Bio

Bio


As Assistant Professor of Pathology at Stanford University School of Medicine, Dr. Charville has a special interest in the diagnosis of rare tumors that derive from bone and soft tissues, including muscle, fat, blood vessels, cartilage, and other connective tissues. He also specializes in the classification and study of disorders related to the gastrointestinal and hepatopancreatobiliary systems.

Dr. Charville particularly enjoys working alongside Stanford's excellent physicians-in-training to classify the most diagnostically challenging cases in collaboration with pathologists from around the world, bringing to bear cutting-edge techniques for comprehensive histologic and molecular characterization in each case. This experience serves as the inspiration for laboratory-based investigation of the molecular basis of human disease, focusing on genetic and epigenetic mechanisms of neoplasia.

Clinical Focus


  • Bone-Soft Tissue pathology
  • Gastrointestinal-Hepatopancreatobiliary pathology
  • Anatomic Pathology

Academic Appointments


  • Assistant Professor - Med Center Line, Pathology

Honors & Awards


  • Anatomic Pathology Junior Faculty Teaching Award, Department of Pathology, Stanford University School of Medicine (2019)
  • Faculty Mentoring Award, Department of Pathology, Stanford University School of Medicine (2019)
  • Arthur Purdy Stout Stipend Award, Arthur Purdy Stout Society of Surgical Pathologists (2017)
  • Ruth L. Kirschstein National Research Service Award (F30), National Institute on Aging, National Institutes of Health (2009-2015)
  • Medical Scientist Training Program, National Institutes of Health, Stanford University School of Medicine (2007-2015)
  • Francis P. Venable Medal, Department of Chemistry, UNC-Chapel Hill (2007)
  • Barry M. Goldwater Scholarship, Barry Goldwater Scholarship and Excellence in Education Foundation (2005-2007)

Professional Education


  • M.D., Stanford University School of Medicine (2015)
  • Ph.D., Stanford University School of Medicine, Developmental Biology (2015)
  • Residency:Stanford University Pathology Residency (2018) CA
  • Board Certification, American Board of Pathology, Anatomic Pathology (2018)

Publications

All Publications


  • OLIG2 is a marker of the fusion protein-driven neurodevelopmental transcriptional signature in alveolar rhabdomyosarcoma. Human pathology Raghavan, S. S., Mooney, K. L., Folpe, A. L., Charville, G. W. 2019

    Abstract

    Alveolar rhabdomyosarcoma (RMS) is associated with an underlying pathogenic translocation involving either PAX3 or PAX7 and FOXO1. The presence or absence of this fusion defines the biology and clinical behavior of this subtype of RMS and its identification in tumors is relevant to prognostication and treatment planning. To further explore the unique characteristics of fusion-driven RMS, we leveraged a published gene expression data set to perform an unbiased comparison of 33 fusion-positive and 25 fusion-negative RMS cases. Our analyses revealed 1790 expressed loci with more than two-fold differential expression at a threshold of P<.05. Genes with increased expression in fusion-positive relative to fusion-negative RMS were significantly enriched for those involved in "nervous system development," "neuron differentiation," and "neurogenesis," highlighting a neurodevelopmental gene expression signature driven by the alveolar RMS-associated fusion protein. We show that neurodevelopmental genes are enriched near PAX3-FOXO1 fusion protein binding sites, suggesting a genome-wide fusion protein-mediated activation of cis regulatory elements. Among the genes with differential expression in fusion-positive versus fusion-negative RMS, we identified expression of the transcriptional regulator of motor neuron and oligodendrocyte development, OLIG2, as a marker of the fusion protein-dependent neurodevelopmental signature. Immunohistochemical analysis of a cohort of 73 RMS specimens revealed OLIG2 expression in 96.4% of fusion-positive RMS (N=27/28), but only in 6.7% of fusion-negative RMS (N=3/45; P<.001). The proportion of OLIG2-expressing cells in fusion-negative cases did not exceed 5%, while 92.9% of fusion-positive cases showed expression in at least 5% of cells. Our findings identify OLIG2 expression as a unique manifestation of a neurodevelopmental gene expression signature driven by the oncogenic fusion protein characteristic of alveolar RMS, which may aid in the diagnostic and prognostic distinction of fusion-positive cases.

    View details for DOI 10.1016/j.humpath.2019.07.003

    View details for PubMedID 31299267

  • EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Charville, G. W., Wang, W. L., Ingram, D. R., Roy, A., Thomas, D., Patel, R. M., Hornick, J. L., van de Rijn, M., Lazar, A. J. 2017

