novel CHKB Mutation are Identified among Clinically Diverse Patients with Megaconial Myopathy Moore, S., Kunecka, P., Swenson, A., Vogel, H., Lewis, A., Harris, B., Deol, R., Hayashi, Y., Nishino, I., McAllister, J., Pattee, G., McComb, R. LIPPINCOTT WILLIAMS & WILKINS. 2013: 545
View details for Web of Science ID 000319454400027
Spinal pilocytic astrocytoma in an elderly patient. World neurosurgery Harraher, C. D., Vogel, H., Steinberg, G. K. 2013; 79 (5-6): 799 E7-9
Abstract

Astrocytomas are the most common intramedullary spinal cord tumor in pediatric and adolescent patients and the incidence decreases with age. There are very few cases of spinal pilocytic astrocytomas (World Health Organization grade 1) reported after the fourth decade. We report the oldest known case of a pathologically confirmed spinal pilocytic astrocytoma.A 78-year-old woman presented with 12 months of bilateral lower extremity numbness. Magnetic resonance imaging revealed cord edema extending from C6 to T4. There was a 12-mm enhancing intramedullary lesion at the C7-T1 level with an associated cyst. Several years prior, she had seen a neurologist for lower extremity numbness and was diagnosed with peripheral neuropathy.She underwent C7-T1 laminectomy with partial resection of the spinal cord tumor and drainage of the cyst. Pathologic examination demonstrated a mildly cellular proliferation of astrocytes set in an eosinophilic fibrillar background. There were numerous Rosenthal fibers and prominent vasculature. There were no malignant features. The pathologic diagnosis was consistent with pilocytic astrocytoma, World Health Organization grade 1. The patient returned to her baseline function after several weeks and the imaging remained stable at the 4-month follow-up.Spinal pilocytic astrocytomas constitute 90% of intramedullary spinal cord tumors in patients younger than 10 years and 60% of those in adolescent patients. There are very few reported cases in patients older than 50 years. Our patient had an indolent course, cervical-thoracic location, imaging characteristics, and pathology that all support a diagnosis of pilocytic astrocytoma. This case highlights that low-grade lesions can occur in elderly patients and an aggressive approach may not be indicated.

View details for DOI 10.1016/j.wneu.2011.10.033

View details for PubMedID 22120566
Diffusion-Weighted MRI: Distinction of Skull Base Chordoma from Chondrosarcoma. AJNR. American journal of neuroradiology Yeom, K. W., Lober, R. M., Mobley, B. C., Harsh, G., Vogel, H., Allagio, R., Pearson, M., Edwards, M. S., Fischbein, N. J. 2013; 34 (5): 1056-1061
View details for DOI 10.3174/ajnr.A3333

View details for PubMedID 23124635
Spinal Pilocytic Astrocytoma in an Elderly Patient WORLD NEUROSURGERY Harraher, C. D., Vogel, H., Steinberg, G. K. 2013; 79 (5-6)
Abstract

Astrocytomas are the most common intramedullary spinal cord tumor in pediatric and adolescent patients and the incidence decreases with age. There are very few cases of spinal pilocytic astrocytomas (World Health Organization grade 1) reported after the fourth decade. We report the oldest known case of a pathologically confirmed spinal pilocytic astrocytoma.A 78-year-old woman presented with 12 months of bilateral lower extremity numbness. Magnetic resonance imaging revealed cord edema extending from C6 to T4. There was a 12-mm enhancing intramedullary lesion at the C7-T1 level with an associated cyst. Several years prior, she had seen a neurologist for lower extremity numbness and was diagnosed with peripheral neuropathy.She underwent C7-T1 laminectomy with partial resection of the spinal cord tumor and drainage of the cyst. Pathologic examination demonstrated a mildly cellular proliferation of astrocytes set in an eosinophilic fibrillar background. There were numerous Rosenthal fibers and prominent vasculature. There were no malignant features. The pathologic diagnosis was consistent with pilocytic astrocytoma, World Health Organization grade 1. The patient returned to her baseline function after several weeks and the imaging remained stable at the 4-month follow-up.Spinal pilocytic astrocytomas constitute 90% of intramedullary spinal cord tumors in patients younger than 10 years and 60% of those in adolescent patients. There are very few reported cases in patients older than 50 years. Our patient had an indolent course, cervical-thoracic location, imaging characteristics, and pathology that all support a diagnosis of pilocytic astrocytoma. This case highlights that low-grade lesions can occur in elderly patients and an aggressive approach may not be indicated.

View details for DOI 10.1016/j.wneu.2011.10.033

View details for Web of Science ID 000320923300051

View details for PubMedID 22120566
Pituitary stalk Langerhans cell histiocytosis treated with CyberKnife radiosurgery. Clinical neurology and neurosurgery Hong, W., Murovic, J. A., Gibbs, I., Vogel, H., Chang, S. D. 2013; 115 (5): 573-577
Abstract

Langerhans cell histiocytosis (LCH) is a rare idiopathic disease that is characterized by clonal proliferation of Langerhans histiocytes in various parts of the body. These atypical cells have been found to infiltrate single or multiple organs, including bone, lungs, liver, spleen, lymph nodes, and skin. Central nervous system invasion in LCH patients has rarely been reported, especially in the adult population.We describe three histopathologically confirmed cases of adult LCH that involves both the pituitary stalk and hypothalamus, and report our limited experience of such cases in this location that has been treated with CyberKnife radio surgery.The treatment goal of controlling lesion growth is achieved by CyberKnife radiosurgery in this case series. All patients tolerated the treatment well without obvious complications.

View details for DOI 10.1016/j.clineuro.2012.07.004

View details for PubMedID 22835714
Defining and targeting a Glioblastoma cancer stem cell population with EGF Receptor Variant III. Emlet, D. R., Del Vecchio, C., Gupta, P., Mitra, S., Han, S., Holgado-Madruga, M., Li, G., Jensen, K., Vogel, H., Skirboll, S., Wong, A. J. AMER ASSOC CANCER RESEARCH. 2013
View details for DOI 10.1158/1538-7445.AM2013-3733

View details for Web of Science ID 000331220602368
Distinctive MRI Features of Pediatric Medulloblastoma Subtypes AMERICAN JOURNAL OF ROENTGENOLOGY Yeom, K. W., Mobley, B. C., Lober, R. M., Andre, J. B., Partap, S., Vogel, H., Barnes, P. D. 2013; 200 (4): 895-903
Abstract

We hypothesized that the apparent diffusion coefficient (ADC) and other MRI features can be used to predict medulloblastoma histologic subtypes, as defined by the World Health Organization (WHO) in WHO Classification of Tumours of the Central Nervous System.A retrospective review of pediatric patients with medulloblastoma between 1989 and 2011 identified 38 patients with both pretreatment MRI and original pathology slides. The mean and minimum tumor ADC values and conventional MRI features were compared among medulloblastoma histologic subtypes.The cohort of 38 patients included the following histologic subtypes: 24 classic medulloblastomas, nine large cell (LC) or anaplastic medulloblastomas, four desmoplastic medulloblastomas, and one medulloblastoma with extensive nodularity. The median age at diagnosis was 8 years (range, 1-21 years) and the median follow-up time was 33 months (range, 0-150 months). The mean ADC (� 10(-3) mm(2)/s) was lower in classic medulloblastoma (0.733 � 0.046 [SD]) than in LC or anaplastic medulloblastoma (0.935 � 0.127) (Mann-Whitney test, p = 0.004). Similarly, the minimum ADC was lower in classic medulloblastoma (average � SD, 0.464 � 0.056) than in LC or anaplastic medulloblastoma (0.630 � 0.053) (p = 0.004). The MRI finding of focal cysts correlated with the classic and desmoplastic subtypes (Fisher exact test, p = 0.026). Leptomeningeal enhancement positively correlated with the LC or anaplastic medulloblastoma subtype and inversely correlated with the classic medulloblastoma and desmoplastic medulloblastoma subtypes (p = 0.04). Ring enhancement correlated with tumor necrosis (p = 0.022) and with the LC or anaplastic medulloblastoma histologic subtype (p < 0.001).The LC or anaplastic medulloblastoma subtype was associated with increased ADC and with ring enhancement, the latter of which correlated with tumor necrosis. These features could be considered in the evaluation of high-risk medulloblastoma subtypes.

View details for DOI 10.2214/AJR.12.9249

View details for PubMedID 23521467
Pericardial Effusion and Cardiac Tamponade in Neonates: Sudden Unexpected Death Associated with Total Parenteral Nutrition via Central Venous Catheterization ANNALS OF CLINICAL AND LABORATORY SCIENCE Warren, M., Thompson, K. S., Popek, E. J., Vogel, H., Hicks, J. 2013; 43 (2): 163-171
Abstract

Total parenteral nutrition (TPN) via central venous catheter (CVC) is used routinely to provide adequate nutrition for neonates, especially those with very low birth weights (VLBWN). Pericardial effusion and cardiac tamponade (PCE/CT) is a potentially life-threatening CVC complication.This autopsy study presents the gross and histopathologic findings in 5 neonates receiving continuous TPN via CVCs, who suddenly and unexpectedly died from PCECT.The study population included five neonates (age 4-29 days, 3 males, 2 females, 4 VLBWN neonates, 1 full-term neonate). Chemical analysis of the milky-white PCE fluid showed high triglyceride levels (717-777 mg/dL) consistent with intralipid. Right atrial microscopic examination with the four VLBWNs showed interstitial edema and dilated lymphatics (n=4), atrial thrombus (n=1), and focal fibrinous epicardial exudate (n=1). The full-term neonate RA revealed focal myocyte coagulative necrosis, acute organizing hemorrhage, focal collagen deposition, myocardial hypertrophy, and endocardial thickening.Right atria in PCE/CT demonstrated marked interstitial edema and dilated fine vascular channels. Endocardial injury with permeation of hyperosmotic TPN fluid into the interstitium and egress into the pericardial sac is hypothesized as the etiology of PCE/CT. Recognition of PCE and impending CT in neonates with CVCs for TPN with expedient intervention may avoid sudden unexpected deaths.

View details for Web of Science ID 000319103200008

View details for PubMedID 23694791
Meningeal Mast Cells Can Exacerbate Stroke Pathology In Mice Arac, A., Grimbaldeston, M. A., Nepomuceno, A. R., Olayiwola, O., Pereira, M. P., Vogel, H., Tsai, M., Galli, S. J., Bliss, T. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2013
View details for Web of Science ID 000330540200433
Late profound muscle weakness following heart transplantation due to danon disease MUSCLE & NERVE van der Starre, P., Deuse, T., Pritts, C., Brun, C., Vogel, H., Oyer, P. 2013; 47 (1): 135-137
Abstract

Postoperative muscle weakness is a serious complication in surgical intensive care patients. It is mostly described as critical illness polyneuromyopathy. Risk factors include intensive care length of stay, sepsis, poor glycemic control, and combined use of corticosteroids and neuromuscular blocking agents, malnutrition, and electrolyte imbalance.We report a case of late-progressive, profound weakness after heart transplantation for noncompaction cardiomyopathy which required prolonged mechanical ventilation. The patient's muscle strength recovered completely after prolonged rehabilitation.Electromyographic assessment showed myopathy. Muscle biopsy revealed Danon disease, a genetic disorder affecting the lysosomal-associated membrane protein 2 gene (LAMP2).The finding of this genetic disorder was unexpected, because the preoperative echocardiographic diagnosis of noncompaction cardiomyopathy has not been reported in Danon disease. This report underlines the need for early availability of pathology results from the explanted heart, which showed the same disorder.

View details for DOI 10.1002/mus.23517

View details for PubMedID 23168931
Neurogenic Muscle Pathology MUSCLE DISEASE: PATHOLOGY AND GENETICS, 2ND EDITION Vogel, H., Goebel, H. H., Sewry, C. A., Weller, R. O. 2013: 68?77
View details for Web of Science ID 000337166200006
Muscle Disease Associated with Age and Systemic Disorders MUSCLE DISEASE: PATHOLOGY AND GENETICS, 2ND EDITION Vogel, H., Goebel, H. H., Sewry, C. A., Weller, R. O. 2013: 339?50
View details for Web of Science ID 000337166200039
Unimpaired Skin Carcinogenesis in Desmoglein 3 Knockout Mice PLOS ONE Baron, S., Anabel Hoang, A., Vogel, H., Attardi, L. D. 2012; 7 (11)
Abstract

The contribution of adherens junction inactivation, typically by downregulation or mutation of the transmembrane core component E-cadherin, to cancer progression is well recognized. In contrast, the role of the desmosomal cadherin components of the related cell-cell adhesion junction, the desmosome, in cancer development has not been well explored. Here, we use mouse models to probe the functional role of desmosomal cadherins in carcinogenesis. Because mice lacking the desmosomal cadherin Desmoglein 3 (Dsg3) have revealed a crucial role for Dsg3 in cell-cell adhesion in stratified epithelia, we investigate the consequence of Dsg3 loss in two models of skin carcinogenesis. First, using Dsg3-/- keratinocytes, we show that these cells display adhesion defects in vitro and compromised tumor growth in allograft assays, suggesting that Dsg3 enables tumor formation in certain settings. In contrast, using an autochthonous model for SCC development in response to chronic UVB treatment, we discover a surprising lack of enhanced tumorigenesis in Dsg3-/- mice relative to controls, unlike mice lacking the desmosomal component Perp. Accordingly, there is no defect in the apoptotic response to UVB or enhanced immune cell infiltration upon Dsg3 loss that could promote tumorigenesis. Thus, Dsg3 does not display a clear function as a tumor suppressor in these mouse skin cancer models. Continued unraveling of the roles of Dsg3 and other desmosomal constituents in carcinogenesis in different contexts will be important for ultimately improving cancer diagnosis, prognostication, and treatment.

View details for DOI 10.1371/journal.pone.0050024

View details for PubMedID 23185521
DIFFERENT RELAPSE PATTERNS IN EMBRYONAL CNS TUMORS Perreault, S., Lober, R. M., Zhang, G., Hershon, L., Decarie, J., Yeom, K., Vogel, H., Partap, S., Carret, A., Fisher, P. G. OXFORD UNIV PRESS INC. 2012: 123
View details for Web of Science ID 000310971300486
Aggressive Cerebellar Neuroepithelial Tumor in a 10 Year Old Boy Vogel, H., Edwards, M., Fisher, P., Partap, S., Cho, Y. LIPPINCOTT WILLIAMS & WILKINS. 2012: 572
View details for Web of Science ID 000304589600100
SURVEILLANCE SPINE MRIS TO DETECT TUMOR RELAPSE IN PATIENTS WITH MEDULLOBLASTOMA Perreault, S., Lober, R., Yeom, K., Carret, A., Vogel, H., Partap, S., Fisher, P. OXFORD UNIV PRESS INC. 2012: 143
View details for Web of Science ID 000308394400542
Oncogenic variant EGFRvIII defines a hierarchy in glioblastoma and expression is restricted by epigenetic mechanisms despite the presence of gene amplification Del Vecchio, C. A., Giacomini, C. P., Vogel, H., Jensen, K. C., Florio, T., Merlo, A., Pollack, J. R., Wong, A. J. AMER ASSOC CANCER RESEARCH. 2012
View details for DOI 10.1158/1538-7445.AM2012-10

View details for Web of Science ID 000209701604393
Extravascular Papillary Endothelial Hyperplasia Mimicking Neoplasm After Radiosurgery: Case Report NEUROSURGERY Karamchandani, J., Vogel, H., Fischbein, N., Gibbs, I., Edwards, M. S., Harsh, G. 2012; 70 (4): E1043-E1048
Abstract

Papillary endothelial hyperplasia (PEH) is a rare form of exuberant reactive endothelial proliferation that can mimic neoplasm. We report the largest series of patients with histologically confirmed intracranial extravascular PEH developing in the field of previous treatment with stereotactic radiosurgery.We collected the clinical, radiological, surgical, and pathological findings from 4 patients in whom intracranial extravascular PEH developed after treatment with stereotactic radiosurgery. In all patients, the development of an enlarging hemorrhagic mass lesion at the site of previous radiotherapy on magnetic resonance imaging was radiographically suspicious for neoplasm and prompted biopsy or resection. All 4 patients elected to undergo biopsy or surgical resection. Histological examination of the biopsy and resection specimens in all patients demonstrated the classic features of PEH.The interval to the development of PEH ranged from 5 months to 6 years, 10 months. Clinical follow-up was available for 3 of the 4 patients. None of these 3 patients have demonstrated evidence of recurrence during a mean follow-up period of 22 months (range, 15-30 months). These patients share common radiological features, potentially allowing preoperative diagnosis and improved guidance of clinical management. These cases suggest a link between radiosurgery and the development of PEH. These findings also suggest that PEH should be considered in the differential diagnosis for patients treated with radiosurgery in whom a hemorrhagic mass lesion subsequently develops at or near the site of previous treatment. We think that complete surgical excision is the best treatment for intracranial PEH.

