Pituitary Center Research
The pituitary and neuroendocrine clinical programs at Stanford bring together knowledge and expertise in both clinical research and teaching applications to treatment of neuroendocrine diseases.
Our expert physicians and surgeons are also researchers, offering the latest clinical trials, and conducting cutting-edge research using state-of-the-art technologies.
Clinical Trials
Clinical trials are research studies that evaluate a new medical approach, device, drug, or other treatment. As a Stanford Health Care patient, you may have access to the latest, advanced clinical trials.
Open trials refer to studies currently accepting participants. Closed trials are not currently enrolling, but may open in the future.
Published Studies
Publications
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Lateral compartment of the cavernous sinus from the endoscopic endonasal approach: anatomical considerations and surgical relevance to adenoma surgery.
Journal of neurosurgery
Xu, Y., Asmaro, K., Lee, C. K., Vigo, V., Mohyeldin, A., Nunez, M. A., Cohen-Gadol, A. A., Fernandez-Miranda, J. C.
2024: 1-13
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Abstract
OBJECTIVE: The cavernous sinus (CS) has 4 compartments: superior, inferior, posterior, and lateral. Among these, the lateral compartment is the most common location for residual tumor, given the risk of neurovascular injury. The authors' study aimed to delineate the anatomical landmarks in this area and illustrate the technical nuances of the lateral transcavernous approach.METHODS: Twenty-two colored silicone-injected specimens were dissected via an endoscopic endonasal approach to the lateral compartment of the CS. The anatomical landmarks and the internal carotid artery (ICA) mobilization technique were investigated. Two illustrative cases are provided.RESULTS: The lateral compartment of the CS is bounded by the carotid-oculomotor membrane (COM) and optic strut as the roof and the petrolingual ligament and lingual process as the floor. It is divided into 2 asymmetrical subcompartments: the upper, larger subcompartment, located superior to the abducens nerve, accommodates the lateral parasellar ligament (LPL), inferolateral trunk (ILT), and branches of the tentorial artery; and the lower, smaller subcompartment, inferior to the abducens nerve, accommodates only the sympathetic nerve branches as they join the abducens nerve. The LPL is a well-defined ligamentous band and was identified in 38 (86%) hemispheres with 2 distinct configurations: 1) robust LPL (59%), with highly compacted ligamentous bands tightly adherent to the ICA; and 2) dispersed LPL (27%), with less compaction and adherence to ICA. The main attachment of the LPL to the cavernous ICA was most commonly observed at the horizontal ICA segment (55%), followed by the anterior (18%) and posterior (14%) genua. The ILT, as the main vessel in the lateral compartment, was identified in 41 (93%) hemispheres and originated from the horizontal ICA segment (80%) or the anterior genu (14%), from either the lateral (52%) or inferior (41%) aspect of the cross-section of the ICA. In 64% of hemispheres, the LPL wrapped the ILT, abducens nerve, and sympathetic nerve to form a broad and firm neurovascular-ligamental complex. Transection of the LPL, ILT, and COM enables medial ICA mobilization and enhances access to the lateral compartment of the CS, potentially increasing the exposure width by 6 ± 1 mm.CONCLUSIONS: This study provides valuable insights into the anatomical intricacies of the lateral compartment of the CS and underscores the potential benefits of the endoscopic endonasal lateral transcavernous approach. Further clinical applications are essential for validating these findings and optimizing surgical outcomes.
View details for DOI 10.3171/2024.4.JNS232662
View details for PubMedID 39126713
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Resection of corticotroph microadenomas invading the medial wall of the cavernous sinus in two cases of a primary and recurrent case of Cushing's disease.
Neurosurgical focus: Video
Mohyeldin, A., Nunez, M. A., Xu, Y., Fernandez-Miranda, J. C.