    Abstract

    PAX7 is a paired-box transcription factor that is required for the developmental specification of adult skeletal muscle progenitors in mice. We previously demonstrated PAX7 expression as a marker of skeletal muscle differentiation in rhabdomyosarcoma. Here, using analyses of published whole-genome gene expression microarray data, we identify PAX7 as a gene with significantly increased expression in Ewing sarcoma in comparison to CIC-DUX4 round cell sarcoma. Analysis of PAX7 in a large cohort of 103 Ewing sarcoma cases by immunohistochemistry revealed expression in 99.0% of cases (102/103). PAX7 expression was noted in cases demonstrating three distinct Ewing sarcoma EWSR1 translocations involving FLI1, ERG, and NFATc2. No PAX7 expression was observed in any of 27 cases of CIC-DUX4 sarcoma by immunohistochemistry (0%; 0/27). Exploring the mechanism of PAX7 expression in Ewing sarcoma using curated RNA- and ChIP-sequencing data, we demonstrate that the EWSR1 fusion protein is required for PAX7 expression in Ewing sarcoma and identify a candidate EWSR1-FLI1-bound PAX7 enhancer that coincides with both a consensus GGAA repeat-containing binding site and a peak of regulatory H3K27 acetylation. Taken together, our findings provide mechanistic support for the utility of PAX7 immunohistochemistry in the diagnosis of Ewing sarcoma, while linking this sarcoma of uncertain histogenesis to a key transcriptional regulator of mammalian muscle progenitor cells.Modern Pathology advance online publication, 23 June 2017; doi:10.1038/modpathol.2017.49.

    View details for PubMedID 28643791

  • PAX7 Expression in Rhabdomyosarcoma, Related Soft Tissue Tumors, and Small Round Blue Cell Neoplasms. American journal of surgical pathology Charville, G. W., Varma, S., Forgó, E., Dumont, S. N., Zambrano, E., Trent, J. C., Lazar, A. J., van de Rijn, M. 2016; 40 (10): 1305-1315

    Abstract

    Rhabdomyosarcoma, the most common soft tissue malignancy of childhood, is a morphologically variable tumor defined by its phenotype of skeletal muscle differentiation. The diagnosis of rhabdomyosarcoma often relies in part on the identification of myogenic gene expression using immunohistochemical or molecular techniques. However, these techniques show imperfect sensitivity and specificity, particularly in scant tissue biopsies. Here, we expand the toolkit for rhabdomyosarcoma diagnosis by studying the expression of PAX7, a transcriptional regulator of mammalian muscle progenitor cells implicated in the pathogenesis of rhabdomyosarcoma. Immunohistochemical analysis of tissue microarrays using a monoclonal anti-PAX7 antibody was used to characterize PAX7 expression in 25 non-neoplastic tissues, 109 rhabdomyosarcomas, and 697 small round blue cell or other soft tissue tumors. Among non-neoplastic tissues, PAX7 was specifically expressed in adult muscle progenitor cells (satellite cells). In embryonal rhabdomyosarcoma, PAX7 expression was positive in 52 of 63 cases (83%), negative in 9 of 63 cases (14%), and focal in 2 of 63 cases (3%). PAX7-positive embryonal rhabdomyosarcoma cases included several showing focal or negative myogenin expression. PAX7 expression in alveolar rhabdomyosarcoma was positive in 6 of 31 cases (19%), negative in 14 of 31 cases (45%), and focal in 11 of 31 cases (36%). In addition, PAX7 was expressed in 5 of 7 pleomorphic rhabdomyosarcomas (71%) and 6 of 8 spindle cell rhabdomyosarcomas (75%). Among histologic mimics, only Ewing sarcoma showed PAX7 expression (7/7 cases, 100%). In contrast, expression of PAX7 was not seen in the large majority (688/690, 99.7%) of examined cases of other soft tissue tumors, small round blue cell neoplasms, and leukemias/lymphomas. In summary, immunohistochemical analysis of PAX7 expression may be a useful diagnostic tool in the assessment of skeletal muscle differentiation in human tumors.

    View details for DOI 10.1097/PAS.0000000000000717

    View details for PubMedID 27526298

  • Diagnostic classification of soft tissue malignancies: A review and update from a surgical pathology perspective. Current problems in cancer Cloutier, J. M., Charville, G. W. 2019

    Abstract

    Soft tissue sarcomas encompass a broad spectrum of histologically, clinically, and molecularly diverse neoplasms that present unique diagnostic and therapeutic challenges. Accurate classification is essential both for appropriate risk stratification and for guiding clinical management. Once classified almost exclusively based on the morphologic appearance of the tumor by light microscopy, many soft tissue sarcomas are now known to manifest recurrent patterns of genetic alterations. In addition to enabling molecular confirmation of histologic diagnoses, discovery of these recurrent genetic alterations has helped to refine existing morphologic definitions of sarcoma subtypes and even prompted the discovery of new subtypes. As therapy for sarcoma has become increasingly tailored to a specific entity, the integration of molecular data has assumed added importance in diagnostic decision making. In this article, we summarize principles of the histologic evaluation of soft tissue sarcomas, discuss specific diagnostic features of several of the most common sarcoma subtypes, and describe our vision for a future of soft tissue sarcoma diagnosis that merges morphologic, genetic, and epigenetic features to arrive at diagnoses that are aligned with tumor-specific, biologically targeted treatment approaches.