View details for DOI 10.1227/NEU.0b013e31822e81f9

View details for PubMedID 22426048
Chordoma: An Ongoing Challenge AJSP-REVIEWS AND REPORTS Vogel, H. 2012; 17 (1): 31?38
View details for DOI 10.1097/PCR.0b013e31824991bd

View details for Web of Science ID 000218355800006
SUPRATENTORIAL SPREAD IN THE NEUROGENIC NICHE OF DIFFUSE INTRINSIC PONTINE GLIOMA Monje, M., Freret, M. E., Masek, M., Fisher, P. G., Haddix, T., Vogel, H. OXFORD UNIV PRESS INC. 2011: 4?5
View details for Web of Science ID 000297026600019
Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway JOURNAL OF EXPERIMENTAL MEDICINE Viatour, P., Ehmer, U., Saddic, L. A., Dorrell, C., Andersen, J. B., Lin, C., Zmoos, A., Mazur, P. K., Schaffer, B. E., Ostermeier, A., Vogel, H., Sylvester, K. G., Thorgeirsson, S. S., Grompe, M., Sage, J. 2011; 208 (10): 1963-1976
Abstract

Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.

View details for DOI 10.1084/jem.20110198

View details for PubMedID 21875955
Gene-protein correlation in single cells NEURO-ONCOLOGY Renfrow, J. J., Scheck, A. C., Dhawan, N. S., Lukac, P. J., Vogel, H., Chandler, J. P., Raizer, J. J., Harsh, G. R., Chakravarti, A., Bredel, M. 2011; 13 (8): 880-885
Abstract

We present a novel methodology combining traditional fluorescent in situ hybridization with an in situ protein detection technology called proximity ligation assay. This method has potential to perform a detailed analysis of the relationship between gene status and corresponding protein expression in cells and tissues. We demonstrate that the fluorescent in situ gene protein assay methodology is capable of resolving gene and protein patterns simultaneously on a cell-by-cell basis.

View details for DOI 10.1093/neuonc/nor071

View details for Web of Science ID 000293820900008

View details for PubMedID 21798849

View details for PubMedCentralID PMC3145472
Mosaic Analysis with Double Markers Reveals Tumor Cell of Origin in Glioma CELL Liu, C., Sage, J. C., Miller, M. R., Verhaak, R. G., Hippenmeyer, S., Vogel, H., Foreman, O., Bronson, R. T., Nishiyama, A., Luo, L., Zong, H. 2011; 146 (2): 209-221
Abstract

Cancer cell of origin is difficult to identify by analyzing cells within terminal stage tumors, whose identity could be concealed by the acquired plasticity. Thus, an ideal approach to identify the cell of origin is to analyze proliferative abnormalities in distinct lineages prior to malignancy. Here, we use mosaic analysis with double markers (MADM) in mice to model gliomagenesis by initiating concurrent p53/Nf1 mutations sporadically in neural stem cells (NSCs). Surprisingly, MADM-based lineage tracing revealed significant aberrant growth prior to malignancy only in oligodendrocyte precursor cells (OPCs), but not in any other NSC-derived lineages or NSCs themselves. Upon tumor formation, phenotypic and transcriptome analyses of tumor cells revealed salient OPC features. Finally, introducing the same p53/Nf1 mutations directly into OPCs consistently led to gliomagenesis. Our findings suggest OPCs as the cell of origin in this model, even when initial mutations occur in NSCs, and highlight the importance of analyzing premalignant stages to identify the cancer cell of origin.

View details for DOI 10.1016/j.cell.2011.06.014

View details for Web of Science ID 000293013000005

View details for PubMedID 21737130

View details for PubMedCentralID PMC3143261
Liposomal cytarabine for central nervous system embryonal tumors in children and young adults JOURNAL OF NEURO-ONCOLOGY Partap, S., Murphy, P. A., Vogel, H., Barnes, P. D., Edwards, M. S., Fisher, P. G. 2011; 103 (3): 561-566
Abstract

To assess the tolerability and efficacy of liposomal cytarabine (LC), an encapsulated, sustained-release, intrathecal (IT) formulation of cytosine arabinoside, in de novo and relapsed central nervous system (CNS) embryonal tumors in children and young adults. We studied retrospectively all patients less than age 30 at our institution treated consecutively with LC for medulloblastoma (MB), primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Seventeen patients received LC (2 mg/kg up to 50 mg, every 2 weeks to monthly) at diagnosis of high-risk CNS embryonal tumor (2 PNET, 3 ATRT) or relapse of MB (12 MB; 9 had leptomeningeal metastases). Sixteen patients received concurrent systemic chemotherapy. A total of 108 doses were administered (IT 82, intraventricular 26) with a mean of six (range 1-16) treatments per patient. Only three administrations were associated with adverse effects of arachnoiditis or headache. None developed malignant cerebrospinal fluid (CSF) cytology while receiving LC. All the six evaluable patients with malignant CSF cytology and treated with at least two doses cleared their CSF (mean 3 doses, range 1-5). Median overall survival in relapse patients was 9.1 months. Five patients (4 de novo and 1 relapsed) remain alive in complete remission for a median 26.8 months from first LC. Liposomal cytarabine is an easily administered, well-tolerated, and active drug in patients with high-risk embryonal neoplasms. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of LC in newly diagnosed or recurrent CNS embryonal tumors.

View details for DOI 10.1007/s11060-010-0419-y

View details for PubMedID 20859651
Alpha-fetoprotein-thymidine kinase-luciferase knockin mice: A novel model for dual modality longitudinal imaging of tumorigenesis in liver JOURNAL OF HEPATOLOGY Lu, X., Guo, H., Molter, J., Miao, H., Gerber, L., Hu, Y., Barnes, E. L., Vogel, H., Lee, Z., Luo, G., Wang, B. 2011; 55 (1): 96-102
Abstract

Hepatocellular carcinoma (HCC) is frequently a lethal disease and one of the few malignancies that is still increasing in incidence around the world. Better animal models are highly desired to investigate the molecular basis of HCC and to develop novel therapeutic strategies. Alpha-fetoprotein (Afp) gene is expressed in fetal liver, silenced soon after birth, and highly re-expressed in hepatocellular carcinomas (HCC). We aimed to take advantage of the dramatic re-expression of the Afp gene in HCC to develop a hepatocarcinogenesis reporter (HCR) mouse model for dual-modality, longitudinal in vivo imaging of liver tumor development, and progression.Knock in mice were established by placing a thymidinekinase (tk)-luciferase (luc) reporter gene cassette under the transcriptional control of the endogenous Afp promoter. DEN, a liver carcinogen, was used to induce liver tumors, which was monitored by both luc-based bioluminescent (BL) and tk-based positron emission tomography (PET) imaging.The expression profile of luc was identical to that of the endogenous Afp gene during development. As early as 2 months after the exposure to DEN, BLI revealed multifocal signals in the liver, long before the appearance of histologically apparent neoplastic lesions. By 6 months, BL and PET dual imaging showed strong signals in malignant HCC. By serendipity, a strong BL signal was also detected in adult testes, a previously unknown site of Afp expression.The HCR model enables longitudinal monitoring of liver tumor development and progression, providing a powerful tool in developing chemoprevention and therapeutic strategies for HCC.

View details for Web of Science ID 000292488800015

View details for PubMedID 21354236

View details for PubMedCentralID PMC3465678
The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor ONCOGENE Renault, V. M., Thekkat, P. U., Hoang, K. L., WHITE, J. L., Brady, C. A., Broz, D. K., Venturelli, O. S., Johnson, T. M., Oskoui, P. R., Xuan, Z., Santo, E. E., Zhang, M. Q., Vogel, H., Attardi, L. D., Brunet, A. 2011; 30 (29): 3207-3221
Abstract

FoxO transcription factors have a conserved role in longevity, and act as tissue-specific tumor suppressors in mammals. Several nodes of interaction have been identified between FoxO transcription factors and p53, a major tumor suppressor in humans and mice. However, the extent and importance of the functional interaction between FoxO and p53 have not been fully explored. Here, we show that p53 regulates the expression of FoxO3, one of the four mammalian FoxO genes, in response to DNA damaging agents in both mouse embryonic fibroblasts and thymocytes. We find that p53 transactivates FoxO3 in cells by binding to a site in the second intron of the FoxO3 gene, a genomic region recently found to be associated with extreme longevity in humans. While FoxO3 is not necessary for p53-dependent cell cycle arrest, FoxO3 appears to modulate p53-dependent apoptosis. We also find that FoxO3 loss does not interact with p53 loss for tumor development in vivo, although the tumor spectrum of p53-deficient mice appears to be affected by FoxO3 loss. Our findings indicate that FoxO3 is a p53 target gene, and suggest that FoxO3 and p53 are part of a regulatory transcriptional network that may have an important role during aging and cancer.

View details for DOI 10.1038/onc.2011.35

View details for Web of Science ID 000293006800001

View details for PubMedID 21423206

View details for PubMedCentralID PMC3136551
Diffuse Astrocytomas of the Childhood Spinal Cord: Correlation Between Incidence and Presence of a Neural Precursor Cell Type Freret, M., Monje, M., Masek, M., Fisher, P., Vogel, H., Beachy, P. LIPPINCOTT WILLIAMS & WILKINS. 2011: 530
View details for Web of Science ID 000290751700128
Supratentorial Extension of Diffuse Intrinsic Pontine Glioma (DIPG) Haddix, T., Monje, M., Masek, M., Freret, M., Fisher, P., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: 509?10
View details for Web of Science ID 000290751700053
Functional Interactions between Retinoblastoma and c-MYC in a Mouse Model of Hepatocellular Carcinoma PLOS ONE Saddic, L. A., Wirt, S., Vogel, H., Felsher, D. W., Sage, J. 2011; 6 (5)
Abstract

Inactivation of the RB tumor suppressor and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Loss of RB function and MYC activation are thought to control both overlapping and distinct cellular processes during cell cycle progression. However, how these two major cancer genes functionally interact during tumorigenesis is still unclear. Here, we sought to test whether loss of RB function would affect cancer development in a mouse model of c-MYC-induced hepatocellular carcinoma (HCC), a deadly cancer type in which RB is frequently inactivated and c-MYC often activated. We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC. However, combined loss of RB and activation of c-MYC led to an increase in polyploidy in mature hepatocytes before the development of tumors. There was a trend for decreased survival in double mutant animals compared to mice developing c-MYC-induced tumors. Thus, loss of RB function does not provide a proliferative advantage to c-MYC-expressing HCC cells but the RB and c-MYC pathways may cooperate to control the polyploidy of mature hepatocytes.

View details for DOI 10.1371/journal.pone.0019758

View details for PubMedID 21573126
Brain Abscess Caused by Phaeoacremonium parasiticum in an Immunocompromised Patient JOURNAL OF CLINICAL MICROBIOLOGY McNeil, C. J., Luo, R. F., Vogel, H., Banaei, N., Ho, D. Y. 2011; 49 (3): 1171-1174
Abstract

Phaeoacremonium parasiticum is an environmental fungus usually associated with subcutaneous infections. We report the first documented case of central nervous system involvement with brain abscess formation in a patient with chronic granulomatous disease and review the literature on Phaeoacremonium parasiticum infections.

View details for DOI 10.1128/JCM.00830-10

View details for PubMedID 21191052
Endocervical Fibroblastic Malignant Peripheral Nerve Sheath Tumor (Neurofibrosarcoma): Report of a Novel Entity Possibly Related to Endocervical CD34 Fibrocytes AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mills, A. M., Karamchandani, J. R., Vogel, H., Longacre, T. A. 2011; 35 (3): 404-412
Abstract

Primary cervical stromal sarcomas are rare neoplasms that have been poorly characterized. We report the clinical, histologic, and immunohistologic features of 3 primary endocervical S100 protein (S100p)-positive and CD34-positive sarcomas, herein designated as fibroblastic malignant peripheral nerve sheath sarcoma (endocervical neurofibrosarcoma), 2 of which occurred in women younger than 35 years of age. All tumors presented as a cervical polyp or mass lesion; 1 extended into the pelvic side wall and vaginal soft tissue. The tumors measured 2.0 to 8.0 cm, and were composed of compact fascicles of spindled cells arranged in herringbone, loose fascicular, or ill-defined storiform patterns. A focal whorled architecture was identified in all 3 tumors, but distinct Antoni A areas and Verocay bodies were absent. Ultrastructural examination in 1 case confirmed the presence of fibrocyte-like differentiation. Strong, diffuse, and in 1 case, patchy S100p expression was seen in all cases; strong and diffuse CD34 expression was also present in all tumors. Adjacent uninvolved endocervical stroma also showed CD34 positivity but expression was much less dramatic than in tumor cells. All other markers of neural, melanocytic, smooth muscle, endometrial stromal, and epithelial differentiation were negative. One of the tumors behaved extremely aggressively with extensive pelvic involvement, resulting in patient death within 16 months of diagnosis; another tumor was associated with pelvic recurrence 13 months after diagnosis; and the third tumor had an indolent course with no evidence of recurrence at 33 months after complete excision and local radiotherapy, although follow-up was limited. Review of large numbers of mesenchymal tumors in the uterus did not show similar tumors. Endocervical neurofibrosarcoma should be distinguished from solitary fibrous tumor, endometrial stromal sarcoma, leiomyosarcoma, melanoma, and other spindle cell neoplasms. The prominent fibroblastic endoneurial-like differentiation seen in this peripheral nerve sheath tumor may be related to the presence of a rich mucosal stromal fibrocyte network in the endocervix.

View details for DOI 10.1097/PAS.0b013e318208f72e

View details for PubMedID 21317712
Delta Np630 alpha Is an Oncogene that Targets Chromatin Remodeler Lsh to Drive Skin Stem Cell Proliferation and Tumorigenesis CELL STEM CELL Keyes, W. M., Pecoraro, M., Aranda, V., Vernersson-Lindahl, E., Li, W., Vogel, H., Guo, X., Garcia, E. L., Michurina, T. V., Enikolopov, G., Muthuswamy, S. K., Mills, A. A. 2011; 8 (2): 164-176
Abstract

The p53 homolog p63 is essential for development, yet its role in cancer is not clear. We discovered that p63 deficiency evokes the tumor-suppressive mechanism of cellular senescence, causing a striking absence of stratified epithelia such as the skin. Here we identify the predominant p63 isoform, ?Np63?, as a protein that bypasses oncogene-induced senescence to drive tumorigenesis in�vivo. Interestingly, bypass of senescence promotes stem-like proliferation and maintains survival of the keratin 15-positive stem cell population. Furthermore, we identify the chromatin-remodeling protein Lsh as a new target of ?Np63? that is an essential mediator of senescence bypass. These findings indicate that ?Np63? is an oncogene that cooperates with Ras to promote tumor-initiating stem-like proliferation and suggest that Lsh-mediated chromatin-remodeling events are critical to this process.

