82 results on '"Simonds WF"'
Search Results
2. Aromatase inhibitor treatment of menorrhagia and subsequent pregnancy in a patient with familial hyperparathyroidism-jaw tumor syndrome.
- Author
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Wolff EF, Hill MJ, Simonds WF, Segars JH, Wolff, Erin F, Hill, Micah J, Simonds, William F, and Segars, James H
- Abstract
Objective: To describe the clinical management of menorrhagia in a woman with hyperparathyroidism-jaw tumor syndrome (HPT-JT).Design: Case report.Setting: Large translation research hospital.Patient(s): A 26-year-old nulligravid woman with familial HPT-JT presented with life-long menorrhagia resistant to progesterone intrauterine device (IUD) therapy and a desire for fertility.Intervention(s): Aromatase inhibitor therapy.Main Outcome Measure(s): Clinical response to therapy and pregnancy.Result(s): Imaging demonstrated an enlarged endometrial lining and thickening of the junctional zone. At operative hysteroscopy, multiple atypical endometrial polyp-like lesions filled the entire uterine cavity and were removed. Histologic evaluation demonstrated the lesions to be adenomyomas with an abundance of aromatase expression. Postoperative treatment included an aromatase inhibitor. The patient's menorrhagia, which had previously been resistant to progesterone IUD therapy, resolved with the aromatase inhibitor. After 10 months of this treatment, the aromatase inhibitor was discontinued and a repeated hysteroscopy revealed a markedly improved uterine cavity. The patient subsequently became pregnant on her first natural cycle and delivered a healthy term infant.Conclusion(s): Aromatase inhibitors may represent a novel treatment for benign uterine pathology in HPT-JT. [ABSTRACT FROM AUTHOR]- Published
- 2012
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3. A Germline ZFX Missense Variant in a Patient With Primary Hyperparathyroidism.
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Guan B, Agarwal SK, Welch JM, Jha S, Weinstein LS, and Simonds WF
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A 51-year-old woman with a history of primary hyperparathyroidism (PHPT) with prior parathyroidectomy, osteoporosis, and learning disability was referred for hypercalcemia discovered after a fall. Family history was negative for PHPT, pituitary, enteropancreatic neuroendocrine, or jaw tumors. Dysmorphic facies, multiple cutaneous melanocytic nevi, café au lait macules, long fingers, and scoliosis were observed. Laboratory evaluation showed an elevated parathyroid hormone (PTH) level, hypercalcemia, and hypophosphatemia, all consistent with PHPT. Preoperative imaging revealed a right inferior candidate parathyroid lesion. The patient underwent right inferior parathyroidectomy with normalization of PTH, calcium, and phosphorus. Genetic testing showed a likely pathogenic de novo heterozygous germline missense variant p.R764W in the ZFX gene that encodes a zinc-finger transcription factor previously shown to harbor somatic missense variants in a subset of sporadic parathyroid tumors. Germline variants in ZFX have been reported in patients with an X-linked intellectual disability syndrome with an increased risk for congenital anomalies and PHPT. Further research may determine if genetic testing for ZFX could be of potential benefit for patients with PHPT and developmental anomalies, even in the absence of a family history of parathyroid disease., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)
- Published
- 2024
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4. The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function.
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Zhang J, Pandey M, Awe A, Lue N, Kittock C, Fikse E, Degner K, Staples J, Mokhasi N, Chen W, Yang Y, Adikaram P, Jacob N, Greenfest-Allen E, Thomas R, Bomeny L, Zhang Y, Petros TJ, Wang X, Li Y, and Simonds WF
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- Mice, Humans, Animals, Genome-Wide Association Study, Neurofibrillary Tangles metabolism, Phenotype, Genomics, Amyloid beta-Peptides genetics, Brain metabolism, Solute Carrier Family 22 Member 5 genetics, Solute Carrier Family 22 Member 5 metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, GTP-Binding Protein beta Subunits genetics, GTP-Binding Protein beta Subunits metabolism
- Abstract
Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gβ5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)
- Published
- 2024
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5. Invasive Testing for Preoperative Localization of Parathyroid Tumors.