2023; 9 (1): V2
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Abstract
Emerging evidence from multiple highly specialized groups continues to support a role for resection of the medial wall of the cavernous sinus when it is invaded by functional pituitary adenomas, to offer durable biochemical remission. The authors present two cases of Cushing's disease that underscore the power of this surgical technique in achieving remission in microadenomas that ectopically present in the cavernous sinus or have invaded the medial wall of the sinus. This video demonstrates key steps in the safe removal of the medial wall of the cavernous sinus and successful resection of tumor burden in the cavernous sinus for sustained postoperative remission. The video can be found here: https://stream.cadmore.media/r10.3171/2023.4.FOCVID2323.
View details for DOI 10.3171/2023.4.FOCVID2323
View details for PubMedID 37416808
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Supramarginal resection of skull base chordomas: proof of concept and preliminary outcomes
NEUROSURGICAL FOCUS
Rychen, J., Constanzo, F., Xu, Y., Johnstone, T. M., Bex, A., Rinaldi, M., Lee, C. K., Fernandez-Miranda, J. C.
2023; 56 (5): E3
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Abstract
The mainstay of treatment for skull base chordoma (SBC) is maximal safe resection followed by radiotherapy. However, even after gross-total resection (GTR), the recurrence rate is high due to microscopic disease in the resection margins. Therefore, supramarginal resection (SMR) could be beneficial, as has been shown for sacral chordoma. The paradigm of postoperative radiation therapy for every patient has also begun to change, as molecular profiling has shown variability in the risk of recurrence. The aim of this study was to present the concept of SMR applied to SBC, along with an individualized decision for postoperative radiation therapy.This is a retrospective analysis of all SBCs operated on by the senior author between 2018 and 2023. SMR was defined as negative histological margins of bone and/or dura mater, along with evidence of bone resection beyond the tumor margins in the craniocaudal and lateral planes on postoperative imaging. Tumors were classified into 3 molecular recurrence risk groups (group A, low risk; group B, intermediate risk; and group C, high risk). Postoperative radiation therapy was indicated in group C tumors, in group B chordomas without SMR, or in cases of patient preference.Twenty-two cases of SBC fulfilled the inclusion criteria. SMR was achieved in 12 (55%) cases, with a mean (range) amount of bone resection beyond the tumor margins of 10 (2-20) mm (+40%) in the craniocaudal axis and 6 (1-15) mm (+31%) in the lateral plane. GTR and near-total resection were each achieved in 5 (23%) cases. Three (19%) tumors were classified as group A, 12 (75%) as group B, and 1 (6%) as group C. Although nonsignificant due to the small sample size, the trends showed that patients in the SMR group had smaller tumor volumes (13.9 vs 19.6 cm3, p = 0.35), fewer previous treatments (33% vs 60% of patients, p = 0.39), and less use of postoperative radiotherapy (25% vs 60%, p = 0.19) compared to patients in the non-SMR group. There were no significant differences in postoperative CSF leak (0% vs 10%, p = 0.45), persistent cranial nerve palsy (8% vs 20%, p = 0.57), and tumor recurrence (8% vs 10%, p = 0.99; mean follow-up 15 months) rates between the SMR and non-SMR groups.In select cases, SMR of SBC appears to be feasible and safe. Larger cohorts and longer follow-up evaluations are necessary to explore the benefit of SMR and individualized postoperative radiation therapy on progression-free survival.
View details for DOI 10.3171/2024.2.FOCUS23909
View details for Web of Science ID 001224534800001
View details for PubMedID 38691859
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Cytodifferentiation of pituitary tumors influences pathogenesis and cavernous sinus invasion.
Journal of neurosurgery
Asmaro, K., Zhang, M., Rodrigues, A. J., Mohyeldin, A., Vigo, V., Nernekli, K., Vogel, H., Born, D. E., Katznelson, L., Fernandez-Miranda, J. C.