    View details for DOI 10.1016/j.currproblcancer.2019.05.006

    View details for PubMedID 31200960

  • INSM1 Expression in Peripheral Neuroblastic Tumors and Other Embryonal Neoplasms. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society Wang, H., Krishnan, C., Charville, G. W. 2019: 1093526619843725

    Abstract

    Insulinoma-associated protein 1 (INSM1) is a transcription factor that functions in neuroepithelial tissue development and shows expression in neuroendocrine neoplasms. Given the role of INSM1 in controlling differentiation of the sympatho-adrenal lineage, we hypothesized that INSM1 expression would define a subset of neuroblastic tumors. This study aimed to characterize the immunohistochemical profile of INSM1 in a cohort of peripheral neuroblastic tumors and compare INSM1 expression in these tumors to that seen in other embryonal neoplasms, using both tissue microarrays and whole-slide histologic sections. INSM1 showed nuclear expression in 39/50 (78%) peripheral neuroblastic tumors, including 27/32 (84%) neuroblastomas, 9/9 (100%) ganglioneuroblastomas, and 3/9 (33%) ganglioneuromas. Altogether, 70% of peripheral neuroblastic tumors showed anti-INSM1 immunoreactivity in more than 20% of tumor nuclei. Although no non-neuroblastic tumors in this study exhibited INSM1 expression in more than 20% of nuclei, focal or patchy staining was identified in 7/14 (50%) rhabdomyosarcomas, 7/22 (32%) nephroblastomas, and 4/20 (20%) Ewing sarcomas. The absence of INSM1 expression in peripheral neuroblastic tumors was restricted to undifferentiated and poorly differentiated neuroblastomas, as well as mature ganglioneuromas, mimicking the transient INSM1 expression seen in sympatho-adrenal differentiation during normal development. No significant association between MYCN amplification status and INSM1 expression was observed. We found that all 3 INSM1-negative neuroblastoma patients with available follow-up were alive at a median of 15 years, in comparison to 9 of 13 INSM1-positive neuroblastoma patients living at a median of 5 years. Additional studies are needed to determine whether INSM1 expression is indicative of a clinically significant differentiation state in neuroblastoma.

    View details for PubMedID 30975032

  • Immune checkpoint blockade as a potential therapeutic strategy for undifferentiated malignancies. Human pathology Devereaux, K. A., Charu, V., Zhao, S., Charville, G. W., Bangs, C. D., van de Rijn, M., Cherry, A. M., Natkunam, Y. 2018; 82: 39?45

    Abstract

    Undifferentiated malignancies (UMs) encompass a diverse set of aggressive tumors that pose not only a diagnostic challenge but also a challenge for clinical management. Most tumors in this category are currently treated empirically with nonspecific chemotherapeutic agents that yield extremely poor clinical response. Given that UMs are inherently genetically unstable neoplasms with the potential for immune dysregulation and increased neoantigen production, they are likely to be particularly amenable to immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) or its ligands, PD-L1 and PD-L2, to promote T-cell antitumor activity. Aberrant expression of PD-L1 and, more recently, chromosomal 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) alterations can be used as biomarkers to predict responsiveness to checkpoint inhibitors. Here we evaluated 93 cases previously diagnosed as an "undifferentiated" malignancy and found that 56% (52/93) of UMs moderately to strongly express PD-L1 by immunohistochemistry (IHC). Concurrent CD274(PD-L1) and PDCD1LG2(PD-L2) fluorescence in situ hybridization (FISH) was performed on 24 of these cases and demonstrates a genetic gain at both loci in 62.5% of UMs. Genetic alterations at the CD274(PD-L1) and PDCD1LG2(PD-L2) loci were found to be completely concordant by FISH. Overall, we found that a significant proportion of UMs express PD-L1 and provide molecular support for using checkpoint inhibitors as a treatment approach for this class of tumors.

    View details for PubMedID 30539796

  • Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells. Cell stem cell Liu, L., Charville, G. W., Cheung, T. H., Yoo, B., Santos, P. J., Schroeder, M., Rando, T. A. 2018

    Abstract

    The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and that this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs invivo. Altogether, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential.

    View details for PubMedID 30244867

  • Gastrointestinal Tract Vasculopathy: Clinicopathology and Description of a Possible "New Entity" With Protean Features. The American journal of surgical pathology Louie, C. Y., DiMaio, M. A., Charville, G. W., Berry, G. J., Longacre, T. A. 2018