View details for DOI 10.1016/j.stem.2010.12.009

View details for Web of Science ID 000287633400010

View details for PubMedCentralID PMC4373450
Isocitrate Dehydrogenase 1 (IDH1)R132H Mutation Is Not Detected in Angiocentric Glioma 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology Raghunathan, A., Olar, A., Vogel, H., Parker, J. R., Coventry, S. C., Debski, R., Albarracin, C. T., Aldape, K. D., Cahill, D. P., Powell, S. Z., Fuller, G. N. NATURE PUBLISHING GROUP. 2011: 384A?384A
View details for Web of Science ID 000287282302077
Isocitrate Dehydrogenase 1 (IDH1) R132H Mutation Is Not Detected in Angiocentric Glioma 100th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Raghunathan, A., Olar, A., Vogel, H., Parker, J. R., Coventry, S. C., Debski, R., Albarracin, C. T., Aldape, K. D., Cahill, D. P., Powell, S. Z., Fuller, G. N. NATURE PUBLISHING GROUP. 2011: 384A?384A
View details for Web of Science ID 000291285001287
Extravascular Papillary Endothelial Hyperplasia Mimicking Neoplasm Following Radiosurgery. Neurosurgery Karamchandani, J., Vogel, H., Fischbein, N., Gibbs, I., Edwards, M. S., Harsh, G. 2011
Abstract

BACKGROUND AND IMPORTANCE:: Papillary endothelial hyperplasia (PEH) is a rare form of exuberant reactive endothelial proliferation that can mimic neoplasm. We report the largest series of patients with histologically confirmed intracranial extravascular PEH developing in the field of prior treatment with stereotactic radiosurgery. CLINICAL PRESENTATION:: We collected the clinical, radiological, surgical, and pathologic findings in four cases of patients who developed intracranial extravascular PEH following treatment with stereotactic radiosurgery. In all cases the development of an enlarging hemorrhagic mass lesion in the site of prior radiotherapy on MRI was radiographically suspicious for neoplasm and prompted biopsy or resection. In all four cases the patients elected to undergo biopsy or surgical resection. Histologic examination of the biopsy and resection specimens in all cases demonstrated the classic features of PEH. CONCLUSION:: The interval to the development of PEH ranged from five months to six years and ten months. Clinical follow up was available for three of the four patients. None of these three patients has demonstrated evidence of recurrence during a mean follow-up period of 22 months (15-30 months). These cases share common radiological features, potentially allowing for pre-operative diagnosis and improved guidance of clinical management. These cases suggest a link between radiosurgery and the development of PEH. These findings also suggest that PEH should be considered in the differential diagnosis for patients treated with radiosurgery who subsequently develop a hemorrhagic mass lesion at or near the site of prior treatment. We think that complete surgical excision is the best treatment for intracranial PEH.

View details for DOI 10.1227/NEU.0b013e31822e81f9

View details for PubMedID 21937944
Primary Pediatric Skull Tumors PEDIATRIC NEUROSURGERY Gephart, M. G., Colglazier, E., Paulk, K. L., Vogel, H., Guzman, R., Edwards, M. S. 2011; 47 (3): 198-203
Abstract

To review the pathological distribution of pediatric primary skull tumors, and to determine the diagnostic value of lesion location, patient age and lesion size.A retrospective chart review identified 51 consecutive pediatric patients with 54 primary skull tumors, treated between 2005 and 2010.The most common diagnoses were dermoid cysts (n = 34) and fibrous dysplasia (n = 5). While dermoid tumors could reside anywhere (sensitivity = 0.41), a midline lesion had a specificity of 0.9 and a positive predictive value of 0.88. All of the fibrous dysplasia lesions were laterally placed, with a negative predictive value (NPV) of 1. Patient age < or >5 years had a high sensitivity and NPV for dermoid cysts and fibrous dysplasia, respectively. Size appeared to be sensitive (0.91, 0.8), but not specific (0.6, 0.78), with good NPV (0.8, 0.97) when considering dermoid cysts (?2 cm) or fibrous dysplasia (>2 cm), respectively.Dermoid cysts followed by fibrous dysplasia are the most common primary skull tumors. Lesion location, patient age and lesion size give important clues as to the diagnosis. For the majority of cases, a clinical diagnosis based on CT is sufficient for presurgical evaluation.

View details for DOI 10.1159/000330544

View details for PubMedID 22301489
ECTOPIC ACROMEGALY DUE TO A PANCREATIC NEUROENDOCRINE TUMOR PRODUCING GROWTH HORMONE-RELEASING HORMONE ENDOCRINE PRACTICE Weiss, D. E., Vogel, H., Lopes, M. B., Chang, S. D., Katznelson, L. 2011; 17 (1): 79-84
Abstract

To present a case of acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion from a pancreatic neuroendocrine tumor in the context of multiple endocrine neoplasia type 1 (MEN 1).We describe the clinical, imaging, and pathologic findings of the study patient.A 46-year-old woman presented with clinical and biochemical findings diagnostic of acromegaly. Magnetic resonance imaging showed a 1.2-cm sellar mass. Following resection of the macroadenoma, serum insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels remained unchanged. Pathologic examination revealed adenomatous changes, including a nonsecretory focus and a prolactin immunopositive area (GH stain negative in both). Octreotide long-acting release was ineffective. Search for an ectopic tumor included normal octreoscan and abdominal computed tomography. GHRH was greater than 1000 pg/mL. Repeated abdominal computed tomography documented a 6.2-cm mass in the tail and body of the pancreas. Distal pancreatectomy revealed a pancreatic neuroendocrine tumor that stained positive for GHRH. Postoperatively, serum GHRH and IGF-1 normalized. Re-evaluation of the initial pituitary pathologic specimen revealed additional somatotroph hyperplasia of the adjacent, normal pituitary gland. Primary hyperparathyroidism was diagnosed, and multigland parathyroid hyperplasia was noted at surgery. Genetic testing was positive for a mutation in the MEN1 gene.This patient's acromegaly was resistant to somatostatin analogue therapy, reflecting the negative octreoscan imaging. In addition, this case is novel because the patient presented with pituitary adenomatous changes, which were presumably associated with MEN 1 and/or possibly the elevated GHRH levels.

View details for DOI 10.4158/EP10165.CR

View details for PubMedID 20713338
NOVEL POPULATION OF NEURAL STEM CELLS IN THE VENTRAL PONS DURING CHILDHOOD AS A CANDIDATE CELL OF ORIGIN FOR DIFFUSE INTRINSIC PONTINE GLIOMA Monje, M., Freret, M., Masek, M., Edwards, M. S., Fisher, P. G., Vogel, H., Beachy, P. OXFORD UNIV PRESS INC. 2010: 127
View details for Web of Science ID 000285082400541
AN RNAI SCREEN IDENTIFIES TRRAP AS A REGULATOR OF BRAIN TUMOR-INITIATING CELL DIFFERENTIATION Advances in Inflammatory Bowel Diseases Crohn's and Colitis Foundations National Clinical and Research Conference Skirboll, S. L., Wurdak, H., Zhu, S., Romero, A., Lorger, M., Watson, J., Chiang, C., Zhang, J., Natu, V. S., Lairson, L. L., Walker, J. R., Trussell, C. M., Harsh, G. R., Vogel, H., Felding-Habermann, B., Orth, A. P., Miraglia, L. J., Rines, D. R., Schultz, P. G. OXFORD UNIV PRESS INC. 2010: 122?122
View details for Web of Science ID 000285082400517
Langerhans cell histiocytosis in a 5-month-old presenting with biparietal masses Case report JOURNAL OF NEUROSURGERY-PEDIATRICS Pricola, K. L., Karamchandani, J., Vogel, H., Dahl, G. V., Yeom, K. W., Edwards, M. S., Guzman, R. 2010; 6 (4): 393-397
Abstract

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder that occurs most commonly in the pediatric population as a result of pathological clonal proliferation of Langerhans cells with subsequent damage and destruction to surrounding tissue. Clinically, LCH presents in a variety of ways, which often results in prolonged time to diagnosis and subsequently poorer outcomes. In this case report, the authors describe an unusually early presentation of multisystem LCH in a patient at birth, which resulted in a 5-month delay to diagnosis and treatment. This patient presented both atypically young and with an uncommon initial manifestation of multisystem disease with multiple soft-tissue swellings rather than early skin involvement. Additionally, this patient had an unusual radiographic appearance with biparietal skull destruction on initial skull radiographs and biparietal soft-tissue lesions on CT resembling cephalohematoma at 3 months of age. The clinical and radiological evaluation, pathology, and treatment strategies are discussed, with particular attention paid to the importance of further workup of atypical nonresolving cephalohematomas to prevent disease progression and poorer outcomes.

View details for DOI 10.3171/2010.7.PEDS10149

View details for PubMedID 20887116
Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis PLOS GENETICS Beaudry, V. G., Jiang, D., Dusek, R. L., Park, E. J., Knezevich, S., Ridd, K., Vogel, H., Bastian, B. C., Attardi, L. D. 2010; 6 (10)
Abstract

Dysregulated cell-cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell-cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

View details for DOI 10.1371/journal.pgen.1001168

View details for PubMedID 20975948
Retrosellar intracranial extracerebral glioneuronal heterotopion: case report CLINICAL NEUROPATHOLOGY Karamchandani, J., Fischbein, N., Harsh, G., Katznelson, L., Vogel, H. 2010; 29 (5): 297-300
Abstract

We report the case of an 18-year-old woman with an intradural retroclival retrosellar glioneuronal heterotopion. At the time of surgery, a well circumscribed pale-tan mass was identified posterior to and distinct from the posterior pituitary. Pathologic examination showed disorganized, non-neoplastic glial tissue characteristic of glioneuronal heterotopia. To our knowledge, this is the first report of such a lesion in this location.

View details for Web of Science ID 000281967000004

View details for PubMedID 20860892
Recurrent Pediatric Ganglion Cell Tumors Mobley, B., Minn, Y., Yeom, K., Fisher, P., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2010: 537?38
View details for Web of Science ID 000277571500074
Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice JOURNAL OF CLINICAL INVESTIGATION Kioi, M., Vogel, H., Schultz, G., Hoffman, R. M., Harsh, G. R., Brown, J. M. 2010; 120 (3): 694-705
Abstract

Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b+ myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.

View details for DOI 10.1172/JCI40283

View details for PubMedID 20179352
Breast cancer brain metastases express the sodium iodide symporter JOURNAL OF NEURO-ONCOLOGY Renier, C., Vogel, H., Offor, O., Yao, C., Wapnir, I. 2010; 96 (3): 331-336
Abstract

Breast cancer brain metastases are on the rise and their treatment is hampered by the limited entry and efficacy of anticancer drugs in this sanctuary. The sodium iodide symporter, NIS, actively transports iodide across the plasma membrane and is exploited clinically to deliver radioactive iodide into cells. As in thyroid cancers, NIS is expressed in many breast cancers including primary and metastatic tumors. In this study NIS expression was analyzed for the first time in 28 cases of breast cancer brain metastases using a polyclonal anti-NIS antibody directed against the terminal C-peptide of human NIS gene and immunohistochemical methods. Twenty-five tumors (84%) in this retrospective series were estrogen/progesterone receptor-negative and 15 (53.6%) were HER2+. Overall 21 (75%) cases and 80% of HER2 positive metastases were NIS positive. While the predominant pattern of NIS immunoreactivity is intracellular, plasma membrane immunopositivity was detected at least focally in 23.8% of NIS-positive samples. Altogether, these findings indicate that NIS expression is prevalent in breast cancer brain metastases and could have a therapeutic role via the delivery of radioactive iodide and selective ablation of tumor cells.

View details for DOI 10.1007/s11060-009-9971-8

View details for PubMedID 19618116
Timing of Bone Marrow Cell Delivery Has Minimal Effects on Cell Viability and Cardiac Recovery After Myocardial Infarction CIRCULATION-CARDIOVASCULAR IMAGING Swijnenburg, R., Govaert, J. A., van der Bogt, K. E., Pearl, J. I., Huang, M., Stein, W., Hoyt, G., Vogel, H., Contag, C. H., Robbins, R. C., Wu, J. C. 2010; 3 (1): 77-U109
Abstract

Despite ongoing clinical trials, the optimal time for delivery of bone marrow mononuclear cells (BMCs) after myocardial infarction is unclear. We compared the viability and effects of transplanted BMCs on cardiac function in the acute and subacute inflammatory phases of myocardial infarction.The time course of acute inflammatory cell infiltration was quantified by FACS analysis of enzymatically digested hearts of FVB mice (n=12) after left anterior descending artery ligation. Mac-1(+)Gr-1(high) neutrophil infiltration peaked at day 4. BMCs were harvested from transgenic FVB mice expressing firefly luciferase (Fluc) and green fluorescent protein (GFP). Afterward, 2.5x10(6) BMCs were injected into the left ventricle of wild-type FVB mice either immediately (acute BMC) or 7 days (subacute BMC) after myocardial infarction, or after a sham procedure (n=8 per group). In vivo bioluminescence imaging showed an early signal increase in both BMC groups at day 7, followed by a nonsignificant trend (P=0.203) toward improved BMC survival in the subacute BMC group that persisted until the bioluminescence imaging signal reached<0.01) and 6 weeks (both BMC groups versus saline; P<0.05) but no significant differences between the 2 BMC groups. FACS analysis of BMC-injected hearts at day 7 revealed that GFP(+) BMCs expressed hematopoietic (CD45, Mac-1, Gr-1), minimal progenitor (Sca-1, c-kit), and no endothelial (CD133, Flk-1) or cardiac (Trop-T) cell markers.Timing of BMC delivery has minimal effects on intramyocardial retention and preservation of cardiac function. In general, there is poor long-term engraftment and BMCs tend to adopt inflammatory cell phenotypes.

View details for DOI 10.1161/CIRCIMAGING.109.872085

View details for PubMedID 19920031
An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell Differentiation CELL STEM CELL Wurdak, H., Zhu, S., Romero, A., Lorger, M., Watson, J., Chiang, C., Zhang, J., Natu, V. S., Lairson, L. L., Walker, J. R., Trussell, C. M., Harsh, G. R., Vogels, H., Feld-Habermann, B., Orth, A. P., Miraglia, L. J., Rines, D. R., Skirboll, S. L., Schultz, P. G. 2010; 6 (1): 37-47
Abstract

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.

View details for DOI 10.1016/j.stem.2009.11.002

View details for Web of Science ID 000274029700010

View details for PubMedID 20085741
The Lysosomal Sialic Acid Transporter Sialin Is Required for Normal CNS Myelination JOURNAL OF NEUROSCIENCE Prolo, L. M., Vogel, H., Reimer, R. J. 2009; 29 (49): 15355-15365
Abstract

Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane protein that transports free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders, and the clinical phenotype is characterized by neurodevelopmental defects, including severe CNS hypomyelination. In this study, we used a sialin-deficient mouse to address how loss of sialin leads to the defect in myelination. Behavioral analysis of the sialin(-/-) mouse demonstrates poor coordination, seizures, and premature death. Analysis by histology, electron microscopy, and Western blotting reveals a decrease in myelination of the CNS but normal neuronal cytoarchitecture and normal myelination of the PNS. To investigate potential mechanisms underlying CNS hypomyelination, we studied myelination and oligodendrocyte development in optic nerves. We found reduced numbers of myelinated axons in optic nerves from sialin(-/-) mice, but the myelin that was present appeared grossly normal. Migration and density of oligodendrocyte precursor cells were normal; however, a marked decrease in the number of postmitotic oligodendrocytes and an associated increase in the number of apoptotic cells during the later stages of myelinogenesis were observed. These findings suggest that a defect in maturation of cells in the oligodendrocyte lineage leads to increased apoptosis and underlies the myelination defect associated with sialin loss.

View details for DOI 10.1523/JNEUROSCI.3005-09.2009

View details for PubMedID 20007460
Intraventricular metaplastic meningioma in a child: case report and review of the literature NEUROPATHOLOGY Dulai, M. S., Khan, A., Edwards, M. S., Vogel, H. 2009; 29 (6): 708-712
Abstract

Childhood meningiomas are rare and display important differences from adult forms. We report the first case of an intraventricular metaplastic meningioma arising in a child. A 7-year-old female underwent resection of an enhancing tumor arising within the left lateral ventricle. It was composed of monomorphic cells embedded within an abundant myxoid stroma. The cells demonstrated epithelial membrane antigen and vimentin immunoreactivity. Ultrastructural analysis demonstrated intermediate filaments, complex intercellular interdigitations and desmosomes, and a diagnosis of myxoid (metaplastic) meningioma was rendered. This case reflects the higher incidence of intraventricular meningiomas in childhood and greater incidence of intraventricular meningiomas in the left lateral ventricle. Recognition of the grade I myxoid meningioma in this case is paramount since chordoid meningiomas, which share similar histologic features, are of a higher grade and worse prognosis.

View details for DOI 10.1111/j.1440-1789.2009.01008.x

View details for PubMedID 19389075
Papillary Tumor of the Spinal Cord Report of 2 Cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mobley, B., Kalani, M. S., Harsh, G. R., Edwards, M. S., Vogel, H. 2009; 33 (8): 1191-1197
Abstract

Intramedullary spinal cord tumors constitute a small fraction of central nervous system tumors in the pediatric population; of these, the majority are ependymomas or astrocytomas. We report 2 pediatric spinal cord tumor cases with unique morphologic and immunohistochemical features. The first patient presented at age 7 with an intramedullary tumor of the thoracic spine. She suffered lumbar, cerebellar, and temporal lobe recurrences despite surgical resection and radiation. The second patient presented at age 17 with an intramedullary tumor of the cervical spine. The tumor recurred locally and in the cerebellum. Magnetic resonance imaging studies demonstrated gadolinium enhancement in each case. Microscopy showed papillary and solid cytoarchitecture with monomorphous epithelioid cells arranged around vascular papillae. Immunohistochemistry in each case revealed diffuse epithelial membrane antigen, cytokeratin, and E-cadherin reactivity. Glial fibrillary acidic protein staining was focal in case 1 and completely negative in case 2. Neural cell adhesion molecule showed patchy membranous reactivity and synaptophysin was negative. Electron microscopy showed ependymal differentiation. The clinical features, including propensity for recurrence and remote subarachnoid spread, and the pathologic features of these tumors are reminiscent of papillary tumor of the pineal region, ependymoma, and choroid plexus papilloma. The cases presented may constitute a new neoplastic entity within the recently described spectrum of central nervous system tumors with ependymal features.