2023: 1-9
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Abstract
Pituitary tumors (PTs) continue to present unique challenges given their proximity to the cavernous sinus, whereby invasive behavior can limit the extent of resection and surgical outcome, especially in functional tumors. The aim of this study was to elucidate patterns of cavernoinvasive behavior by PT subtype.A total of 169 consecutive first-time surgeries for PTs were analyzed; 45% of the tumors were functional. There were 64 pituitary transcription factor-1 (PIT-1)-expressing, 62 steroidogenic factor-1 (SF-1)-expressing, 38 T-box transcription factor (TPIT)-expressing, and 5 nonstaining PTs. The gold standard for cavernous sinus invasion (CSI) was based on histopathological examination of the cavernous sinus medial wall and intraoperative exploration.Cavernous sinus disease was present in 33% of patients. Of the Knosp grade 3 and 4 tumors, 12 (19%) expressed PIT-1, 7 (11%) expressed SF-1, 8 (21%) expressed TPIT, and 2 (40%), were nonstaining (p = 0.36). PIT-1 tumors had a significantly higher predilection for CSI: 53% versus 24% and 18% for TPIT and SF-1 tumors, respectively (OR 6.08, 95% CI 2.86-13.55; p < 0.001). Microscopic CSI-defined as Knosp grade 0-2 tumors with confirmed invasion-was present in 44% of PIT-1 tumors compared with 7% and 13% of TPIT and SF-1 tumors, respectively (OR 11.72, 95% CI 4.35-35.50; p < 0.001). Using the transcavernous approach to excise cavernous sinus disease, surgical biochemical remission rates for patients with acromegaly, prolactinoma, and Cushing disease were 88%, 87%, and 100%, respectively. The granule density of PIT-1 tumors and corticotroph functional status did not influence CSI.The likelihood of CSI differed by transcription factor expression; PIT-1-expressing tumors had a higher predilection for invading the cavernous sinus, particularly microscopically, compared with the other tumor subtypes. This elucidates a unique cavernoinvasive behavior absent in cells from other lineages. Innovative surgical techniques, however, can mitigate tumor behavior and achieve robust, reproducible biochemical remission and gross-total resection rates. These findings can have considerable implications on the surgical management and study of PT biology and behavior.
View details for DOI 10.3171/2023.3.JNS221949
View details for PubMedID 37119095
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The Pterygosphenoidal Triangle: Surgical Anatomy and Case Series in Endoscopic Endonasal Skull Base Surgery.
Operative neurosurgery (Hagerstown, Md.)
Xu, Y., Asmaro, K., Mohyeldin, A., Zhang, M., Nunez, M. A., Mao, Y., Cohen-Gadol, A. A., Fernandez-Miranda, J. C.
2023
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Abstract
BACKGROUND: Safe exposure of the lacerum segment of the carotid artery remains a challenge in endoscopic endonasal surgery.OBJECTIVE: To introduce the pterygosphenoidal triangle as a novel and reliable landmark for facilitating access to the foramen lacerum.METHODS: Fifteen colored silicone-injected anatomic specimens were dissected using an endoscopic endonasal approach to the foramen lacerum region in a stepwise manner. Twelve dried skulls were studied and 30 high-resolution computed tomography scans were analyzed to measure the borders and angles of the pterygosphenoidal triangle. Surgical cases incorporating the foramen lacerum exposure between July 2018 and December 2021 were reviewed to provide surgical outcomes of the proposed surgical technique.RESULTS: The pterygosphenoidal triangle is delineated by the pterygosphenoidal fissure medially and the vidian nerve laterally. The palatovaginal artery is located at the base of the triangle anteriorly, while the apex is formed by the pterygoid tubercle posteriorly, which leads to the anterior wall of the foramen lacerum and lacerum internal carotid artery. In the reviewed surgical cases, 39 patients underwent 46 foramen lacerum approaches for resection of pituitary adenoma (12 patients), meningioma (6 patients), chondrosarcoma (5 patients), chordoma (5 patients), or other lesions (11 patients). There were no carotid injuries or ischemic events. Near-total resection was achieved in 33 (85%) of 39 patients (gross-total in 20 [51%]).CONCLUSION: This study details the pterygosphenoidal triangle as a novel and practical anatomic surgical landmark for safe and effective exposure of the foramen lacerum in endoscopic endonasal surgery.