    Abstract

    Noninfectious gastrointestinal (GI) vasculopathic disorders are rare and are often overlooked in histopathologic examination or when forming differential diagnoses due to their rarity. However, involvement of the GI tract may lead to serious complications, including ischemia and perforation. Since awareness of the types of vasculopathy that may involve the GI tract is central to arriving at a correct diagnosis, we reviewed our institutional experience with GI tract vasculopathy in order to enhance diagnostic accuracy of these rare lesions. We report the clinical and histologic features of 16 cases (excluding 16 cases of immunoglobulin A vasculitis) diagnosed over a 20-year period. Of the 16 patients, 14 presented with symptoms related to the GI vasculopathy (including 2 presenting with a mass on endoscopic examination). The remaining 2 patients presented with incarcerated hernia and invasive adenocarcinoma. The vasculopathy was not associated with systemic disease and appeared limited to the GI tract in 8 patients. Eight had associated systemic disease, but only 6 had a prior diagnosis. The underlying diagnoses in these 6 patients included systemic lupus erythematosus (1), dermatomyositis (2), rheumatoid arthritis (1), eosinophilic granulomatosis with polyangiitis (1), and Crohn disease (1). One patient with granulomatous polyangiitis and 1 patient with systemic lupus erythematosus initially presented with GI symptoms. The 8 cases of isolated GI tract vasculopathy consisted of enterocolic lymphocytic phlebitis (4), idiopathic myointimal hyperplasia of the sigmoid colon (1), idiopathic myointimal hyperplasia of the ileum (1), granulomatous vasculitis (1), and polyarteritis nodosa-like arteritis (1). Isolated GI tract vasculopathy is rare, but appears to be almost as common as that associated with systemic disease. The chief primary vasculopathies are enterocolic lymphocytic colitis and idiopathic myointimal hyperplasia. Although the latter occurs predominantly in the left colon, rare examples occur in the small bowel and likely represent a complex, more protean disorder.

    View details for PubMedID 29624512

  • Bioengineered Viral Platform for Intramuscular Passive Vaccine Delivery to Human Skeletal Muscle. Molecular therapy. Methods & clinical development Paulk, N. K., Pekrun, K., Charville, G. W., Maguire-Nguyen, K., Wosczyna, M. N., Xu, J., Zhang, Y., Lisowski, L., Yoo, B., Vilches-Moure, J. G., Lee, G. K., Shrager, J. B., Rando, T. A., Kay, M. A. 2018; 10: 144?55

    Abstract

    Skeletal muscle is ideal for passive vaccine administration as it is easily accessible by intramuscular injection. Recombinant adeno-associated virus (rAAV) vectors are in consideration for passive vaccination clinical trials for HIV and influenza. However, greater human skeletal muscle transduction is needed for therapeutic efficacy than is possible with existing serotypes. To bioengineer capsids with therapeutic levels of transduction, we utilized a directed evolution approach to screen libraries of shuffled AAV capsids in pools of surgically resected human skeletal muscle cells from five patients. Six rounds of evolution were performed in various muscle cell types, and evolved variants were validated against existing muscle-tropic serotypes rAAV1, 6, and 8. We found that evolved variants NP22 and NP66 had significantly increased primary human and rhesus skeletal muscle fiber transduction from surgical explants ex vivo and in various primary and immortalized myogenic lines in vitro. Importantly, we demonstrated reduced seroreactivity compared to existing serotypes against normal human serum from 50 adult donors. These capsids represent powerful tools for human skeletal muscle expression and secretion of antibodies from passive vaccines.

    View details for PubMedID 30101152

  • Serous Neoplasms of the Pancreas: A Comprehensive Review. Archives of pathology & laboratory medicine Charville, G. W., Kao, C. S. 2018; 142 (9): 1134?40

    Abstract

    Serous neoplasms are uncommon, usually cystic tumors that account for less than 1% of all primary pancreatic lesions. They consist predominantly of a monomorphic epithelial cell population with a glycogen-rich, clear cytoplasm, reminiscent of clear cell renal cell carcinoma, with which serous neoplasms share an association with underlying VHL loss-of-function mutations. Serous neoplasms have no metastatic potential. Accurate recognition of this entity, including its various architectural subtypes, is critical to appropriate prognostication and treatment. Immunohistochemical detection of inhibin and calponin expression, along with the absence of both estrogen and progesterone receptors and nuclear ?-catenin, can help to distinguish serous neoplasms from mimics. With the advent of minimally invasive and molecularly driven diagnostic techniques, the pathologist's role in the assessment and management of serous neoplasms has become increasingly complex and important. We provide an update on the histologic, immunohistochemical, and molecular features of pancreatic serous neoplasms for the practicing pathologist.

    View details for PubMedID 30141993

  • PAX7 expression in sarcomas bearing the EWSR1-NFATC2 translocation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Charville, G. W., Wang, W. L., Ingram, D. R., Roy, A., Thomas, D., Patel, R. M., Hornick, J. L., van de Rijn, M., Lazar, A. J. 2018

    View details for PubMedID 29985454

  • The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. Cancer cell McBride, M. J., Pulice, J. L., Beird, H. C., Ingram, D. R., D'Avino, A. R., Shern, J. F., Charville, G. W., Hornick, J. L., Nakayama, R. T., Garcia-Rivera, E. M., Araujo, D. M., Wang, W. L., Tsai, J. W., Yeagley, M., Wagner, A. J., Futreal, P. A., Khan, J., Lazar, A. J., Kadoch, C. 2018

    Abstract

    Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

    View details for PubMedID 29861296

  • When Lightning Strikes Twice. Digestive diseases and sciences Baiu, I., Charville, G. W., Visser, B. C. 2018

    View details for PubMedID 29302877

  • A Chance to Cut Is a Chance to Cure: Endoscopic Submucosal Dissection for Early Gastric Cancer. Digestive diseases and sciences Huang, R. J., Charville, G. W., Hwang, J. H., Friedland, S. 2018