View details for PubMedID 19417584
Unlike p53, p27 failed to exhibit an anti-tumor genetic interaction with Ku80 CELL CYCLE Holcomb, V. B., Vogel, H., Hasty, P. 2009; 8 (15): 2463?66
Abstract

Ku80 is often referred to as a tumor suppressor since it maintains the genome by repairing DNA double-strand breaks (DSBs) via the nonhomologous end joining (NHEJ) pathway. Even though Ku80 deletion causes hypersensitivity to gamma-radiation, DNA damage and chromosomal rearrangements, Ku80-mutant mice exhibit very low cancer levels. We previously hypothesized these low cancer levels were caused by enhanced cell cycle checkpoints that responded to inefficiently repaired DNA damage because Ku80-mutant fibroblasts exhibit premature cellular senescence that was dependent on a p53-mediated DNA damage response. In addition, Ku80 and p53 show a genetic interaction to suppress pro-B cell lymphoma and medulloblastoma. Here we tested for a similar anti-tumor genetic interaction between Ku80 and the cyclin kinase inhibitor, p27(Kip1) (p27) since p27 mutant mice showed elevated levels of pituitary adenoma that were exacerbated by gamma-radiation-induced DNA damage (damage repaired by Ku80). We found that deleting both Ku80 and p27 did not exacerbate cancer as compared to either single mutant. In addition, fibroblasts deleted for both exhibited premature cellular senescence similar to Ku80-mutant fibroblasts. Thus, p27 did not exhibit an obvious genetic interaction with Ku80 to suppress tumors. This observation suggests that DNA damage (or DNA damage responses) induced by either gamma-radiation or Ku80 deletion are not equivalent since gamma-radiation exacerbates oncogenesis in mice deleted for either p53 or p27 while Ku80 deletion exacerbates oncogenesis for only the former genotype.

View details for DOI 10.4161/cc.8.15.9249

View details for Web of Science ID 000268535700031

View details for PubMedID 19597334
Primary T-cell Lymphoma of the CNS Expressing PD-1, a Marker of Germinal Center T-cells Karamchandani, J., Moes, G., Guppy, K., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2009: 589?90
View details for Web of Science ID 000265758600156
Distinguishing Chordoid Meningiomas From Their Histologic Mimics An Immunohistochemical Evaluation 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Sangoi, A. R., Dulai, M. S., Beck, A. H., Brat, D. J., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2009: 669?81
Abstract

Chordoid meningioma, World Health Organization grade II, is an uncommon variant of meningioma with a propensity for aggressive behavior and increased likelihood of recurrence. As such, recognition of this entity is important in cases that show similar morphologic overlap with other chondroid/myxoid neoplasms that can arise within or near the central nervous system. A formal comparison of the immunohistochemical features of chordoid meningioma versus tumors with significant histologic overlap has not been previously reported. In this study, immunohistochemical staining was performed with antibodies against D2-40, S100, pankeratin, epithelial membrane antigen (EMA), brachyury, and glial fibrillary acidic protein (GFAP) in 4 cases of chordoid glioma, 6 skeletal myxoid chondrosarcomas, 10 chordoid meningiomas, 16 extraskeletal myxoid chondrosarcoma, 18 chordomas, 22 low-grade chondrosarcomas, and 27 enchondromas. Staining extent and intensity were evaluated semiquantitatively and mean values for each parameter were calculated. Immunostaining with D2-40 showed positivity in 100% of skeletal myxoid chondrosarcomas, 96% of enchondromas, 95% of low-grade chondrosarcomas, 80% of chordoid meningiomas, and 75% of chordoid gliomas. Staining with S100 demonstrated diffuse, strong positivity in all (100%) chordoid gliomas, skeletal myxoid chondrosarcomas, low-grade chondrosarcomas, and enchondromas, 94% of chordomas, and 81% of extraskeletal myxoid chondrosarcomas, with focal, moderate staining in 40% of chordoid meningiomas. Pankeratin highlighted 100% of chordoid gliomas and chordomas, 38% of extraskeletal myxoid chondrosarcomas, and 20% of chordoid meningiomas. EMA staining was positive in 100% of chordoid gliomas, 94% of chordomas, 90% of chordoid meningiomas, and 25% of extraskeletal myxoid chondrosarcomas. Brachyury was positive only in the chordomas (100%), whereas GFAP was positive only in the chordoid gliomas (100%). EMA was the most effective antibody for differentiating chordoid meningioma from skeletal myxoid chondrosarcoma, low-grade chondrosarcoma, and enchondroma, whereas D2-40 was the most effective antibody for differentiating chordoid meningioma from extraskeletal myxoid chondrosarcoma and chordoma. Our findings demonstrate that in conjunction with clinical and radiographic findings, immunohistochemical evaluation with a panel of D2-40, EMA, brachyury, and GFAP is most useful in distinguishing chordoid meningioma from chordoid glioma, skeletal myxoid chondrosarcoma, extraskeletal myxoid chondrosarcoma, chordoma, low-grade chondrosarcoma, and enchondroma. A lack of strong, diffuse S100 reactivity may also be useful in excluding chordoid meningioma. Among the neoplasms evaluated, brachyury and GFAP proved to be both sensitive and specific markers for chordoma and chordoid glioma, respectively. Of note, this study is the first to characterize the D2-40 immunoprofile in extraskeletal myxoid chondrosarcoma, results that could be of utility in differential diagnostic assessment.

View details for PubMedID 19194275
Intracerebral Extravascular Masson's Tumor Mimicking Glioma Fujiwara, M., Harsh, G., Karamchandani, J., Gibbs, I., Fischbein, N., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2009: 587
View details for Web of Science ID 000265758600147
A novel homozygous SCO2 mutation, p.G193S, causing fatal infantile cardioencephalomyopathy CLINICAL NEUROPATHOLOGY Mobley, B. C., Enns, G. M., Wong, L., Vogel, H. 2009; 28 (2): 143-149
Abstract

Cytochrome c oxidase (COX) deficiency is a frequent cause of mitochondrial disease in infants. Mutations in the COX assembly gene SCO2 cause fatal infantile cardioencephalomyopathy. All patients reported to date with SCO2 deficiency share a common p.E140K mutation in at least 1 allele. In order to further the understanding of the genotype-phenotype spectrum associated with fatal infantile cardioencephalomyopathy, we describe a novel homozygous SCO2 mutation p.G193S in a patient with fatal infantile cardioencephalomyopathy born to consanguineous parents of Indian ancestry.

View details for Web of Science ID 000264437100011

View details for PubMedID 19353847
The Transcription Factor LMO2 Is a Robust Marker of Vascular Endothelium and Vascular Neoplasms and Selected Other Entities AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gratzinger, D., Zhao, S., West, R., Rouse, R. V., Vogel, H., Gil, E. C., Levy, R., Lossos, I. S., Natkunam, Y. 2009; 131 (2): 264-278
Abstract

The transcription factor LMO2 is involved in vascular and hematopoietic development and hematolymphoid neoplasia. We have demonstrated that LMO2 is expressed nearly ubiquitously in native and neoplastic vasculature, including lymphatics. LMO2 reactivity is otherwise virtually absent in nonhematolymphoid tissues except in breast myoepithelium, prostatic basal cells, and secretory phase endometrial glands. Vasculature is LMO2- in adult and fetal heart, brain of older adults, hepatic sinusoids, and hepatocellular carcinoma. LMO2 is uniformly expressed in benign vascular and lymphatic neoplasms and in most malignant vascular neoplasms with the exception of epithelioid vascular neoplasms of pleura and bone. Among nonvascular neoplasms, LMO2 reactivity is present in giant cell tumor of tendon sheath, juvenile xanthogranuloma, a subset of gastrointestinal stromal tumors, small round blue cell tumors, and myoepithelial-derived neoplasms. The restricted expression pattern, nuclear localization, and crisp staining of LMO2 in paraffin blocks make it an attractive candidate for the diagnostic immunohistochemistry laboratory.

View details for DOI 10.1309/AJCP5FP3NAXAXRJE

View details for PubMedID 19141387
Drosophila Models of Neurodegenerative Diseases ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE Lu, B., Vogel, H. 2009; 4: 315-342
Abstract

Neurodegenerative diseases are progressive disorders of the nervous system that affect specific cellular populations in the central and peripheral nervous systems. Although most cases are sporadic, genes associated with familial cases have been identified, thus enabling the development of animal models. Invertebrates such as Drosophila have recently emerged as model systems for studying mechanisms of neurodegeneration in several major neurodegenerative diseases. These models are also excellent in vivo systems for the testing of therapeutic compounds. Genetic studies using these animal models have provided novel insights into the disease process. We anticipate that further exploration of the animal models will further our understanding of mechanisms of neurodegeneration as well as facilitate the development of rational treatments for debilitating degenerative diseases.

View details for DOI 10.1146/annurev.pathol.3.121806.151529

View details for PubMedID 18842101
Ku80 Deletion Suppresses Spontaneous Tumors and Induces a p53-Mediated DNA Damage Response CANCER RESEARCH Holcomb, V. B., Rodier, F., Choi, Y., Busuttil, R. A., Vogel, H., Vijg, J., Campisi, J., Hasty, P. 2008; 68 (22): 9497?9502
Abstract

Ku80 facilitates DNA repair and therefore should suppress cancer. However, ku80(-/-) mice exhibit reduced cancer, although they age prematurely and have a shortened life span. We tested the hypothesis that Ku80 deletion suppresses cancer by enhancing cellular tumor-suppressive responses to inefficiently repaired DNA damage. In support of this hypothesis, Ku80 deletion ameliorated tumor burden in APC(MIN) mice and increased a p53-mediated DNA damage response, DNA lesions, and chromosomal rearrangements. Thus, contrary to its assumed role as a caretaker tumor suppressor, Ku80 facilitates tumor growth most likely by dampening baseline cellular DNA damage responses.

View details for DOI 10.1158/0008-5472.CAN-08-2085

View details for Web of Science ID 000261136600048

View details for PubMedID 19010925

View details for PubMedCentralID PMC4034752
Wnt-mediated self-renewal of neural stem/progenitor cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kalani, M. Y., Cheshier, S. H., Cord, B. J., Bababeygy, S. R., Vogel, H., Weissman, I. L., Palmer, T. D., Nusse, R. 2008; 105 (44): 16970-16975
Abstract

In this work we have uncovered a role for Wnt signaling as an important regulator of stem cell self-renewal in the developing brain. We identified Wnt-responsive cells in the subventricular zone of the developing E14.5 mouse brain. Responding cell populations were enriched for self-renewing stem cells in primary culture, suggesting that Wnt signaling is a hallmark of self-renewing activity in vivo. We also tested whether Wnt signals directly influence neural stem cells. Using inhibitors of the Wnt pathway, we found that Wnt signaling is required for the efficient cloning and expansion of single-cell derived populations that are able to generate new stem cells as well as neurons, astrocytes, and oligodendrocytes. The addition of exogenous Wnt3a protein enhances clonal outgrowth, demonstrating not only a critical role for the Wnt pathway for the regulation of neurogenesis but also its use for the expansion of neural stem cells in cell culture and in tissue engineering.

View details for DOI 10.1073/pnas.0808616105

View details for PubMedID 18957545
Effect of Timing of Bone Marrow Cell Delivery on Cell Viability and Cardiac Recovery Following Myocardial Infarction Swijnenburg, R., Govaert, J. A., Stein, W., van der Bogt, K., Pearl, J. I., Hoyt, G., Vogel, H., Robbins, R. G., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2008: S790
View details for Web of Science ID 000262104502633
Suprasellar giant cell ependymoma: a rare neoplasm in a unique location HUMAN PATHOLOGY Sangoi, A. R., Lim, M., Dulai, M. S., Vogel, H., Chang, S. D. 2008; 39 (9): 1396-1401
Abstract

Ependymomas are glial tumors that usually present in the posterior fossa in children and in the spinal cord in adults. Giant cell ependymoma, a rare ependymal subtype only recently recognized as a diagnostic entity in the last decade, demonstrates pleomorphic giant cells admixed with features of typical ependymoma. Although only 8 giant cell ependymomas have been reported to date, none have been reported in the suprasellar space. Moreover, as these neoplasms demonstrate a high incidence of anaplastic grade, recognition of this ependymal subtype is paramount. We describe the presentation and pertinent radiologic, histologic, immunologic, and ultrastructural findings in conjunction with relevant clinical implications of the first reported case of a suprasellar giant cell ependymoma occurring in a 34-year-old female 7 years after an initial diagnosis of a medullary ependymoma with rare atypical giant cells, a potential tumor seeding culprit.

View details for DOI 10.1016/j.humpath.2008.01.007

View details for PubMedID 18602668
Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure CLINICAL GENETICS Schule, B., Armstrong, D. D., Vogel, H., Oviedo, A., Francke, U. 2008; 74 (2): 116-126
Abstract

Non-mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal-onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi-stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post-mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9-nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2-/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.

View details for DOI 10.1111/j.1399-0004.2008.01005.x

View details for Web of Science ID 000257476200003

View details for PubMedID 18477000
Reactive oxygen species act remotely to cause synapse loss in a Drosophila model of developmental mitochondrial encephalopathy DEVELOPMENT Mast, J. D., Tomalty, K. M., Vogel, H., Clandinin, T. R. 2008; 135 (15): 2669-2679
Abstract

Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases, yet its precise role in disease pathology remains unclear. To examine this link directly, we subtly perturbed electron transport chain function in the Drosophila retina, creating a model of Leigh Syndrome, an early-onset neurodegenerative disorder. Using mutations that affect mitochondrial complex II, we demonstrate that mild disruptions of mitochondrial function have no effect on the initial stages of photoreceptor development, but cause degeneration of their synapses and cell bodies in late pupal and adult animals. In this model, synapse loss is caused by reactive oxygen species (ROS) production, not energy depletion, as ATP levels are normal in mutant photoreceptors, and both pharmacological and targeted genetic manipulations that reduce ROS levels prevent synapse degeneration. Intriguingly, these manipulations of ROS uncouple synaptic effects from degenerative changes in the cell body, suggesting that mitochondrial dysfunction activates two genetically separable processes, one that induces morphological changes in the cell body, and another that causes synapse loss. Finally, by blocking mitochondrial trafficking into the axon using a mutation affecting a mitochondrial transport complex, we find that ROS action restricted to the cell body is sufficient to cause synaptic degeneration, demonstrating that ROS need not act locally at the synapse. Thus, alterations in electron transport chain function explain many of the neurodegenerative changes seen in both early- and late-onset disorders.

View details for DOI 10.1242/dev.020644

View details for PubMedID 18599508
Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Yang, Y., Ouyang, Y., Yang, L., Beal, M. F., McQuibban, A., Vogel, H., Lu, B. 2008; 105 (19): 7070-7075
Abstract

Mitochondria form dynamic tubular networks that undergo frequent morphological changes through fission and fusion, the imbalance of which can affect cell survival in general and impact synaptic transmission and plasticity in neurons in particular. Some core components of the mitochondrial fission/fusion machinery, including the dynamin-like GTPases Drp1, Mitofusin, Opa1, and the Drp1-interacting protein Fis1, have been identified. How the fission and fusion processes are regulated under normal conditions and the extent to which defects in mitochondrial fission/fusion are involved in various disease conditions are poorly understood. Mitochondrial malfunction tends to cause diseases with brain and skeletal muscle manifestations and has been implicated in neurodegenerative diseases such as Parkinson's disease (PD). Whether abnormal mitochondrial fission or fusion plays a role in PD pathogenesis has not been shown. Here, we show that Pink1, a mitochondria-targeted Ser/Thr kinase linked to familial PD, genetically interacts with the mitochondrial fission/fusion machinery and modulates mitochondrial dynamics. Genetic manipulations that promote mitochondrial fission suppress Drosophila Pink1 mutant phenotypes in indirect flight muscle and dopamine neurons, whereas decreased fission has opposite effects. In Drosophila and mammalian cells, overexpression of Pink1 promotes mitochondrial fission, whereas inhibition of Pink1 leads to excessive fusion. Our genetic interaction results suggest that Fis1 may act in-between Pink1 and Drp1 in controlling mitochondrial fission. These results reveal a cell biological role for Pink1 and establish mitochondrial fission/fusion as a paradigm for PD research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in PD intervention.