View details for DOI 10.1227/ons.0000000000000627
View details for PubMedID 37071748
Publications
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Functional Suppression of a Prolactinoma by a Dopamine-Secreting Paraganglioma.
JCEM case reports
Fox, T., Needleman, L., Bharani, K. L., Mihm, F., Annes, J. P., Chang, J. J.
2025; 3 (6): luaf080
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Abstract
Prolactin-secreting pituitary adenomas are typically treated with dopamine agonists to inhibit prolactin secretion and reduce tumor size. Dopamine-secreting paragangliomas are rare neuroendocrine tumors of sympathetic and parasympathetic paraganglia and often do not provoke symptoms of catecholamine excess. Although overlapping genetic drivers have been described for paragangliomas and pituitary adenomas, biochemical crosstalk between coexisting tumors is underexplored. We describe the case of a 52-year-old male individual who presented with cerebrospinal fluid (CSF) rhinorrhea and was found to have an invasive, 4.2-cm pituitary mass with modestly elevated prolactin (130.9 ng/mL [130.9 µg/L], reference range [RR] 2-18 ng/mL [2-18 µg/L]). Additional imaging discovered a mediastinal mass suspicious for a thoracic paraganglioma. Biochemical screening demonstrated marked elevation of plasma and urinary dopamine. Following paraganglioma resection, dopamine levels normalized, but prolactin rose significantly (877.8 ng/mL [877.8 µg/L]), suggesting an endogenous dopamine agonist-like effect from the paraganglioma to suppress pituitary prolactin hypersecretion. Pituitary pathology was notable for a PIT1 (pituitary transcription factor-1)-lineage pituitary adenoma with absent immunohistochemical staining for prolactin. Genetic testing found a previously unreported germline SDHC variant of uncertain significance. In this case, we report a novel biologic signaling mechanism between 2 rare primary endocrine tumors and highlight challenges in their diagnosis and management.
View details for DOI 10.1210/jcemcr/luaf080
View details for PubMedID 40264563
View details for PubMedCentralID PMC12011523
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Injectable Estradiol Use in Transgender and Gender-Diverse Individuals in the U.S.: A Multicenter Retrospective Study.
The Journal of clinical endocrinology and metabolism
Misakian, A. L., Kelley, C. E., Sullivan, E. A., Chang, J. J., Singh, G., Kokosa, S., Avila, J., Cooper, H., Liang, J. W., Botzheim, B., Quint, M., Jeevananthan, A., Chi, E., Harmer, M., Hiatt, L., Kowalewski, M., Steinberg, B., Tausinga, T., Tanner, H., Ho, T. F., Mark, B., Zenger, B., Hu, S., Gebregzabheir, A., Penny, J. M., Loeb, D. F., Strickland, T., Iwamoto, S. J., Rothman, M. S., Hamnvik, O. R., Ariel, D.