    View details for PubMedID 30350240

  • Resolution of Crizotinib-Associated Fulminant Hepatitis following Cessation of Treatment. Case reports in hepatology Charville, G. W., Padda, S. K., Sibley, R. K., Puthillath, A., Kwo, P. Y. 2018; 2018: 3413592

    Abstract

    Targeted cancer treatments offer the prospect of precise inhibition of tumor growth without the untoward off-target toxicity of traditional chemotherapies. Still, unintended, often idiosyncratic side effects, such as drug-induced liver injury, can occur. We discuss the case of a 26-year-old female with a history of ROS1-rearranged lung adenocarcinoma, undergoing treatment with the tyrosine kinase inhibitor crizotinib, who presented to our hospital with abdominal pain and scleral icterus. Liver chemistries were notable for hyperbilirubinemia (5mg/dL total) and marked transaminasemia (AST 1736 U/L, ALT >3500 U/L); liver biopsy demonstrated acute hepatitis with extensive necrosis. There was no evidence of an infectious or autoimmune etiology. It was discovered that the patient was taking a 500mg once daily dose of crizotinib, in lieu of the intended dose of 250mg twice daily. After immediate cessation of crizotinib therapy upon hospital admission, there was complete biochemical resolution of the hepatitis. This case highlights the potential reversibility of fulminant crizotinib-associated hepatoxicity, possibly related to supratherapeutic dosing, when managed with abrupt stoppage of the drug and initiation of supportive care.

    View details for PubMedID 30155324

  • Immunohistochemistry for PAX7 is a useful confirmatory marker for Ewing sarcoma in decalcified bone marrow core biopsy specimens. Virchows Archiv : an international journal of pathology Fernandez-Pol, S., van de Rijn, M., Natkunam, Y., Charville, G. W. 2018

    Abstract

    PAX7 has been recently demonstrated to be a highly sensitive marker for Ewing sarcoma, and thus far has only been shown to label a relatively small set of other mesenchymal neoplasms. Because the processing of bone marrow core biopsies can often hinder the performance of immunohistochemical stains, we set out to determine if our laboratory's PAX7 staining protocol effectively detects Ewing sarcoma in Bouin's fixed, decalcified bone marrow core biopsies. We stained ten core biopsies involved by Ewing sarcoma, nine non-involved core biopsies, and 13 core biopsies involved by histologic mimics of Ewing sarcoma. Only the ten biopsies involved by Ewing sarcoma and four biopsies with rhabdomyosarcoma showed strong nuclear PAX7 staining. None of the other tumors demonstrated PAX7 expression. This study demonstrates that the PAX7 staining protocol used in our laboratory is a useful marker for Ewing sarcoma and other PAX7-positive tumors in decalcified bone marrow core biopsies.

    View details for PubMedID 30014288

  • Endoscopic Resection of Skull Base Teratoma in Klippel-Feil Syndrome through Use of Combined Ultrasonic and Bipolar Diathermy Platforms. Case reports in otolaryngology Edward, J. A., Psaltis, A. J., Williams, R. A., Charville, G. W., Dodd, R. L., Nayak, J. V. 2017; 2017: 6384586-?

    Abstract

    Klippel-Feil syndrome (KFS) is associated with numerous craniofacial abnormalities but rarely with skull base tumor formation. We report an unusual and dramatic case of a symptomatic, mature skull base teratoma in an adult patient with KFS, with extension through the basisphenoid to obstruct the nasopharynx. This benign lesion was associated with midline palatal and cerebral defects, most notably pituitary and vertebrobasilar arteriolar duplications. A multidisciplinary workup and a complete endoscopic, transnasal surgical approach between otolaryngology and neurosurgery were undertaken. Out of concern for vascular control of the fibrofatty dense tumor stalk at the skull base and need for complete teratoma resection, we successfully employed a tissue resection tool with combined ultrasonic and bipolar diathermy to the tumor pedicle at the sphenoid/clivus junction. No CSF leak or major hemorrhage was noted using this endonasal approach, and no concerning postoperative sequelae were encountered. The patient continues to do well now 3 years after tumor extirpation, with resolution of all preoperative symptoms and absence of teratoma recurrence. KFS, teratoma biology, endocrine gland duplication, and the complex considerations required for successfully addressing this type of advanced skull base pathology are all reviewed herein.

    View details for DOI 10.1155/2017/6384586

    View details for PubMedID 28133560

  • Prognostic Gene Expression Signatures in Sarcoma: Finding Clarity in Complexity. Annals of oncology : official journal of the European Society for Medical Oncology Charville, G. W., Lazar, A. J. 2017

    View details for PubMedID 29982358

  • Surgical Pathology of Gastrointestinal Stromal Tumors: Practical Implications of Morphologic and Molecular Heterogeneity for Precision Medicine. Advances in anatomic pathology Charville, G. W., Longacre, T. A. 2017