View details for DOI 10.1073/pnas.0711845105

View details for PubMedID 18443288
Disseminated subpial demyelination presenting as respiratory stridor Dulai, M., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2008: 517
View details for Web of Science ID 000255442300151
Papillary tumor of the spinal cord. Report of two cases Mobley, B., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2008: 504
View details for Web of Science ID 000255442300092
Intracerebral hemorrhage caused by cerebral amyloid angiopathy in a 53-year-old man JOURNAL OF NEUROLOGY Campbell, D. M., Bruins, S., Vogel, H., Shuer, L. M., Wijman, C. A. 2008; 255 (4): 597-598
View details for DOI 10.1007/s00415-008-0742-9

View details for Web of Science ID 000255255300021

View details for PubMedID 18227992
Disseminated Subpial Demyelination Presenting as Respiratory Stridor Dulai, M., Vogel, H. FEDERATION AMER SOC EXP BIOL. 2008
View details for Web of Science ID 000208467806649
Papillary tumor of the spinal cord. Report of two cases Mobley, B., Vogel, H. FEDERATION AMER SOC EXP BIOL. 2008
View details for Web of Science ID 000208467808423
CNS T-cell lymphoma: an under-recognized entity? ACTA NEUROPATHOLOGICA Dulai, M. S., Park, C. Y., Howell, W. D., Smyth, L. T., Desai, M., Carter, D. M., Vogel, H. 2008; 115 (3): 345-356
Abstract

The incidence of CNS lymphoma has increased significantly in the past 30 years, primarily in the elderly and immunocompromised. While T-cell lymphomas comprise 15-20% of systemic lymphomas, they comprise less than 4% of primary CNS lymphomas, suggesting that they may be under-recognized compared to their systemic counterparts. To investigate this, we studied brain biopsies from three patients who were diagnosed with T-cell lymphoma confined to the brain. They had enhancing lesions by MRI, arising in the cerebellum and brainstem in one and temporal lobe in two. We compared these to biopsies from three patients who had reactive lymphoid infiltrates and who had clinical signs/symptoms and radiographic findings that were indistinguishable from the lymphoma group. Biopsies from both the lymphoma group and reactive group showed considerable cytomorphologic heterogeneity. Although one lymphoma case contained large atypical cells, the other two contained small, mature lymphocytes within a heterogeneous infiltrate of neoplastic and reactive inflammatory cells. Surface marker aberrancies were present in two lymphoma cases, but this alone could not reliably diagnose T-cell lymphoma. The proliferation index was not useful for differentiating lymphoma from reactive infiltrates. In five of the six cases the diagnosis was most influenced by clonality studies for T-cell receptor-gamma gene rearrangements. We conclude that because of the high degree of overlap in cytomorphologic and immunophenotypic features between T-cell lymphoma and reactive infiltrates, T-cell lymphoma may not be recognized unless studies for T-cell receptor gene rearrangements are performed for CNS lesions composed of a polymorphous but predominantly T-cell infiltrate.

View details for DOI 10.1007/s00401-007-0338-y

View details for PubMedID 18196250
An unusual case of Pompe disease presenting as muscular dystrophy Cusmano-Ozog, K., Vogel, H., Cowan, T., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2008: S18
View details for DOI 10.1016/j.ymgme.2007.10.031

View details for Web of Science ID 000253358500036
Progressive cerebral vascular degeneration with mitochondrial encephalopathy AMERICAN JOURNAL OF MEDICAL GENETICS PART A Longo, N., Schrijver, I., Vogel, H., Pique, L. M., Cowan, T. M., Pasquali, M., Steinberg, G. K., Hedlund, G. L., Ernst, S. L., Gallagher, R. C., Enns, G. M. 2008; 146A (3): 361-367
Abstract

MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a maternally inherited disorder characterized by recurrent cerebral infarctions that do not conform to discreet vascular territories. Here we report on a patient who presented at 7 years of age with loss of consciousness and severe metabolic acidosis following vomiting and dehydration. She developed progressive sensorineural hearing loss, myopathy, ptosis, short stature, and mild developmental delays after normal early development. Biochemical testing identified metabolites characteristic of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (hexanoylglycine and suberylglycine), but also severe lactic acidemia (10-25 mM) and, in urine, excess of lactic acid, intermediates of the citric cycle, and marked ketonuria, suggesting mitochondrial dysfunction. She progressed rapidly to develop temporary cortical blindness. Brain imaging indicated generalized atrophy, more marked on the left side, in addition to white matter alterations consistent with a mitochondrial disorder. Magnetic resonance angiography indicated occlusion of the left cerebral artery with development of collateral circulation (Moyamoya syndrome). This process worsened over time to involve the other side of the brain. A muscle biopsy indicated the presence of numerous ragged red fibers. Molecular testing confirmed compound heterozygosity for the common mutation in the MCAD gene (985A>G) and a second pathogenic mutation (233T>C). MtDNA testing indicated that the muscle was almost homoplasmic for the 3243A>T mutation in tRNALeu, with a lower mutant load (about 50% heteroplasmy) in blood and skin fibroblasts. These results indicate that mitochondrial disorders may be associated with severe vascular disease resulting in Moyamoya syndrome. The contribution of the concomitant MCAD deficiency to the development of the phenotype in this case is unclear.

View details for DOI 10.1002/ajmg.a.31841

View details for Web of Science ID 000253008300014
Congenital glioblastoma multiforme: Case report and review of the literature PEDIATRIC NEUROSURGERY Hou, L. C., Bababeygy, S. R., Sarkissian, V., Fisher, P. G., Vogel, H., Barnes, P., Huhn, S. L. 2008; 44 (4): 304-312
Abstract

Congenital glioblastoma multiforme is a rare primary brain tumor that has a unique biology distinct from pediatric and adult variants. In this report, we present a case of congenital glioblastoma with complicated management course. A literature review of previously reported cases is included to illustrate the epidemiology and natural history of this disease. A 9-month-old male infant developed acute lethargy, hemiparesis and unilaterally dilated pupil. Imaging studies revealed a large hemispheric tumor, resulting in significant midline shift suggestive of impending herniation. Emergent tumor cystic fluid drainage was performed at initial presentation. A frontotemporoparietal craniotomy was performed on the following day to attempt a gross total resection. Adjuvant chemotherapy consisting of oral temozolomide was administered. The patient eventually succumbed 4 months later due to aggressive tumor progression. Congenital glioblastoma should be included in the differential diagnosis of infants with large intracranial tumors. Although surgical intervention may increase survival, the overall outcome remains poor despite maximal multimodal treatment.

View details for DOI 10.1159/000134922

View details for PubMedID 18504417
Muscle lymphocytic infiltrates in thymoma-associated myasthenia gravis are phenotypically different from those in polymyositis NEUROMUSCULAR DISORDERS Zamecnik, J., Vesely, D., Jakubicka, B., Simkova, L., Pitha, J., Schutmer, J., Mazanec, R., Vogel, H. 2007; 17 (11-12): 935-942
Abstract

The aim of the study is to provide evidence that the lymphocytic infiltration of myasthenia gravis (MG) muscle do not represent a true autoimmune myositis, rather an infiltration by naive lymphocytes derived from lymphocyte-rich thymomas. Muscle biopsies from 179 patients with pure MG, 6 thymoma patients without MG and 15 patients with definite polymyositis were analyzed. In 18 patients with MG (all associated with lymphocyte-rich thymomas) and in two thymoma patients without MG, lymphocytic infiltrates were identified in muscles. By use of immunohistochemistry, we demonstrated that the lymphocytes in MG differ from those in polymyositis, being mature but in contrast to polymyositis naive CD45RA+ T lymphocytes. We suggest that the lymphocytic infiltrates in patients with MG and thymoma represent an infiltration of muscle by thymoma-derived mature but naive T cells. The finding of CD8+CD45RA+ lymphocytes in muscle may signify an underlying thymoma and should not be misdiagnosed as polymyositis.

View details for DOI 10.1016/j.nmd.2007.05.010

View details for Web of Science ID 000252118200004

View details for PubMedID 17651972
RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments GENES & DEVELOPMENT Hu, Y., Raynard, S., Sehorn, M. G., Lu, X., Bussen, W., Zheng, L., Stark, J. M., Barnes, E. L., Chi, P., Janscak, P., Jasin, M., Vogel, H., Sung, P., Luo, G. 2007; 21 (23): 3073-3084
Abstract

Members of the RecQ helicase family play critical roles in genome maintenance. There are five RecQ homologs in mammals, and defects in three of these (BLM, WRN, and RECQL4) give rise to cancer predisposition syndromes in humans. RECQL and RECQL5 have not been associated with a human disease. Here we show that deletion of Recql5 in mice results in cancer susceptibility. Recql5-deficient cells exhibit elevated frequencies of spontaneous DNA double-strand breaks and homologous recombination (HR) as scored using a reporter that harbors a direct repeat, and are prone to gross chromosomal rearrangements in response to replication stress. To understand how RECQL5 regulates HR, we use purified proteins to demonstrate that human RECQL5 binds the Rad51 recombinase and inhibits Rad51-mediated D-loop formation. By biochemical means and electron microscopy, we show that RECQL5 displaces Rad51 from single-stranded DNA (ssDNA) in a reaction that requires ATP hydrolysis and RPA. Together, our results identify RECQL5 as an important tumor suppressor that may act by preventing inappropriate HR events via Rad51 presynaptic filament disruption.

View details for DOI 10.1101/gad.1609107

View details for Web of Science ID 000251512400006

View details for PubMedID 18003859

View details for PubMedCentralID PMC2081974
Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer MOLECULAR AND CELLULAR BIOLOGY Li, H., Vogel, H., Holcomb, V. B., Gu, Y., Hasty, P. 2007; 27 (23): 8205-8214
Abstract

Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in the reported phenotypes. For example, only Ku70 mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80 mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 functions outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds or environments influence the phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70, Ku80, and double-mutant mice in the same genetic background raised in the same environment. We show that these three cohorts have similar phenotypes that most resemble the previous report for Ku80 mutant mice, i.e., early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.

View details for DOI 10.1128/MCB.00785-07

View details for Web of Science ID 000251527100015

View details for PubMedID 17875923

View details for PubMedCentralID PMC2169178
Deletion of Ku80 causes early aging independent of chronic inflammation and Rag-1-induced DSBs MECHANISMS OF AGEING AND DEVELOPMENT Holcomb, V. B., Vogel, H., Hasty, P. 2007; 128 (11-12): 601?8
Abstract

Animal models of premature aging are often defective for DNA repair. Ku80-mutant mice are disabled for nonhomologous end joining; a pathway that repairs both spontaneous DNA double-strand breaks (DSBs) and induced DNA DSBs generated by the action of a complex composed of Rag-1 and Rag-2 (Rag). Rag is essential for inducing DSBs important for assembling V(D)J segments of antigen receptor genes that are required for lymphocyte development. Thus, deletion of either Rag-1 or Ku80 causes severe combined immunodeficiency (scid) leading to chronic inflammation. In addition, Rag-1 induces breaks at non-B DNA structures. Previously we reported Ku80-mutant mice undergo premature aging, yet we do not know the root cause of this phenotype. Early aging may be caused by either defective repair of spontaneous DNA damage, defective repair of Rag-1-induced breaks or chronic inflammation caused by scid. To address this issue, we analyzed aging in control and Ku80-mutant mice deleted for Rag-1 such that both cohorts are scid and suffer from chronic inflammation. We make two observations: (1) chronic inflammation does not cause premature aging in these mice and (2) Ku80-mutant mice exhibit early aging independent of Rag-1. Therefore, this study supports defective repair of spontaneous DNA damage as the root cause of early aging in Ku80-mutant mice.

View details for DOI 10.1016/j.mad.2007.08.006

View details for Web of Science ID 000253078400003

View details for PubMedID 17928034

View details for PubMedCentralID PMC2692937
Intraventricular myxoid meningioma in a 7-year-old female 12th Annual Meeting of the Society-for-Neuro-Oncology Dulai, M. S., Khan, A., Edwards, M. S., Vogel, H. OXFORD UNIV PRESS INC. 2007: 550?51
View details for Web of Science ID 000249999100321
A 35-year-old woman with a dural-based mass. Brain pathology Haddix, T., Chang, S., Vogel, H. 2007; 17 (3): 331-332
View details for PubMedID 17598829
CNS T-cell lymphoma: an underrecognized entity? Dulai, M., Park, C., Smyth, L. T., Desai, M., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2007: 429
View details for DOI 10.1097/01.jnen.0000268846.28101.b5

View details for Web of Science ID 000246852900057
CNS T-cell lymphoma: an underrecognized entity? Dulai, M., Park, C., Smyth, L. T., Desai, M., Vogel, H. FEDERATION AMER SOC EXP BIOL. 2007: A28
View details for Web of Science ID 000245708500132
Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF(121)/rGel JOURNAL OF NUCLEAR MEDICINE Hsu, A. R., Cai, W., Veeravagu, A., Mohamedali, K. A., Chen, K., Kim, S., Vogel, H., Hou, L. C., Tse, V., Rosenblum, M. G., Chen, X. 2007; 48 (3): 445-454
Abstract

Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF(121)/rGel) composed of the VEGF-A isoform VEGF(121) linked with a G(4)S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI), MRI, and PET.Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with (64)Cu-1,4,7,10-tetraazacyclododedane-N,N',N'',N'''-tetraacetic acid (DOTA)-VEGF(121)/rGel was performed before VEGF(121)/rGel treatment. (18)F-Fluorothymidine ((18)F-FLT) scans were obtained before and after treatment to evaluate VEGF(121)/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses.Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with (64)Cu-DOTA-VEGF(121)/rGel before treatment revealed a tumor accumulation (mean +/- SD) of 11.8 +/- 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF(121). PET with (18)F-FLT revealed significant a decrease in tumor proliferation in VEGF(121)/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF(121)/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity.The results of this study suggest that future clinical multimodality imaging and therapy with VEGF(121)/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF(121)/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.

View details for PubMedID 17332623
CHD5 is a tumor suppressor at human 1p36 CELL Bagchi, A., Papazoglu, C., Wu, Y., Capurso, D., Brodt, M., Francis, D., Bredel, M., Vogel, H., Mills, A. A. 2007; 128 (3): 459-475
Abstract

Cancer gene discovery has relied extensively on analyzing tumors for gains and losses to reveal the location of oncogenes and tumor suppressor genes, respectively. Deletions of 1p36 are extremely common genetic lesions in human cancer, occurring in malignancies of epithelial, neural, and hematopoietic origin. Although this suggests that 1p36 harbors a gene that drives tumorigenesis when inactivated, the identity of this tumor suppressor has remained elusive. Here we use chromosome engineering to generate mouse models with gain and loss of a region corresponding to human 1p36. This approach functionally identifies chromodomain helicase DNA binding domain 5 (Chd5) as a tumor suppressor that controls proliferation, apoptosis, and senescence via the p19(Arf)/p53 pathway. We demonstrate that Chd5 functions as a tumor suppressor in vivo and implicate deletion of CHD5 in human cancer. Identification of this tumor suppressor provides new avenues for exploring innovative clinical interventions for cancer.