2025
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Abstract
Guidelines for use of injectable estradiol esters (valerate [EV] and cypionate [EC]) among transgender and gender diverse (TGD) individuals designated male at birth vary considerably, with many providers noting supraphysiologic serum estradiol concentrations based on current dosing recommendations.1. Determine dose of injectable estradiol (subcutaneous [SC] and intramuscular [IM]) needed to reach guideline-recommended estradiol concentrations for TGD adults using EC/EV. 2. Describe relationship between estradiol concentration relative to timing/dose of last estradiol injection and other covariates. 3. Determine dosing differences between IM/SC EV/EC.Cross-sectional retrospective study across six United States medical centers including TGD adults on same-dose injectable estradiol for >75 days, with confirmed timing of estradiol concentration relative to last injection, from 1/1/2019---12/31/2023. Descriptive statistics were used to describe patient characteristics and weighted linear mixed models to evaluate relationship between various covariates and estradiol concentration.Data from 562 patients were included. Among those injecting every seven days who reached the guideline-recommended estradiol concentration (n=131, 27.5%), the median estradiol dose was 4.0 mg (interquartile range 3.0---5.0 mg). Among all patients, the majority reached supraphysiologic estradiol concentrations (>200 pg/mL [>734 pmol/L]) while dose and timing in the injection cycle were significant covariates for the estradiol concentration. There were no significant dosing differences between IM/SC EV/EC.Injectable estradiol esters effectively reach guideline-recommended estradiol concentrations but at lower doses than previously recommended. Estradiol concentrations are best interpreted relative to timing of last injection. Route of administration and type of ester do not significantly impact estradiol concentrations.
View details for DOI 10.1210/clinem/dgaf015
View details for PubMedID 39797602
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Patient and caregiver perspectives of fluid discharge protocols following pituitary surgery.
Journal of clinical & translational endocrinology
Chang, J. J., Amano, A., Brown-Johnson, C., Chu, O., Gates-Bazarbay, V., Wipff, E., Kling, S. M., Alhadha, M., Carlos Fernandez-Miranda, J., Vilendrer, S.
2024; 35: 100336
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Abstract
Post-operative fluid restriction after transsphenoidal surgery (TSS) for pituitary tumors may effectively prevent delayed hyponatremia, the most common cause of readmission. However, implementation of individualized fluid restriction interventions after discharge is often complex and poses challenges for provider and patient. The purpose of this study was to understand the factors necessary for successful implementation of fluid restriction and discharge care protocols following TSS.Semi-structured interviews with fifteen patients and four caregivers on fluid discharge protocols were conducted following TSS. Patients and caregivers who had surgery before and after the implementation of updated discharge protocols were interviewed. Data were analyzed inductively using a procedure informed by rapid and thematic analysis.Most patients and caregivers perceived fluid restriction protocols as acceptable and feasible when indicated. Facilitators to the protocols included clear communication about the purpose of and strategies for fluid restriction, access to the care team, and involvement of patients' caregivers in care discussions. Barriers included patient confusion about differences in the care plan between teams, physical discomfort of fluid restriction, increased burden of tracking fluids during recovery, and lack of clarity surrounding desmopressin prescriptions.Outpatient fluid restriction protocols are a feasible intervention following pituitary surgery but requires frequent patient communication and education. This evaluation highlights the importance of patient engagement and feedback to effectively develop and implement complex clinical interventions.
View details for DOI 10.1016/j.jcte.2024.100336
View details for PubMedID 38545460
View details for PubMedCentralID PMC10965805
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Fertility issues in hypopituitarism.
Reviews in endocrine & metabolic disorders
Chen, J., Chang, J. J., Chung, E. H., Lathi, R. B., Aghajanova, L., Katznelson, L.
2023
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Abstract
Women with hypopituitarism have lower fertility rates and worse pregnancy outcomes than women with normal pituitary function. These disparities exist despite the use of assisted reproductive technologies and hormone replacement. In women with hypogonadotropic hypogonadism, administration of exogenous gonadotropins can be used to successfully induce ovulation. Growth hormone replacement in the setting of growth hormone deficiency has been suggested to potentiate reproductive function, but its routine use in hypopituitary women remains unclear and warrants further study. In this review, we will discuss the clinical approach to fertility in a woman with hypopituitarism.
View details for DOI 10.1007/s11154-023-09863-9
View details for PubMedID 38095806
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Use of the Community of Inquiry Framework to Measure Student and Facilitator Perceptions of Online Flipped Classroom Compared with Online Lecture Learning in Undergraduate Medical Education.
Advances in medical education and practice
Chang, J. J., Hain, A., Dosiou, C., Gesundheit, N.