    Abstract

    Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the gastrointestinal tract, exhibits diverse histologic and clinical manifestations. With its putative origin in the gastrointestinal pacemaker cell of Cajal, GIST can arise in association with any portion of the tubular gastrointestinal tract. Morphologically, GISTs are classified as spindled or epithelioid, though each of these subtypes encompasses a broad spectrum of microscopic appearances, many of which mimic other histologic entities. Despite this morphologic ambiguity, the diagnosis of GIST is aided in many cases by immunohistochemical detection of KIT (CD117) or DOG1 expression. The natural history of GIST ranges from that of a tumor cured by surgical resection to that of a locally advanced or even widely metastatic, and ultimately fatal, disease. This clinicopathologic heterogeneity is paralleled by an underlying molecular diversity: the majority of GISTs are associated with spontaneous activating mutations in KIT, PDGFRA, or BRAF, while additional subsets are driven by genetic lesions-often inherited-of NF1 or components of the succinate dehydrogenase enzymatic complex. Specific gene mutations correlate with particular anatomic or morphologic characteristics and, in turn, with distinct clinical behaviors. Therefore, prognostication and treatment are increasingly dictated not only by morphologic clues, but also by accompanying molecular genetic features. In this review, we provide a comprehensive description of the heterogenous molecular underpinnings of GIST, including implications for the practicing pathologist with regard to morphologic identification, immunohistochemical diagnosis, and clinical management.

    View details for PubMedID 28820749

  • Evidence for a 'preinvasive' variant of fungal sinusitis: Tissue invasion without angioinvasion. World journal of otorhinolaryngology - head and neck surgery Paknezhad, H., Borchard, N. A., Charville, G. W., Ayoub, N. F., Choby, G. W., Thamboo, A., Nayak, J. V. 2017; 3 (1): 37?43

    Abstract

    Clinical experience has suggested the existence of an intermediate form of fungal sinusitis between the categories of non-invasive fungal sinusitis (non-IFS) and invasive fungal sinusitis (IFS). This fungal sinusitis variant demonstrates unhealthy mucosa by endoscopy with fungal invasion, but lacks angioinvasion microscopically, representing what clinically behaves as a 'pre-invasive' subtype of fungal sinusitis. Unlike non-IFS disease, patients with pre-invasive fungal sinusitis were still felt to require anti-fungal medications due to histologic presence of invasive fungus. While sharing some clinical features of IFS, these 'intermediate' patients were successfully spared extended and repeated surgical debridements given the microscopic findings, and have been successfully treated with shorter courses of antifungal therapy. These select patients have had favorable outcomes when managed in a judicious and semi-aggressive manner, in an undefined zone between the treatments for routine fungal ball and aggressive IFS.

    View details for PubMedID 29204577

  • 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

  • Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells STEM CELL REPORTS Charville, G. W., Cheung, T. H., Yoo, B., Santos, P. J., Lee, G. K., Shrager, J. B., Rando, T. A. 2015; 5 (4): 621-632

    Abstract

    Adult skeletal muscle stem cells, or satellite cells (SCs), regenerate functional muscle following transplantation into injured or diseased tissue. To gain insight into human SC (huSC) biology, we analyzed transcriptome dynamics by RNA sequencing of prospectively isolated quiescent and activated huSCs. This analysis indicated that huSCs differentiate and lose proliferative potential when maintained in high-mitogen conditions ex vivo. Further analysis of gene expression revealed that p38 MAPK acts in a transcriptional network underlying huSC self-renewal. Activation of p38 signaling correlated with huSC differentiation, while inhibition of p38 reversibly prevented differentiation, enabling expansion of huSCs. When transplanted, expanded huSCs differentiated to generate chimeric muscle and engrafted as SCs in the sublaminar niche with a greater frequency than freshly isolated cells or cells cultured without p38 inhibition. These studies indicate characteristics of the huSC transcriptome that promote expansion ex vivo to allow enhanced functional engraftment of a defined population of self-renewing huSCs.

    View details for DOI 10.1016/j.stemcr.2015.08.004

    View details for PubMedID 26344908

  • Isolation of skeletal muscle stem cells by fluorescence-activated cell sorting NATURE PROTOCOLS Liu, L., Cheung, T. H., Charville, G. W., Rando, T. A. 2015; 10 (10): 1612-1624

    Abstract

    The prospective isolation of purified stem cell populations has dramatically altered the field of stem cell biology, and it has been a major focus of research across tissues in different organisms. Muscle stem cells (MuSCs) are now among the most intensely studied stem cell populations in mammalian systems, and the prospective isolation of these cells has allowed cellular and molecular characterizations that were not dreamed of a decade ago. In this protocol, we describe how to isolate MuSCs from limb muscles of adult mice by fluorescence-activated cell sorting (FACS). We provide a detailed description of the physical and enzymatic dissociation of mononucleated cells from limb muscles, a procedure that is essential in order to maximize cell yield. We also describe a FACS-based method that is used subsequently to obtain highly pure populations of either quiescent or activated MuSCs (VCAM(+)CD31(-)CD45(-)Sca1(-)). The isolation process takes ?5-6 h to complete. The protocol also allows for the isolation of endothelial cells, hematopoietic cells and mesenchymal stem cells from muscle tissue.