View details for DOI 10.1016/j.cell.2006.11.052

View details for Web of Science ID 000244842700014

View details for PubMedID 17289567
In vivo near-infrared fluorescence imaging of integrin alpha(v)beta(3) in an orthotopic glioblastoma model MOLECULAR IMAGING AND BIOLOGY Hsu, A. R., Hou, L. C., Veeravagu, A., Greve, J. M., Vogel, H., Tse, V., Chen, X. 2006; 8 (6): 315-323
Abstract

Expression of cell adhesion molecule integrin alpha(v)beta(3) is significantly up-regulated during tumor growth, and sprouting of tumor vessels and correlates well with tumor aggressiveness. The purpose of this study was to visualize tumor integrin alpha(v)beta(3) expression in vivo by using near-infrared fluorescence (NIRF) imaging of Cy5.5-linked cyclic arginine-glycine-aspartic acid (RGD) peptide in an orthotopic brain tumor model.U87MG glioma cells transfected with the firefly luciferase gene were stereotactically injected into nude mice in the right frontal lobe. Bioluminescence imaging (BLI) using D: -luciferin substrate and small animal magnetic resonance imaging (MRI) using gadolinium contrast enhancement were conducted weekly after tumor cell inoculation to monitor intracranial tumor growth. Integrin alpha(v)beta(3) expression was assessed by using a three-dimensional optical imaging system (IVIS 200) 0-24 hours after administration of 1.5 nmol monomeric Cy5.5-RGD via the tail vein. Animals were injected intravenously with both Texas Red-tomato lectin and Cy5.5-RGD prior to sacrifice to visualize peptide localization to tumor vasculature using histology.Fluorescence microscopy demonstrated specific Cy5.5-RGD binding to both U87MG tumor vessels and tumor cells with no normal tissue binding. NIRF imaging showed highest tumor uptake and tumor to normal brain tissue ratio two hours postinjection (2.64 +/- 0.20). Tumor uptake of Cy5.5-RGD was effectively blocked by using unlabeled c(RGDyK), and injection of Cy5.5 dye alone showed nonspecific binding.Optical imaging via BLI and NIRF offer a simple, effective, and rapid technique for noninvasive in vivo monitoring and semiquantitative analysis of intracranial tumor growth and integrin alpha(v)beta(3) expression. This study suggests that NIRF via fluorescently labeled RGD peptides may provide enhanced surveillance of tumor angiogenesis and anti-integrin treatment efficacy in orthotopic brain tumor models.

View details for DOI 10.1007/s11307-006-0059-y

View details for PubMedID 17053862
Wilm's tumor gene WT1 and p53 immunohistochemistry: Diagnostic utility in mixed glial neoplasia Moes, G., Vogel, H. NATURE PUBLISHING GROUP. 2006: 145
View details for Web of Science ID 000239999400671
Immunohistochemical analysis of cytochrome oxidase deficiency using fixed tissues Vogel, H., Masek, M., Gallagher, R., Enns, G. BLACKWELL PUBLISHING. 2006: S167
View details for Web of Science ID 000239938600373
Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused inactivation of Drosophila Pink1 is rescued by by Parkin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Yang, Y., Gehrke, S., Imai, Y., Huang, Z., Ouyang, Y., Wang, J., Yang, L., Beal, M. F., Vogel, H., Lu, B. 2006; 103 (28): 10793-10798
Abstract

Mutations in Pink1, a gene encoding a Ser/Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.

View details for DOI 10.1073/pnas.0602493103

View details for PubMedID 16818890
Transcriptional profiling of aging in human muscle reveals a common aging signature PLOS GENETICS Zahn, J. M., Sonu, R., Vogel, H., Crane, E., Mazan-Mamczarz, K., Rabkin, R., Davis, R. W., Becker, K. G., Owen, A. B., Kim, S. K. 2006; 2 (7): 1058-1069
Abstract

We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.

View details for DOI 10.1371/journal.pgen.0020115

View details for PubMedID 16789832
p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Keyes, W. M., Vogel, H., Koster, M. I., Guo, X., Qi, Y., Petherbridge, K. M., Roop, D. R., Bradley, A., Mills, A. A. 2006; 103 (22): 8435-8440
Abstract

Homology between p63 and p53 has suggested that these proteins might function similarly. However, the majority of data from human tumors have not supported a similar role for p63 in tumor suppression. To investigate this issue, we studied spontaneous tumorigenesis in p63+/- mice in both WT and p53-compromised backgrounds. We found that p63+/- mice were not tumor prone and mice heterozygous for both p63 and p53 had fewer tumors than p53+/- mice. The rare tumors that developed in mice with compromised p63 were also distinct from those of p53+/- mice. Furthermore, p63+/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. These findings demonstrate that, in agreement with data from human tumors, p63 plays a markedly different biological role in cancer than p53.

View details for DOI 10.1073/pnas.0602477103

View details for Web of Science ID 000238206800026

View details for PubMedID 16714381

View details for PubMedCentralID PMC1482510
Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport HUMAN MOLECULAR GENETICS Ding, J. Q., Allen, E., Wang, W., Valle, A., Wu, C. B., Nardine, T., Cui, B. X., Yi, J., Taylor, A., Jeon, N. L., Chu, S., So, Y., Vogel, H., Tolwani, R., Mobley, W., Yang, Y. M. 2006; 15 (9): 1451-1463
Abstract

Mutations in gigaxonin were identified in giant axonal neuropathy (GAN), an autosomal recessive disorder. To understand how disruption of gigaxonin's function leads to neurodegeneration, we ablated the gene expression in mice using traditional gene targeting approach. Progressive neurological phenotypes and pathological lesions that developed in the GAN null mice recapitulate characteristic human GAN features. The disruption of gigaxonin results in an impaired ubiquitin-proteasome system leading to a substantial accumulation of a novel microtubule-associated protein, MAP8, in the null mutants. Accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures and leads to neuronal death in cultured wild-type neurons, which replicates the process occurring in GAN null mutants. Defective axonal transport is evidenced by the in vitro assays and is supported by vesicular accumulation in the GAN null neurons. We propose that the axonal transport impairment may be a deleterious consequence of accumulated, toxic MAP8 protein.

View details for DOI 10.1093/hmg/ddl069

View details for PubMedID 16565160
Osteopontin expression in intratumoral astrocytes marks tumor progression in gliomas induced by prenatal exposure to N-ethyl-N-nitrosourea AMERICAN JOURNAL OF PATHOLOGY Jang, T. C., Savarese, T., Low, H. P., Kim, S., Vogel, H., Lapointe, D., Duong, T., Litofsky, N. S., Weimann, J. M., Ross, A. H., Recht, L. 2006; 168 (5): 1676-1685
Abstract

To better study early events in glioma genesis, markers that reliably denote landmarks in glioma development are needed. In the present study, we used microarray analysis to compare the gene expression patterns of magnetic resonance imaging (MRI)-localized N-ethyl-N-nitrosourea (ENU)-induced tumors in rat brains with those of uninvolved contralateral side and normal brains. Our analysis identified osteopontin (OPN) as the most up-regulated gene in glioma. Using immunohistochemistry we then confirmed OPN expression in every tumor examined (n = 17), including those with diameters as small as 300 mum. By contrast, no OPN immunostaining was seen in normal brain or in brains removed from ENU-exposed rats before the development of glioma. Further studies confirmed that OPN was co-localized exclusively in intratumoral glial fibrillary acidic protein-expressing cells and was notably absent from nestin-expressing ones. In conjunction with this, we confirmed that both normal neurosphere cells and ENU-im-mortalized subventricular zone/striatal cells produced negligible amounts of OPN compared to the established rat glioma cell line C6. Furthermore, inducing OPN expression in an immortalized cell line increased cell proliferation. Based on these findings, we conclude that OPN overexpression in ENU-induced gliomas occurs within a specific subset of intratumoral glial fibrillary acidic protein-positive cells and becomes evident at the stage of tumor progression.

View details for DOI 10.2353/ajpath.2006.050400

View details for PubMedID 16651633
Gene-dosage effects in the human glioma transcriptome and their potential biological impact based on in silico interactome mapping Bredel, M., Juric, D., Bredel, C., Harsh, G. R., Vogel, H., Recht, L. D., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2006
View details for Web of Science ID 000454606200304
TNFAIP3/A20 as a potential regulator of NF-kappa B-mediated resistance to O-6-alkylating chemotherapy in glioblastoma multiforme Bredel, M., Bredel, C., Juric, D., Duran, G., Yu, R. X., Harsh, G. R., Vogel, H., Recht, L. D., Scheck, A. C., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2006
View details for Web of Science ID 000454608803061
Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappa B-mediated resistance to O-6-alkylating agents in human glioblastomas JOURNAL OF CLINICAL ONCOLOGY Bredel, M., Bredel, C., Juric, D., Duran, G. E., Yu, R. X., Harsh, G. R., Vogel, H., Recht, L. D., Scheck, A. C., Sikic, B. I. 2006; 24 (2): 274-287
Abstract

Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas.We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells.We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-kappaB (NF-kappaB), which included the persistent alterations of various NF-kappaB pathway elements. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-kappaB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-kappaB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022).Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-kappaB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.

View details for DOI 10.1200/JCO.2005.02.9405

View details for PubMedID 16365179
Vascular-type disruptive defects in fetuses with homozygous alpha-thalassemia: report of two cases and review of the literature PRENATAL DIAGNOSIS Adam, M. P., Chueh, J., El-Sayed, Y. Y., Stenzel, A., Voge, H., Weaver, D. D., Hoyme, H. E. 2005; 25 (12): 1088-1096
Abstract

The thalassemias are an inherited group of heterogeneous anemias in which one or more of the globin chains in the hemoglobin tetramer are absent. Fetuses with homozygous alpha-thalassemia, which is particularly prevalent in people of Southeast Asian extraction, experience deficient alpha-globin chain synthesis and cannot produce hemoglobin F (the primary fetal hemoglobin after 8 weeks' gestation). Instead, they produce an anomalous hemoglobin, hemoglobin Bart's, with an unusually high affinity for oxygen, leading to profound anemia and tissue hypoxia.Here we report on two fetuses with homozygous alpha-thalassemia who displayed structural defects of a vascular disruptive type. Both fetuses demonstrated limb anomalies, including terminal transverse limb deficiencies, and one fetus was found to have a brain malformation consisting of a neuronal migrational defect. The limb anomalies and suspected brain malformation were detected on prenatal ultrasound prior to confirmation of the diagnosis of alpha-thalassemia in one case; in the other case prenatal records were not available. While microcephaly, hydrocephalus, and retarded brain growth have been rarely reported in association with homozygous alpha-thalassemia, this is the first report of a true brain malformation in an affected fetus. Limb anomalies, on the other hand, appear to be more frequent. Recently, aggressive in utero and postnatal therapies for homozygous alpha-thalassemia have been attempted with some success.Our cases and those from the medical literature suggest that couples need to be counseled about the risks of congenital anomalies of a vascular disruptive type in affected fetuses. Furthermore, data from the literature suggests that in utero therapy may not significantly decrease these risks as such anomalies may be present prior to the institution of therapy. In addition, in hydropic infants with vascular disruptive defects, especially in those of Southeast Asian origin, homozygous alpha-thalassemia should be suspected as a likely etiology.

View details for DOI 10.1002/pd.1276

View details for Web of Science ID 000234280900003

View details for PubMedID 16231329
Gigaxonin interacts with tubulin folding cofactor B and controls its degradation through the ubiquitin-proteasome pathway CURRENT BIOLOGY Wang, W., Ding, J. Q., Allen, E., Zhu, P., Zhang, L., Vogel, H., Yang, Y. M. 2005; 15 (22): 2050-2055
Abstract

Gigaxonin is mutated in human giant axonal neuropathy (GAN), an autosomal recessive neurodegenerative disorder. The presence of generalized cytoskeletal abnormalities , including few microtubules and accumulated intermediate filaments (IFs), in GAN suggests an essential role of gigaxonin in cytoskeletal organization and dynamics. However, the molecular mechanisms underlying the cytoskeletal pathology remain to be elucidated. Over the years, the ubiquitin-proteasome system (UPS) of intracellular protein degradation has been implicated in the control of many fundamental cellular processes. Defects in this system seem to be directly linked to the development of human diseases, including cancers and neurodegenerative diseases . Here, we show that gigaxonin controls protein degradation of tubulin folding cofactor B (TBCB) , a function disrupted by GAN-associated mutations. The substantial TBCB protein accumulation caused by impaired UPS may be a causative factor of cytoskeletal pathology in GAN. Our study provides important insight into pathogenesis of neurodegenerative diseases associated with cytoskeletal abnormalities.

View details for DOI 10.1016/j.cub.2005.10.052

View details for PubMedID 16303566
Identification of phenotypic neural stem cells in a pediatric astroblastoma JOURNAL OF NEUROSURGERY Huhn, S. L., Yung, Y., Cheshier, S., Harsh, G., Ailles, L., Weissman, I., Vogel, H., Tse, V. 2005; 103 (5): 446-450
Abstract

The goal of this study was to illustrate the findings of a significant subpopulation of cells within a pediatric astroblastoma that have the specific cell surface phenotype found on known human neural stem cells.Cells with a cell surface marker profile characteristic of human neural stem cells were isolated using fluorescence-activated cell sorting from a mostly nonmitotic astroblastoma removed from the brain of an 11-year-old girl. An unusually high proportion (24%) of the cells were CD133 positive and CD24, CD34, and CD45 negative (CD133(+)CD24(-)CD34(-)CD45(-) cells), the phenotypic antigenic pattern associated with neural stem cells; very few CD133-positive cells were not also CD24, CD34, and CD45 negative. Some cells (12%) were CD34 positive, indicating the presence within the tumor of hematopoietic stem cells. Cells formed cytospheres that resembled neurospheres when seeded into stem cell media and coexpressed beta-tubulin and glial fibrillary acidic protein (GFAP) but did not express the oligodendrocyte marker O4. Cell proliferation was demonstrated by incorporation of bromodeoxyuridine. The cells lost their capacity for self-renewal in vitro after four to six passages, although they continued to coexpress beta-tubulin and GFAP. The cells did not differentiate into neurons or astrocytes when placed in differentiation medium.Although this astroblastoma contained a high proportion of phenotypic neural stemlike cells, the cells had limited proliferative capacity and multipotency. Their role in astroblastoma formation and growth is unknown.

View details for PubMedID 16302618
Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas CANCER RESEARCH Bredel, M., Bredel, C., Juric, D., Harsh, G. R., Vogel, H., Recht, L. D., Sikic, B. I. 2005; 65 (19): 8679-8689
Abstract

Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.

View details for DOI 10.1158/0008-5472

View details for PubMedID 16204036
p63 deficiency activates a program of cellular senescence and leads to accelerated aging GENES & DEVELOPMENT Keyes, W. M., Wu, Y., Vogel, H., Guo, X. C., Lowe, S. W., Mills, A. A. 2005; 19 (17): 1986-1999
Abstract

The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.

View details for DOI 10.1101/gad.342305

View details for Web of Science ID 000231630100005

View details for PubMedID 16107615

View details for PubMedCentralID PMC1199570
A new ENU-induced allele of mouse quaking causes severe CNS dysmyelination MAMMALIAN GENOME Noveroske, J. K., Hardy, R., Dapper, J. D., Vogel, H., Justice, M. J. 2005; 16 (9): 672-682
Abstract

The mutant allelic series of the mouse quaking gene consists of the spontaneous quaking(viable) (qk(v)) allele, which is homozygous viable with a dysmyelination phenotype, and four ENU-induced alleles (qk(kt 1), qk(k2), qk(kt3/4), and qk(l-1)), which are homozygous embryonic lethal. Here we report the isolation of qk(e5), the first ENU-induced viable allele of quaking. Unlike qk(v)/qk(v), qk(e5)/qk(e5) animals have early-onset seizures, severe ataxia, and a dramatically reduced lifespan. Ultrastructural analysis of qk(e5)/qk(e5) brains reveals severe dysmyelination when compared with both wild-type and qk(v)/qk(v) brains. In addition, Calbindin detection in young adult qk(e5)/qk(e5) mice reveals Purkinje cell axonal swellings indicative of neurodegeneration , which is not seen in young adult qk(v)/qk(v) mice. Although the molecular defect in the qk(e5) allele is not evident by sequencing, protein expression studies show that qk(e5)/qk(e5) postnatal oligodendrocytes lack the QKI-6 and QKI-7 isoforms and have reduced QKI-5 levels. The oligodendrocyte developmental markers PDGF alpha R, NG 2, O4, CNP, and MBP are also present in the qk(e5)/qk(e5) postnatal brain although CNP and MBP levels are considerably reduced. Because the qk(v) allele is a large deletion that affects the expression of three genes, the new neurologic qk(e5) allele is an important addition to this allelic series.