2023; 14: 963-972
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Abstract
Background: The COVID-19 pandemic and a movement away from traditional lecture-based learning have increased the use of online flipped classroom (FC) and active learning models in medical education. The Community of Inquiry (CoI) framework for online learning may be used to evaluate the effectiveness and strengths of the online FC model compared with other learning formats.Methods: An observational survey study was conducted to measure medical student and facilitator perceptions of an online FC endocrinology tutorial compared with online lecture experiences. For the tutorial, students were instructed to watch short, pre-recorded lecture videos on thyroid pathophysiology prior to class. During class, small groups of students were paired with a faculty facilitator in online Zoom rooms for case discussion. Students were surveyed using the CoI framework to assess elements of cognitive, social, and teaching presence between the two online learning modalities. Facilitators were also surveyed. Survey questions were rated on a 5-point Likert scale.Results: Fifty-three out of 92 students (58% response rate) and seven out of eight facilitators (88% response rate) completed surveys. In general, students felt that online FC learning improved cognitive, teaching, and social presence compared with online lecture. Areas of cognitive presence (mean score 3.9 ± 1.0 SD), such as stimulating curiosity and applying concepts, were highly rated. Certain elements of social presence (3.6 ± 0.9) and teaching presence (3.7 ± 0.9), such as expression of emotion and communication of expectations, garnered lower ratings. All surveyed facilitators felt that online FC was more effective and enjoyable to teach than online lectures but did not feel it was superior to in-person instruction.Conclusion: Medical students and facilitators viewed an online FC tutorial in endocrinology positively. Most, but not all, areas of the CoI framework were enhanced with the online FC tutorial compared with online lecture-based learning.
View details for DOI 10.2147/AMEP.S413201
View details for PubMedID 37701423
Publications
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LncRNA Osilr9 coordinates promoter DNA demethylation and the intrachromosomal loop structure required for maintaining stem cell pluripotency.
Molecular therapy : the journal of the American Society of Gene Therapy
Zhu, Y., Yan, Z., Fu, C., Wen, X., Jia, L., Zhou, L., Du, Z., Wang, C., Wang, Y., Chen, J., Nie, Y., Wang, W., Cui, J., Wang, G., Hoffman, A. R., Hu, J., Li, W.
2022
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Abstract
Nuclear reprogramming of somatic cells into a pluripotent status has the potential to create patient-specific pluripotent stem cells (iPSCs) for regenerative medicine. Currently, however, the epigenetic mechanisms underlying this pluripotent reprogramming are poorly understood. To delineate this epigenetic regulatory network, we utilized a chromatin RNA in situ reverse transcription sequencing (CRIST-seq) approach to identify long noncoding RNAs (lncRNAs) embedded in the 3-dimensional intrachromosomal architecture of stem cell core factor genes. By combining CRIST-seq and RNA-seq, we identified Osilr9 (Oct4-Sox2 interacting lncRNA 9) as a pluripotency-associated lncRNA. Osilr9 expression was associated with the status of stem cell pluripotency in reprogramming. Using shRNA knockdown, we showed that this lncRNA was required for the optimal maintenance of stem cell pluripotency. Overexpression of Osilr9 induced robust activation of endogenous stem cell core factor genes in fibroblasts. Osilr9 participated in the formation of the intrachromosomal looping required for maintenance of pluripotency. After binding to the Oct4 promoter, Osilr9 recruited the DNA demethylase TET1, leading to promoter demethylation. These data demonstrate that Osilr9 is a critical chromatin epigenetic modulator that coordinates the promoter activity of core stem cell factor genes, highlighting the critical role of pluripotency-associated lncRNAs in stem cell pluripotency and reprogramming.
View details for DOI 10.1016/j.ymthe.2022.12.010
View details for PubMedID 36523163
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Tracking and Cumulative Lifetime Exposure to IGF-I in 6,459 Healthy Individuals and in SGA Children Treated with GH.