    View details for DOI 10.1038/nprot.2015.110

    View details for PubMedID 26401916

  • Bordetella petrii Sinusitis in an Immunocompromised Adolescent. Pediatric infectious disease journal Nagata, J. M., Charville, G. W., Klotz, J. M., Wickremasinghe, W. R., Kann, D. C., Schwenk, H. T., Longhurst, C. A. 2015; 34 (4): 458-?

    View details for DOI 10.1097/INF.0000000000000564

    View details for PubMedID 25760569

  • mTORC1 controls the adaptive transition of quiescent stem cells from G(0) to G(Alert) NATURE Rodgers, J. T., King, K. Y., Brett, J. O., Cromie, M. J., Charville, G. W., Maguire, K. K., Brunson, C., Mastey, N., Liu, L., Tsai, C., Goodell, M. A., Rando, T. A. 2014; 510 (7505): 393-?

    Abstract

    A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term G(Alert). Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into G(Alert) and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-G(Alert) transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G(Alert) possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G(Alert) functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.

    View details for DOI 10.1038/nature13255

    View details for Web of Science ID 000337350200034

    View details for PubMedCentralID PMC4065227

  • mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature Rodgers, J. T., King, K. Y., Brett, J. O., Cromie, M. J., Charville, G. W., Maguire, K. K., Brunson, C., Mastey, N., Liu, L., Tsai, C., Goodell, M. A., Rando, T. A. 2014; 510 (7505): 393-396

    Abstract

    A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term G(Alert). Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into G(Alert) and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-G(Alert) transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G(Alert) possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G(Alert) functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.

    View details for DOI 10.1038/nature13255

    View details for PubMedID 24870234

  • The mortal strand hypothesis: Non-random chromosome inheritance and the biased segregation of damaged DNA. Seminars in cell & developmental biology Charville, G. W., Rando, T. A. 2013; 24 (8-9): 653-660

    Abstract

    If a eukaryotic cell is to reproduce, it must duplicate its genetic information in the form of DNA, and faithfully segregate that information during a complex process of cell division. During this division process, the resulting cells inherit one, and only one, copy of each chromosome. Over thirty years ago, it was predicted that the segregation of sister chromosomes could occur non-randomly, such that a daughter cell would preferentially inherit one of the two sister chromosomes according to some characteristic of that chromosome's template DNA strand. Although this prediction has been confirmed in studies of various cell-types, we know little of both the mechanism by which the asymmetric inheritance occurs and the significance it has to cells. In this essay, we propose a new model of non-random chromosome segregation-the mortal strand hypothesis-and discuss tests of the model that will provide insight into the molecular choreography of this intriguing phenomenon.

    View details for DOI 10.1016/j.semcdb.2013.05.006

    View details for PubMedID 23701893

  • Chromatin Modifications as Determinants of Muscle Stem Cell Quiescence and Chronological Aging CELL REPORTS Liu, L., Cheung, T. H., Charville, G. W., Hurgo, B. M., Leavitt, T., Shih, J., Brunet, A., Rando, T. A. 2013; 4 (1): 189-204

    Abstract

    The ability to maintain quiescence is critical for the long-term maintenance of a functional stem cell pool. To date, the epigenetic and transcriptional characteristics of quiescent stem cells and how they change with age remain largely unknown. In this study, we explore the chromatin features of adult skeletal muscle stem cells, or satellite cells (SCs), which reside predominantly in a quiescent state in fully developed limb muscles of both young and aged mice. Using a ChIP-seq approach to obtain global epigenetic profiles of quiescent SCs (QSCs), we show that QSCs possess a permissive chromatin state in which few genes are epigenetically repressed by Polycomb group (PcG)-mediated histone 3 lysine 27 trimethylation (H3K27me3), and a large number of genes encoding regulators that specify nonmyogenic lineages are demarcated by bivalent domains at their transcription start sites (TSSs). By comparing epigenetic profiles of QSCs from young and old mice, we also provide direct evidence that, with age, epigenetic changes accumulate and may lead to a functional decline in quiescent stem cells. These findings highlight the importance of chromatin mapping in understanding unique features of stem cell identity and stem cell aging.

    View details for DOI 10.1016/j.celrep.2013.05.043

    View details for PubMedID 23810552

  • A sexy spin on nonrandom chromosome segregation. Cell stem cell Charville, G. W., Rando, T. A. 2013; 12 (6): 641-643

    Abstract

    Nonrandom chromosome segregation is an intriguing phenomenon linked to certain asymmetric stem cell divisions. In a recent report in Nature, Yadlapalli and Yamashita (2013) observe nonrandom segregation of X and Y chromosomes in Drosophila germline stem cells and shed light on the complex mechanisms of this fascinating process.