View details for DOI 10.1007/s00335-005-0035-x

View details for Web of Science ID 000232303800003

View details for PubMedID 16245024
Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium CIRCULATION Swijnenburg, R. J., Tanaka, M., Vogel, H., Baker, J., Kofidis, T., Gunawan, F., Lebl, D. R., Caffarelli, A. D., de Bruin, J. L., Fedoseyeva, E. V., Robbins, R. C. 2005; 112 (9): I166-I172
Abstract

We investigated whether differentiation of embryonic stem cells (ESCs) in ischemic myocardium enhances their immunogenicity, thereby increasing their chance for rejection.In one series, 129/SvJ-derived mouse ESCs (ES-D3 line) were transplanted by direct myocardial injection (1 x 10(6) cells) into murine hearts of both allogeneic (BALB/c, n=20) and syngeneic (129/SvJ, n=12) recipients after left anterior artery ligation. Hearts were procured at 1, 2, 4, and 8 weeks after ESC transplantation and analyzed by immunohistochemistry to assess immune cell infiltration (CD3, CD4, CD8, B220, CD11c, Mac-1, and Gr-1) and ESC differentiation (hematoxylin and eosin). In a second series (allogeneic n=5, sham n=3), ESC transplantation was performed similarly; however after 2 weeks, left anterior descending artery-ligated and ESC-injected hearts were heterotopically transplanted into naive BALB/c recipients. After an additional 2 weeks, donor hearts were procured and analyzed by immunohistochemistry. In the first series, the size of all ESC grafts remained stable and there was no evidence of ESC differentiation 2 weeks after transplantation; however, after 4 weeks, both allogeneic and syngeneic ESC grafts showed the presence of teratoma. By 8 weeks, surviving ESCs could be detected in the syngeneic but not in the allogeneic group. Mild inflammatory cellular infiltrates were found in allogeneic recipients at 1 and 2 weeks after transplantation, progressing into vigorous infiltration at 4 and 8 weeks. The second series demonstrated similar vigorous infiltration of immune cells as early as 2 weeks after heterotopic transplantation.In vivo differentiated ESCs elicit an accelerated immune response as compared with undifferentiated ESCs. These data imply that clinical transplantation of allogeneic ESCs or ESC derivatives for treatment of cardiac failure might require immunosuppressive therapy.

View details for DOI 10.1161/CIRCULATIONAHA.104.525824

View details for Web of Science ID 000231741600025

View details for PubMedID 16159810
alpha(v)beta(3) integrin in central nervous system tumors HUMAN PATHOLOGY Lim, M., Guccione, S., Haddix, T., Sims, L., Cheshier, S., Chu, P., Vogel, H., Harsh, G. 2005; 36 (6): 665-669
Abstract

alpha(v)beta(3) Is an integrin specifically expressed in endothelial cells of newly forming blood vessels. Integrin-mediated angiogenesis is hypothesized to play a central role in the development and the progression of central nervous system neoplasms. Accordingly, it is considered a potential target for antiangiogenic therapy. In the current study, we compare the expression of alpha(v)beta(3) in ependymomas, oligodendrogliomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas (acoustic neuromas). Samples of 5 tumors of each of the 5 tumor types were harvested surgically and frozen. After the pathological diagnosis was confirmed, immunohistochemistry was performed using an anti- alpha(v)beta(3) monoclonal antibody (LM609). The expression of alpha(v)beta(3) was assessed using a 4-tiered (0-3) grading scheme reflecting the percentage of positively staining vessels. All vestibular schwannomas demonstrated strong (grade 3) alpha(v)beta(3) expression. The expression was uniformly prominent in Antoni B regions of the tumors. Of 5 ependymomas, 4 demonstrated uniformly strong alpha(v)beta(3). Oligodendrogliomas, medulloblastomas, and pilocytic astrocytomas demonstrated more variable alpha(v)beta(3). alpha(v)beta(3) may contribute significantly to angiogenesis in vestibular schwannomas and ependymomas. Despite the high vascular density of oligodendrogliomas, pilocytic astrocytomas, and medulloblastomas, these tumors had variable moderate alpha(v)beta(3) expression. This discrepancy suggests temporal and/or regional variability in the angiogenesis in these types of tumor. This study provides the first demonstration of alpha(v)beta(3) expression in vestibular schwannomas, medulloblastomas, and pilocytic astrocytomas.

View details for DOI 10.1016/j.humpath.2005.03.014

View details for PubMedID 16021573
Hematopoietic cells maintain hematopoietic fates upon entering the brain JOURNAL OF EXPERIMENTAL MEDICINE Massengale, M., Wagers, A. J., Vogel, H., Weissman, I. L. 2005; 201 (10): 1579-1589
Abstract

Several studies have reported that bone marrow (BM) cells may give rise to neurons and astrocytes in vitro and in vivo. To further test this hypothesis, we analyzed for incorporation of neural cell types expressing donor markers in normal or injured brains of irradiated mice reconstituted with whole BM or single, purified c-kit(+)Thy1.1(lo)Lin(-)Sca-1(+) (KTLS) hematopoietic stem cells (HSCs), and of unirradiated parabionts with surgically anastomosed vasculature. Each model showed low-level parenchymal engraftment of donor-marker(+) cells with 96-100% immunoreactivity for panhematopoietic (CD45) or microglial (Iba1 or Mac1) lineage markers in all cases studied. Other than one arborizing structure in the olfactory bulb of one BM-transplanted animal, possibly representing a neuronal or glial cell process, we found no donor-marker-expressing astrocytes or non-Purkinje neurons among >10,000 donor-marker(+) cells from 21 animals. These data strongly suggest that HSCs and their progeny maintain lineage fidelity in the brain and do not adopt neural cell fates with any measurable frequency.

View details for DOI 10.1084/jem.20050030

View details for PubMedID 15897275
High-resolution genome-wide mapping of genetic alterations in human glial brain tumors CANCER RESEARCH Bredel, M., Bredel, C., Juric, D., Harsh, G. R., Vogel, H., Recht, L. D., Sikic, B. I. 2005; 65 (10): 4088-4096
Abstract

High-resolution genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of glial brain tumors. We have done such mapping using cDNA microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade. This gene-by-gene approach permitted the precise sizing of critical amplicons and deletions and the detection of multiple new genetic aberrations. It has also revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships and showed that gliomas can be clustered into distinct genetic subgroups. A subset of detected alterations was shown predominantly associated with either astrocytic or oligodendrocytic tumor phenotype. Finally, five novel minimally deleted regions were identified in a subset of tumors, containing putative candidate tumor suppressor genes (TOPORS, FANCG, RAD51, TP53BP1, and BIK) that could have a role in gliomagenesis.

View details for PubMedID 15899798
NF90 regulates cell cycle exit and terminal myogenic differentiation by direct binding to the 3 '-untranslated region of MyoD and p21(WAF1/CIP1) mRNAs JOURNAL OF BIOLOGICAL CHEMISTRY Shi, L. F., Zhao, G. H., Qiu, D. M., Godfrey, W. R., Vogel, H., Rando, T. A., Hu, H., Kao, P. N. 2005; 280 (19): 18981-18989
Abstract

NF90 and splice variant NF110/ILF3/NFAR are double-stranded RNA-binding proteins that regulate gene expression. Mice with targeted disruption of NF90 were engineered. NF90(-/-) mice were born small and weak and succumbed to perinatal death within 12 h because of neuromuscular respiratory failure. Lung inflation and morphology were normal in NF90(-/-) mice. The diaphragm and other skeletal muscles in NF90(-/-) mice demonstrated disorganized arrangement and paucity of myofibers, evidence of myocyte degeneration and increased apoptosis. The expression of myogenic regulators, MyoD, myogenin, and p21WAF1/CIP1, was severely decreased in NF90(-/-) mice. These myogenic transcription factors and cell cycle inhibitors are regulated in part through post-transcriptional mRNA stabilization. Northwestern blotting revealed that NF90 is the principal and specific p21WAF1/CIP1 and MyoD 3'-untranslated region RNA-binding protein in developing skeletal muscles. NF90 regulates transcription factors and a cell cycle inhibitor essential for skeletal muscle differentiation and for survival.

View details for DOI 10.1074/jbc.M411034200

View details for PubMedID 15746098
Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations NEUROLOGY Grogan, P. M., Tanner, S. M., Orstavik, K. H., Knudsen, G. P., Saperstein, D. S., Vogel, H., Barohn, R. J., Herbelin, L. L., McVey, A. L., Katz, J. S. 2005; 64 (9): 1638-1640
Abstract

The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-inactivation appeared to explain the clinical manifestations in only one of the two families.

View details for Web of Science ID 000228995600032

View details for PubMedID 15883335
Amplification of whole tumor genomes and geneby-gene mapping of genomic aberrations from limited sources of fresh-frozen and paraffin-embedded DNA JOURNAL OF MOLECULAR DIAGNOSTICS Bredel, M., Bredel, C., Juric, D., Kim, Y., Vogel, H., Harsh, G. R., Recht, L. D., Pollack, J. R., Sikic, B. I. 2005; 7 (2): 171-182
Abstract

Sufficient quantity of genomic DNA can be a bottleneck in genome-wide analysis of clinical tissue samples. DNA polymerase Phi29 can be used for the random-primed amplification of whole genomes, although the amplification may introduce bias in gene dosage. We have performed a detailed investigation of this technique in archival fresh-frozen and formalin-fixed/paraffin-embedded tumor DNA by using cDNA microarray-based comparative genomic hybridization. Phi29 amplified DNA from matched pairs of fresh-frozen and formalin-fixed/paraffin-embedded tumor samples with similar efficiency. The distortion in gene dosage representation in the amplified DNA was nonrandom and reproducibly involved distinct genomic loci. Regional amplification efficiency was significantly linked to regional GC content of the template genome. The biased gene representation in amplified tumor DNA could be effectively normalized by using amplified reference DNA. Our data suggest that genome-wide gene dosage alterations in clinical tumor samples can be reliably assessed from a few hundred tumor cells. Therefore, this amplification method should lend itself to high-throughput genetic analyses of limited sources of tumor, such as fine-needle biopsies, laser-microdissected tissue, and small paraffin-embedded specimens.

View details for PubMedID 15858140
Overexpression of osteopontin (OPN) in glioblastoma multiforme (GBM). 81st Annual Meeting of the American-Association-of-Neuropathologists Haddix, T. L., Recht, L. D., Myles, T., Leung, L. L., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2005: 456?56
View details for Web of Science ID 000228945800110
Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome HUMAN MOLECULAR GENETICS Mann, M. B., Hodges, C. A., Barnes, E., Vogel, H., Hassold, T. J., Luo, G. 2005; 14 (6): 813-825
Abstract

Type II Rothmund-Thomson syndrome (Type II RTS) is a rare autosomal recessive genetic disorder characterized by a congenital skin rash, birth defects of the skeleton, genomic instability and cancer predisposition. It is caused by mutations in the RECQL4 gene and thus represents one of the three cancer-prone genetic diseases that are caused by mutations in a RecQ helicase-encoding gene. Genomic instability has been suspected as a major underlying cause of this disease, and analyses of Type II RTS patient-derived cells demonstrate unusually high frequencies of chromosomal aberrations, suggesting the involvement of chromosomal instability. However, the nature of the instability induced by RECQL4 mutations has not been clearly defined. We created a viable Recql4 mutant mouse model. These mice exhibit a distinctive skin abnormality, birth defects of the skeletal system, genomic instability and increased cancer susceptibility in a sensitized genetic background. Thus, they provide a useful model for studying Type II RTS. In addition, we demonstrate that cells from these mutant mice have high frequencies of premature centromere separation and aneuploidy. Thus, our observations provide evidence for a previously unsuspected role for Recql4 in sister-chromatid cohesion, and suggest that the chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice.

View details for DOI 10.1093/hmg/ddi075

View details for Web of Science ID 000227404700008

View details for PubMedID 15703196
Diagnostic immunohistology of muscle diseases JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Vogel, H., Zamecnik, J. 2005; 64 (3): 181-193
Abstract

The diagnostic muscle biopsy has seen the use of virtually every histologic technique in existence over the past 50 years. Since the 1960s, enzyme histochemistry has become the chief technique in evaluating muscle biopsies. However, the increasing knowledge of cellular constituents and associated connective tissue of the myofiber coupled with the increasing availability of a broad diversity of antibodies to these proteins promises to bring the diagnosis of muscle disease to the same state of dependency upon immunohistochemistry as in the contemporary pathologic diagnosis of neoplasia. Immunohistochemistry may be used for both the identification of normal antigenic constituents in skeletal muscle and their loss, accumulation, or maldistribution in corresponding myopathies, sometimes with small biopsies or lacking frozen tissue, in paraffin sections. Three broad categories of muscle diseases will be characterized in terms of diagnostic antibodies in current use: dystrophic, congenital/structural, and inflammatory myopathies.

View details for PubMedID 15804049
Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity JOURNAL OF BONE AND MINERAL RESEARCH Offley, S. C., Guo, T. Z., Wei, T. P., Clark, J. D., Vogel, H., Lindsey, D. P., Jacobs, C. R., Yao, W., Lane, N. E., Kingery, W. S. 2005; 20 (2): 257-267
Abstract

This investigation used capsaicin to selectively lesion unmyelinated sensory neurons in rats. Neuronal lesioning induced a loss of trabecular integrity, reduced bone mass and strength, and depleted neuropeptides in nerve and bone. These data suggest that capsaicin-sensitive sensory nerves contribute to trabecular bone integrity.Familial dysautomia is an autosomal recessive disease in which patients suffer from unmyelinated sensory neuron loss, reduced BMD, and frequent fractures. It has been proposed that the loss of neurotransmitters synthesized by unmyelinated neurons adversely affects bone integrity in this hereditary syndrome. The purpose of this study was to determine whether small sensory neurons are required for the maintenance of bone integrity in rats.Ten-month-old male Sprague-Dawley rats were treated with either capsaicin or vehicle. In vivo DXA scanning and micro CT scanning, and histomorphometry were used to evaluate BMD, structure, and cellular activity. Bone strength was measured in distal femoral sections. Body weight and gastrocnemius/soleus weights were measured and spontaneous locomotor activity was monitored. Peroneal nerve morphometry was evaluated using light and electron microscopy. Substance P and calcitonin gene-related peptide (CGRP) content in the sciatic nerve and proximal tibia were determined by enzyme immunoassay (EIA). Substance P signaling was measured using a sciatic nerve stimulation extravasation assay.Four weeks after capsaicin treatment, there was a loss of BMD in the metaphyses of the tibia and femur. In the proximal tibia, the osteoclast number and surface increased, osteoblast activity and bone formation were impaired, and trabecular bone volume and connectivity were diminished. There was also a loss of bone strength in the distal femur. No changes occurred in body weight, 24-h grid-crossing activity, weight bearing, or muscle mass after capsaicin treatment, indicating that skeletal unloading did not contribute to the loss of bone integrity. Capsaicin treatment destroyed 57% of the unmyelinated sensory axons, reduced the substance P and CGRP content in the sciatic nerve and proximal tibia, and inhibited neurogenic extravasation.These results support the hypothesis that capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. Capsaicin-sensitive neurons have efferent functions in the tissues they innervate, effects mediated by transmitters released from the peripheral nerve terminals. We postulate that the deleterious effects of capsaicin treatment on trabecular bone are mediated by reductions in local neurotransmitter content and release.

View details for DOI 10.1359/JBMR.041108

View details for Web of Science ID 000226460800011

View details for PubMedID 15647820
Characterization of the integrin alpha v beta 3 in arteriovenous malformations and cavernous malformations CEREBROVASCULAR DISEASES Lim, M., Haddix, T., Harsh, G. R., Vogel, H., Steinberg, G. K., Guccione, S. 2005; 20 (1): 23-27
Abstract

Alpha V beta 3 (alphavbeta3) is an integrin specifically expressed on the endothelial cells of central nervous system (CNS) neoplasms. However, no data exist on the expression of alphavbeta3 in vascular malformations of the CNS. In this study, we investigate the expression of alphavbeta3 in arteriovenous malformations (AVMs) and cavernous malformations (CMs).Frozen samples of AVMs from 12 patients and CMs from 5 patients were obtained intraoperatively. Once the final pathology had been confirmed, immunohistochemistry was performed using an antibody to the integrin alphavbeta3. The alphavbeta3 expression pattern was graded according to the percentage of positively staining vessels.Ten of 12 AVMs demonstrated alphavbeta3 immunopositivity. Six of these 10 AVMs had moderate or strong staining. Most notably, 5 of the 6 moderate or strongly staining AVMs came from patients 22 years of age or younger. Four of these 6 AVMs had previously been embolized. None of the cavernous malformations demonstrated alphavbeta3 immunopositivity.alphavbeta3 may contribute to the formation of AVMs in younger patients. alphavbeta3 may also provide a potential therapeutic target. The lack of alphavbeta3 expression in cavernous malformations, despite their high vascular densities, suggests that the pathophysiology of their formation differs from that of AVMs.