The Journal of clinical endocrinology and metabolism
Kjaer, A. S., Jensen, R. B., Petersen, J. H., Linneberg, A., Karhus, L. L., Henriksen, L. S., Johannsen, T. H., Main, K. M., Hoffman, A. R., Juul, A.
2022
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Abstract
CONTEXT: Supraphysiological serum insulin-like growth-factor-I (IGF-I) concentrations have been a matter of concern in children treated with growth hormone (GH) because high IGF-I levels were associated with risk of later disease in former epidemiological studies.OBJECTIVE: To determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding-protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals.METHODS: We included 6,459 healthy participants (cross-sectional=5,326; longitudinal=1,133) aged 0----76 years (9,963 serum samples) and nine patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment.Intraindividual tracking of IGF-I and IGFBP-3 (SDS) was determined by intraclass correlation coefficients (ICC). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS-trajectory from 0-76 years.RESULTS: For IGF-I (SDS), ICCs were 0.50 (95% CI: 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12,723±3,691 SD) than in male participants (12,563±3,393); p=0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9,512±1,889 to 11,271±1,689, corresponding to an increase in lifetime IGF-I trajectory from -0.89 SD±0.57 to -0.35 SD±0.49.CONCLUSION: Since IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population.
View details for DOI 10.1210/clinem/dgac605
View details for PubMedID 36250350
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Pluripotency exit is guided by the Peln1-mediated disruption of intrachromosomal architecture.
The Journal of cell biology
Wang, Y., Jia, L., Wang, C., Du, Z., Zhang, S., Zhou, L., Wen, X., Li, H., Chen, H., Nie, Y., Li, D., Liu, S., Figueroa, D. S., Ay, F., Xu, W., Zhang, S., Li, W., Cui, J., Hoffman, A. R., Guo, H., Hu, J. F.
2022; 221 (4)
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Abstract
The molecular circuitry that causes stem cells to exit from pluripotency remains largely uncharacterized. Using chromatin RNA in situ reverse transcription sequencing, we identified Peln1 as a novel chromatin RNA component in the promoter complex of Oct4, a stem cell master transcription factor gene. Peln1 was negatively associated with pluripotent status during somatic reprogramming. Peln1 overexpression caused E14 cells to exit from pluripotency, while Peln1 downregulation induced robust reprogramming. Mechanistically, we discovered that Peln1 interacted with the Oct4 promoter and recruited the DNA methyltransferase DNMT3A. By de novo altering the epigenotype in the Oct4 promoter, Peln1 dismantled the intrachromosomal loop that is required for the maintenance of pluripotency. Using RNA reverse transcription-associated trap sequencing, we showed that Peln1 targets multiple pathway genes that are associated with stem cell self-renewal. These findings demonstrate that Peln1 can act as a new epigenetic player and use a trans mechanism to induce an exit from the pluripotent state in stem cells.
View details for DOI 10.1083/jcb.202009134
View details for PubMedID 35171230
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Chromatin lncRNA Platr10 controls stem cell pluripotency by coordinating an intrachromosomal regulatory network.
Genome biology
Du, Z., Wen, X., Wang, Y., Jia, L., Zhang, S., Liu, Y., Zhou, L., Li, H., Yang, W., Wang, C., Chen, J., Hao, Y., Chen, H., Li, D., Chen, N., Celik, I., Zhu, Y., Yan, Z., Fu, C., Liu, S., Jiao, B., Wang, Z., Zhang, H., Gulsoy, G., Luo, J., Qin, B., Gao, S., Kapranov, P., Esteban, M. A., Zhang, S., Li, W., Ay, F., Chen, R., Hoffman, A. R., Cui, J., Hu, J.