    View details for DOI 10.1016/j.stem.2013.05.013

    View details for PubMedID 23746972

  • Maintenance of muscle stem-cell quiescence by microRNA-489 NATURE Cheung, T. H., Quach, N. L., Charville, G. W., Liu, L., Park, L., Edalati, A., Yoo, B., Hoang, P., Rando, T. A. 2012; 482 (7386): 524-U247

    Abstract

    Among the key properties that distinguish adult mammalian stem cells from their more differentiated progeny is the ability of stem cells to remain in a quiescent state for prolonged periods of time. However, the molecular pathways for the maintenance of stem-cell quiescence remain elusive. Here we use adult mouse muscle stem cells (satellite cells) as a model system and show that the microRNA (miRNA) pathway is essential for the maintenance of the quiescent state. Satellite cells that lack a functional miRNA pathway spontaneously exit quiescence and enter the cell cycle. We identified quiescence-specific miRNAs in the satellite-cell lineage by microarray analysis. Among these, miRNA-489 (miR-489) is highly expressed in quiescent satellite cells and is quickly downregulated during satellite-cell activation. Further analysis revealed that miR-489 functions as a regulator of satellite-cell quiescence, as it post-transcriptionally suppresses the oncogene Dek, the protein product of which localizes to the more differentiated daughter cell during asymmetric division of satellite cells and promotes the transient proliferative expansion of myogenic progenitors. Our results provide evidence of the miRNA pathway in general, and of a specific miRNA, miR-489, in actively maintaining the quiescent state of an adult stem-cell population.

    View details for DOI 10.1038/nature10834

    View details for PubMedID 22358842

  • Stem cell ageing and non-random chromosome segregation PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Charville, G. W., Rando, T. A. 2011; 366 (1561): 85-93

    Abstract

    Adult stem cells maintain the mature tissues of metazoans. They do so by reproducing in such a way that their progeny either differentiate, and thus contribute functionally to a tissue, or remain uncommitted and replenish the stem cell pool. Because ageing manifests as a general decline in tissue function, diminished stem cell-mediated tissue maintenance may contribute to age-related pathologies. Accordingly, the mechanisms by which stem cell regenerative potential is sustained, and the extent to which these mechanisms fail with age, are fundamental determinants of tissue ageing. Here, we explore the mechanisms of asymmetric division that account for the sustained fitness of adult stem cells and the tissues that comprise them. In particular, we summarize the theory and experimental evidence underlying non-random chromosome segregation-a mitotic asymmetry arising from the unequal partitioning of chromosomes according to the age of their template DNA strands. Additionally, we consider the possible consequences of non-random chromosome segregation, especially as they relate to both replicative and chronological ageing in stem cells. While biased segregation of chromosomes may sustain stem cell replicative potential by compartmentalizing the errors derived from DNA synthesis, it might also contribute to the accrual of replication-independent DNA damage in stem cells and thus hasten chronological ageing.

    View details for DOI 10.1098/rstb.2010.0279

    View details for PubMedID 21115534

  • Reduced bacterial adhesion to fibrinogen-coated substrates via nitric oxide release BIOMATERIALS Charville, G. W., Hetrick, E. M., Geer, C. B., Schoenfisch, M. H. 2008; 29 (30): 4039-4044

    Abstract

    The ability of nitric oxide (NO)-releasing xerogels to reduce fibrinogen-mediated adhesion of Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli is described. A negative correlation was observed between NO surface flux and bacterial adhesion for each species tested. For S. aureus and E. coli, reduced adhesion correlated directly with NO flux from 0 to 30 pmol cm(-2)s(-1). A similar dependence for S. epidermidis was evident from 18 to 30 pmol cm(-2)s(-1). At a NO flux of 30 pmol cm(-2)s(-1), surface coverage of S. aureus, S. epidermidis, and E. coli was reduced by 96, 48, and 88%, respectively, compared to non-NO-releasing controls. Polymeric NO release was thus demonstrated to be an effective approach for significantly reducing fibrinogen-mediated adhesion of both gram-positive and gram-negative bacteria in vitro, thereby illustrating the advantage of active NO release as a strategy for inhibiting bacterial adhesion in the presence of pre-adsorbed protein.

    View details for DOI 10.1016/j.biomaterials.2008.07.005

    View details for Web of Science ID 000260025100002

    View details for PubMedID 18657857

  • Nitric oxide-releasing xerogel-based fiber-optic pH sensors ANALYTICAL CHEMISTRY Dobmeier, K. P., Charville, G. W., Schoenfisch, M. H. 2006; 78 (21): 7461-7466

    Abstract

    A xerogel-based optical pH sensor capable of releasing low levels of nitric oxide (NO) and measuring changes in solution pH is reported. Through simple dip-coating procedures, aminoalkoxysilane-based xerogel films modified with N-diazeniumdiolate NO donor precursors and the fluorescent pH indicator seminaphthorhodamine-1 carboxylate (SNARF-1) were sequentially deposited onto optical fibers. The resulting sensors were characterized by fast and linear response to pH throughout the physiological range (pH 7.0-7.8). Real-time chemiluminescence measurements confirmed that the presence of the overlying SNARF-1-containing TMOS layer did not have an inhibitory effect on N-diazeniumdiolate formation or NO release, and the NO-releasing coatings were capable of maintaining NO fluxes >0.4 pmol/cm(2) s up to 16 h. In vitro blood compatibility studies using porcine platelets confirmed the expected thromboresistivity of the NO-releasing xerogel coatings.

    View details for DOI 10.1021/ac060995p

    View details for Web of Science ID 000241670000028

    View details for PubMedID 17073413

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