View details for DOI 10.1159/000086123

View details for PubMedID 15925879
In reply to: Proving pathogenicity - When evolution is not enough AMERICAN JOURNAL OF MEDICAL GENETICS PART A Scaglia, F., Vogel, H., Hawkins, E. P., Vladutiu, G. D., Guan, M. X., Liu, L. L., Wong, L. J. 2004; 131A (1): 109?10
View details for DOI 10.1002/ajmg.a.30319

View details for Web of Science ID 000224899600021
Burden of proof in the postmortem diagnosis of mitochondrial disease: Leigh disease PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Vogel, H. 2004; 7 (6): 615-619
View details for DOI 10.1007/s10024-004-5054-1

View details for PubMedID 15630530
Immunogenicity of embryonic stem cells increases upon differentiation in ischemic myocardium 77th Scientific Meeting of the American-Heart-Association Swijnenburg, R. J., Tanaka, M., Baker, J., Vogel, H., Lebl, D. R., Caffarelli, A. D., Kofidis, T., Robbins, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2004: 507?
View details for Web of Science ID 000224783502699
Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease PEDIATRICS Scaglia, F., Towbin, J. A., Craigen, W. J., Belmont, J. W., Smith, E. O., Neish, S. R., Ware, S. M., Hunter, J. V., Fernbach, S. D., Vladutiu, G. D., Wong, L. J., Vogel, H. 2004; 114 (4): 925-931
Abstract

The aim of this study was to elucidate the frequency of major clinical manifestations in children with mitochondrial disease and establish their clinical course, prognosis, and rates of survival depending on their clinical features.We performed a retrospective review of the medical records of 400 patients who were referred for evaluation of mitochondrial disease. By use of the modified Walker criteria, only patients who were assigned a definite diagnosis were included in the study.A total of 113 pediatric patients with mitochondrial disease were identified. A total of 102 (90%) patients underwent a muscle biopsy as part of the diagnostic workup. A significant respiratory chain (RC) defect, according to the diagnostic criteria, was found in 71% of the patients who were evaluated. In this cohort, complex I deficiency (32%) and combined complex I, III, and IV deficiencies (26%) were the most common causes of RC defects, followed by complex IV (19%), complex III (16%), and complex II deficiencies (7%). Pathogenic mitochondrial DNA abnormalities were found in 11.5% of the patients. A substantial fraction (40%) of patients with mitochondrial disorders exhibited cardiac disease, diagnosed by Doppler echocardiography; however, the majority (60%) of patients had predominant neuromuscular manifestations. No correlation between the type of RC defect and the clinical presentation was observed. Overall, the mean age at presentation was 40 months. However, the mean age at presentation was 33 months in the cardiac group and 44 months in the noncardiac group. Twenty-six (58%) patients in the cardiac group exhibited hypertrophic cardiomyopathy, 29% had dilated cardiomyopathy, and the remainder (13%) had left ventricular noncompaction. Patients with cardiomyopathy had an 18% survival rate at 16 years of age. Patients with neuromuscular features but no cardiomyopathy had a 95% survival at the same age.This study gives strong support to the view that in patients with RC defects, cardiomyopathy is more common than previously thought and tends to follow a different and more severe clinical course. Although with a greater frequency than previously reported, mitochondrial DNA mutations were found in a minority of patients, emphasizing that most mitochondrial disorders of childhood follow a Mendelian pattern of inheritance.

View details for DOI 10.1542/peds.2004-0718

View details for Web of Science ID 000224242200024

View details for PubMedID 15466086
Primitive neuroectodermal tumors, embryonal tumors, and other small cell and poorly differentiated malignant neoplasms of the central and peripheral nervous systems. Annals of diagnostic pathology Vogel, H., Fuller, G. N. 2003; 7 (6): 387-398
Abstract

Many different types of small cell, embryonal, and poorly differentiated neoplasms originate within the central and peripheral nervous systems. Because appropriate treatment is based on a correct diagnosis, the surgical pathologist must be familiar both with basic characteristics of each of the numerous entities as well as the spectrum of morphologic features that each may display. The nosology and nomenclature of these tumors have a rich and varied history. One basic distinction is between primitive neuroectodermal tumors of the central nervous system (cPNETs) and primitive neuroectodermal tumors of the peripheral nervous system (pPNETs), which are clinicopathologically and genetically distinct. Among the cPNETs are medulloblastoma, pineoblastoma, cerebral neuroblastoma, ependymoblastoma, medulloepithelioma, primary rhabdomyosarcoma, and atypical teratoid/rhabdoid tumor, whereas the pPNETs comprise the more differentiated end of a spectrum of neoplasms that include skeletal and extraskeletal Ewing's sarcoma.

View details for PubMedID 15018124
Novel homoplasmic mutation in the mitochondrial tRNA(Tyr) gene associated with atypical mitochondrial cytopathy presenting with focal segmental glomeruloselerosis AMERICAN JOURNAL OF MEDICAL GENETICS PART A Scaglia, F., Vogel, H., Hawkins, E. P., Vladutiu, G. D., Liu, L. L., Wong, L. J. 2003; 123A (2): 172-178
Abstract

We report a 9-year-old girl with a mitochondrial cytopathy preceded by steroid-resistant focal segmental glomerulosclerosis (FSGS). The proband presented at the age of 2 years with steroid-resistant nephrotic syndrome caused by FSGS. Her renal function progressively deteriorated and a dilated cardiomyopathy developed at the age of 7 years. A skeletal muscle biopsy showed a combined respiratory chain (RC) defect and a partial deficiency of coenzyme Q(10). A novel mutation in the evolutionary highly conserved region of the mitochondrial tRNA(Tyr) gene was found in homoplasmic state in skeletal muscle, blood, and renal tissue. The mutation was also found in homoplasmic state in her mildly symptomatic mother. No other maternal family members were available for testing. The present case of mitochondrial cytopathy initially presenting with steroid-resistant nephrotic syndrome, unusual biochemical and renal findings associated with a novel tRNA point mutation suggests that steroid-resistant FSGS can predate other features of mitochondrial disease for a prolonged period of time and that the progressive glomerulopathy associated with combined mitochondrial RC defects is genetically heterogeneous.

View details for DOI 10.1002/ajmg.a.20315

View details for Web of Science ID 000186612500008

View details for PubMedID 14598342
COP9 signalosome subunit 3 (Csn3) is essential for maintenance of cell proliferation in the mouse embryonic epiblast. 53rd Annual Meeting of the American-Society-of-Human-Genetics Yan, J., Walz, K., Nakamura, H., Carattini-Rivera, S., Zhao, Q., Vogel, H., Wei, N., JUSTICE, M. J., Bradley, A., Lupski, J. R. CELL PRESS. 2003: 328?28
View details for Web of Science ID 000185599700929
Cooperativity of p19(ARF), Mdm2, and p53 in murine tumorigenesis ONCOGENE Moore, L., Venkatachalam, S., Vogel, H., Watt, J. C., Wu, C. L., Steinman, H., Jones, S. N., Donehower, L. A. 2003; 22 (49): 7831-7837
Abstract

The p19ARF gene product responds to oncogenic stresses by interfering with the inhibitory effects of Mdm2 on p53, thus enhancing p53 activity and its antiproliferative functions. The absence of p19ARF in the mouse leads to early tumor susceptibility, presumably in part due to decreased p53 activity. To examine the tumorigenic cooperativity of p19ARF, Mdm2, and p53 in vivo, p19ARF-deficient mice were crossed first to p53-deficient mice and then to Mdm2 transgenic mice. The progeny were monitored for tumors. Cooperativity between p19ARF and p53 deficiencies in accelerating tumor formation was observed for most genotypes except p53-/- p19ARF-/- mice. p53-/- p19ARF-/- mice had a tumor incidence similar to p53-/- mice. In this context, tumor suppression by ARF appears to be primarily p53 dependent. The majority of the p19ARF+/- tumors deleted the wildtype p19ARF allele, in agreement with the previous studies, suggesting that p19ARF is a classic 'two hit' tumor suppressor. In a p53+/- background, however, all p19ARF+/- tumors retained a wildtype ARF allele and most also retained wildtype p53. In the second cross between p19ARF-deficient and Mdm2 transgenic mice, cooperativity in tumor incidence between Mdm2 overexpression and ARF deficiency was observed, consistent with the role of p19ARF in negatively regulating Mdm2 activity. These experiments further demonstrate in vivo the inter-relationships of the p19ARF-Mdm2-p53 signaling axis in tumor suppression.

View details for DOI 10.1038/sj.onc.1206985

View details for Web of Science ID 000186240200013

View details for PubMedID 14586409
COP9 signalosome subunit 3 is essential for maintenance of cell proliferation in the mouse embryonic epiblast MOLECULAR AND CELLULAR BIOLOGY Yan, J., Walz, K., Nakamura, H., Carattini-Rivera, S., Zhao, Q., Vogel, H., Wei, N., JUSTICE, M. J., Bradley, A., Lupski, J. R. 2003; 23 (19): 6798-6808
Abstract

Csn3 (Cops3) maps to the mouse chromosome 11 region syntenic to the common deletion interval for the Smith-Magenis syndrome, a contiguous gene deletion syndrome. It encodes the third subunit of an eight-subunit protein complex, the COP9 signalosome (CSN), which controls a wide variety of molecules of different functions. Mutants of this complex caused lethality at early development of both plants and Drosophila melanogaster. CSN function in vivo in mammals is unknown. We disrupted the murine Csn3 gene in three independent ways with insertional vectors, including constructing a approximately 3-Mb inversion chromosome. The heterozygous mice appeared normal, although the protein level was reduced. Csn3(-/-) embryos arrested after 5.5 days postcoitum (dpc) and resorbed by 8.5 dpc. Mutant embryos form an abnormal egg cylinder which does not gastrulate. They have reduced numbers of epiblast cells, mainly due to increased cell death. In the Csn3(-/-) mice, subunit 8 of the COP9 complex was not detected by immunohistochemical techniques, suggesting that the absence of Csn3 may disrupt the entire COP9 complex. Therefore, Csn3 is important for maintaining the integrity of the COP9 signalosome and is crucial to maintain the survival of epiblast cells and thus the development of the postimplantation embryo in mice.

View details for DOI 10.1128/MCB.23.19.6798-6808.2003

View details for Web of Science ID 000185525700009

View details for PubMedID 12972600

View details for PubMedCentralID PMC193933
Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: Phenotypic consequences of gene dosage imbalance MOLECULAR AND CELLULAR BIOLOGY Walz, K., Caratini-Rivera, S., Bi, W. M., Fonseca, P., Mansouri, D. L., Lynch, J., Vogel, H., Noebels, J. L., Bradley, A., Lupski, J. R. 2003; 23 (10): 3646-3655
Abstract

Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangements of which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitive genes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome 17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have been described as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomes carrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome 11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/+ animals are underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination of Df(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dosage effects. Our murine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomic interval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).

View details for DOI 10.1128/MCB.23.10.3646-3655.2003

View details for Web of Science ID 000182696100025

View details for PubMedID 12724422

View details for PubMedCentralID PMC154242
Phenotypic consequences of gene dosage imbalance in chromosome engineered mouse models for del(17)p11.2 (Smith-Magenis syndrome) and it's reciprocal duplication. 52nd Annual Meeting of the American-Society-of-Human-Genetics Walz, K., Carattini-Rivera, S., Bi, W., Mansouri, D., Vogel, H., Paylor, R., Lynch, J. K., Noebels, J. L., Bradley, A., Lupski, J. L. CELL PRESS. 2002: 195?95
View details for Web of Science ID 000178025800162
Mitochondrial DNA depletion associated with partial complex II and IV deficiencies and 3-methylglutaconic aciduria 49th Annual Meeting of the American-Society-of-Human-Genetics Scaglia, F., Sutton, V. R., Bodamer, O. A., Vogel, H., Shapira, S. K., Naviaux, R. K., Vladutiu, G. D. SAGE PUBLICATIONS INC. 2001: 136?38
Abstract

We report a patient with mitochondrial DNA depletion, partial complex II and IV deficiencies, and 3-methylglutaconic aciduria. Complex II deficiency has not been previously observed in mitochondrial DNA depletion syndromes. The observation of 3-methylglutaconic and 3-methylglutaric acidurias may be a useful indicator of a defect in respiratory chain function caused by mitochondrial DNA depletion.

View details for Web of Science ID 000171025300014

View details for PubMedID 11292221
p63 is a p53 homologue required for limb and epidermal morphogenesis NATURE Mills, A. A., Zheng, B. H., Wang, X. J., Vogel, H., Roop, D. R., Bradley, A. 1999; 398 (6729): 708-713
Abstract

The p53 tumour suppressor is a transcription factor that regulates the progression of the cell through its cycle and cell death (apoptosis) in response to environmental stimuli such as DNA damage and hypoxia. Even though p53 modulates these critical cellular processes, mice that lack p53 are developmentally normal, suggesting that p53-related proteins might compensate for the functions of p53 during embryogenesis. Two p53 homologues, p63 and p73, are known and here we describe the function of p63 in vivo. Mice lacking p63 are born alive but have striking developmental defects. Their limbs are absent or truncated, defects that are caused by a failure of the apical ectodermal ridge to differentiate. The skin of p63-deficient mice does not progress past an early developmental stage: it lacks stratification and does not express differentiation markers. Structures dependent upon epidermal-mesenchymal interactions during embryonic development, such as hair follicles, teeth and mammary glands, are absent in p63-deficient mice. Thus, in contrast to p53, p63 is essential for several aspects of ectodermal differentiation during embryogenesis.

View details for Web of Science ID 000079920100051

View details for PubMedID 10227293
Embryonic lethality and tumorigenesis caused by segmental aneuploidy on mouse chromosome 11 GENETICS Liu, P. T., Zhang, H. J., Mclellan, A., Vogel, H., Bradley, A. 1998; 150 (3): 1155-1168
Abstract

Chromosome engineering in mice enables the construction of models of human chromosomal diseases and provides key reagents for genetic studies. To begin to define functional information for a small portion of chromosome 11, deficiencies, duplications, and inversions were constructed in embryonic stem cells with sizes ranging from 1 Mb to 22 cM. Two deficiencies and three duplications were established in the mouse germline. Mice with a 1-Mb duplication developed corneal hyperplasia and thymic tumors, while two different 3- to 4-cM deficiencies were embryonically lethal in heterozygous mice. A duplication corresponding to one of these two deficiencies was able to rescue its haplolethality.

View details for Web of Science ID 000076807800018

View details for PubMedID 9799267
Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation EMBO JOURNAL Venkatachalam, S., Shi, Y. P., Jones, S. N., Vogel, H., Bradley, A., Pinkel, D., Donehower, L. A. 1998; 17 (16): 4657-4667
Abstract

Tumor suppressor genes are generally viewed as being recessive at the cellular level, so that mutation or loss of both tumor suppressor alleles is a prerequisite for tumor formation. The tumor suppressor gene, p53, is mutated in approximately 50% of human sporadic cancers and in an inherited cancer predisposition (Li-Fraumeni syndrome). We have analyzed the status of the wild-type p53 allele in tumors taken from p53-deficient heterozygous (p53+/-) mice. These mice inherit a single null p53 allele and develop tumors much earlier than those mice with two functional copies of wild-type p53. We present evidence that a high proportion of the tumors from the p53+/- mice retain an intact, functional, wild-type p53 allele. Unlike p53+/- tumors which lose their wild-type allele, the tumors which retain an intact p53 allele express p53 protein that induces apoptosis following gamma-irradiation, activates p21(WAF1/CIP1) and Mdm2 expression, represses PCNA expression (a negatively regulated target of wild-type p53), shows high levels of binding to oligonucleotides containing a wild-type p53 response element and prevents chromosomal instability as measured by comparative genomic hybridization. These results indicate that loss of both p53 alleles is not a prerequisite for tumor formation and that mere reduction in p53 levels may be sufficient to promote tumorigenesis.

View details for Web of Science ID 000075613200011

View details for PubMedID 9707425
EFFECTS OF GENETIC BACKGROUND ON TUMORIGENESIS IN P53-DEFICIENT MICE 8th International Conference on Carcinogenesis and Risk Assessment: Genetics and Susceptibility - Impact on Risk Assessment Donehower, L. A., Harvey, M., Vogel, H., McArthur, M. J., Montgomery, C. A., Park, S. H., Thompson, T., Ford, R. J., Bradley, A. WILEY-LISS. 1995: 16?22
Abstract

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.

View details for Web of Science ID A1995RW55100004

View details for PubMedID 7546219

Hannes Vogel MD

Professor of Pathology and of Pediatrics (Pediatric Genetics) and, by courtesy, of Neurosurgery and of Comparative Medicine at the Stanford University Medical Center

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