2021; 22 (1): 233
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Abstract
BACKGROUND: A specific 3-dimensional intrachromosomal architecture of core stem cell factor genes is required to reprogram a somatic cell into pluripotency. As little is known about the epigenetic readers that orchestrate this architectural remodeling, we used a novel chromatin RNA in situ reverse transcription sequencing (CRIST-seq) approach to profile long noncoding RNAs (lncRNAs) in the Oct4 promoter.RESULTS: We identify Platr10 as an Oct4 - Sox2 binding lncRNA that is activated in somatic cell reprogramming. Platr10 is essential for the maintenance of pluripotency, and lack of this lncRNA causes stem cells to exit from pluripotency. In fibroblasts, ectopically expressed Platr10 functions in trans to activate core stem cell factor genes and enhance pluripotent reprogramming. Using RNA reverse transcription-associated trap sequencing (RAT-seq), we show that Platr10 interacts with multiple pluripotency-associated genes, including Oct4, Sox2, Klf4, and c-Myc, which have been extensively used to reprogram somatic cells. Mechanistically, we demonstrate that Platr10 helps orchestrate intrachromosomal promoter-enhancer looping and recruits TET1, the enzyme that actively induces DNA demethylation for the initiation of pluripotency. We further show that Platr10 contains an Oct4 binding element that interacts with the Oct4 promoter and a TET1-binding element that recruits TET1. Mutation of either of these two elements abolishes Platr10 activity.CONCLUSION: These data suggest that Platr10 functions as a novel chromatin RNA molecule to control pluripotency in trans by modulating chromatin architecture and regulating DNA methylation in the core stem cell factor network.
View details for DOI 10.1186/s13059-021-02444-6
View details for PubMedID 34412677
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Nuclear-Encoded lncRNA MALAT1 Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway.
Molecular therapy. Nucleic acids
Zhao, Y., Zhou, L., Li, H., Sun, T., Wen, X., Li, X., Meng, Y., Li, Y., Liu, M., Liu, S., Kim, S., Xiao, J., Li, L., Zhang, S., Li, W., Cohen, P., Hoffman, A. R., Hu, J., Cui, J.
2021; 23: 264–76
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Abstract
Mitochondrial dysfunction is a metabolic hallmark of cancer cells. In search of molecular factors involved in this dysregulation in hepatocellular carcinoma (HCC), we found that the nuclear-encoded long noncoding RNA (lncRNA) MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was aberrantly enriched in the mitochondria of hepatoma cells. Using RNA reverse transcription-associated trap sequencing (RAT-seq), we showed that MALAT1 interacted with multiple loci on mitochondrial DNA (mtDNA), including D-loop, COX2, ND3, and CYTB genes. MALAT1 knockdown induced alterations in the CpG methylation of mtDNA and in mitochondrial transcriptomes. This was associated with multiple abnormalities in mitochondrial function, including altered mitochondrial structure, low oxidative phosphorylation (OXPHOS), decreased ATP production, reduced mitophagy, decreased mtDNA copy number, and activation of mitochondrial apoptosis. These alterations in mitochondrial metabolism were associated with changes in tumor phenotype and in pathways involved in cell mitophagy, mitochondrial apoptosis, and epigenetic regulation. We further showed that the RNA-shuttling protein HuR and the mitochondria transmembrane protein MTCH2 mediated the transport of MALAT1 in this nuclear-mitochondrial crosstalk. This study provides the first evidence that the nuclear genome-encoded lncRNA MALAT1 functions as a critical epigenetic player in the regulation of mitochondrial metabolism of hepatoma cells, laying the foundation for further clarifying the roles of lncRNAs in tumor metabolic reprogramming.
View details for DOI 10.1016/j.omtn.2020.09.040
View details for PubMedID 33425485
Pituitary Center
Featured Lab
The Surgical Neuroanatomy, Fiber Tractography, and Virtual Reality Research Center, under the direction of Juan C. Fernandez-Miranda, MD, has a dual educational and research role aiming to improve surgical techniques and outcomes by mastering knowledge of relevant surgical neuroanatomy.