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Graf A, Cochran C, Sadowski S, Nilubol N, Simonds WF, Weinstein LS, Chang R, and Jha S
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Context: The identification of parathyroid tumor(s) in patients with persistent/recurrent primary hyperparathyroidism (PHPT) is critical for a successful reoperative surgery. If noninvasive studies (ultrasound, computed tomography, magnetic resonance imaging, sestamibi) fail to conclusively localize the tumor, invasive procedures (arteriography and selective venous sampling) are performed., Objective: To describe our experience with invasive studies for parathyroid tumor localization and provide follow-up data on selective arterial hypocalcemic stimulation with central venous sampling, a technique developed at our center., Methods: We identified patients who underwent preoperative invasive testing for localization of parathyroid tumor from 1991 to 2020. The result of each invasive localization study [arteriogram, hypocalcemic stimulation and selective venous sampling (SVS)] was categorized as true-positive, false-positive, and false-negative based on histology and biochemical outcome., Results: Ninety-four patients with 96 tumor occurrences underwent invasive testing for parathyroid tumor localization. Arteriogram, hypocalcemic stimulation, and SVS accurately localized the tumor in 47 of 94 (50%), 56 of 93 (60%), and 51 of 62 (82%) tumors, respectively. Hypocalcemic stimulation was more likely to correctly localize the tumor when arteriogram showed a blush [37 of 50 (74%) vs 19 of 43 (44%), P = .01]. When both arteriogram and hypocalcemic stimulation yielded concordant positive findings, SVS did not change management in the 18 cases in which all 3 were performed. Twelve patients remained with persistent PHPT; all had recurrent disease with multiple affected glands., Conclusion: Hypocalcemic stimulation is a useful adjunct in patients with PHPT who require invasive localization and can obviate the need for SVS. Clinical Trial number : NCT04969926., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)
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- 2024
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6. A Knock-In Mouse Model of the Gcm2 Variant p.Y392S Develops Normal Parathyroid Glands.
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Parekh VI, Brinster LR, Guan B, Simonds WF, Weinstein LS, and Agarwal SK
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Context: The glial cells missing 2 ( GCM2 ) gene functions as a transcription factor that is essential for parathyroid gland development, and variants in this gene have been associated with 2 parathyroid diseases: isolated hypoparathyroidism in patients with homozygous germline inactivating variants and primary hyperparathyroidism in patients with heterozygous germline activating variants. A recurrent germline activating missense variant of GCM2 , p.Y394S, has been reported in patients with familial primary hyperparathyroidism., Objective: To determine whether the GCM2 p.Y394S missense variant causes overactive and enlarged parathyroid glands in a mouse model., Methods: CRISPR/Cas9 gene editing technology was used to generate a mouse model with the germline heterozygous Gcm2 variant p.Y392S that corresponds to the human GCM2 p.Y394S variant. Wild-type ( Gcm2
+/+ ) and germline heterozygous ( Gcm2+/Y392S ) mice were evaluated for serum biochemistry and parathyroid gland morphology., Results: Gcm2+/Y392S mice did not show any change compared to Gcm2+/+ mice in serum calcium and parathyroid hormone levels, parathyroid gland histology, cell proliferation, or parathyroid gland size., Conclusion: The mouse model of the p.Y392S variant of Gcm2 shows that this variant is tolerated in mice, as it does not increase parathyroid gland cell proliferation and circulating calcium or PTH levels. Further investigation of Gcm2+/Y392S mice to study the effect of this variant of Gcm2 on early events in parathyroid gland development will be of interest., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)- Published
- 2023
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7. Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.
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Jha S, Welch J, Tora R, Lack J, Warner A, Del Rivero J, Sadowski SM, Nilubol N, Schmidt LS, Linehan WM, Weinstein LS, Simonds WF, and Agarwal SK
- Subjects
- Humans, Germ-Line Mutation, DNA, Proto-Oncogene Proteins genetics, Tumor Suppressor Proteins genetics, Parathyroid Neoplasms genetics, Parathyroid Neoplasms complications, Birt-Hogg-Dube Syndrome complications, Birt-Hogg-Dube Syndrome genetics, Birt-Hogg-Dube Syndrome pathology, Kidney Neoplasms, Cysts
- Abstract
Context: Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease., Objective: To investigate for novel genes causing parathyroid cancer., Methods: We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants., Results: We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant., Conclusion: The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)
- Published
- 2023
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8. Molecular and Clinical Spectrum of Primary Hyperparathyroidism.
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Jha S and Simonds WF
- Subjects
- Humans, Adult, Parathyroidectomy adverse effects, Genetic Testing, Hyperparathyroidism, Primary diagnosis, Hyperparathyroidism, Primary genetics, Parathyroid Neoplasms complications, Parathyroid Neoplasms diagnosis, Parathyroid Neoplasms genetics, Renal Insufficiency, Chronic complications
- Abstract
Recent data suggest an increase in the overall incidence of parathyroid disorders, with primary hyperparathyroidism (PHPT) being the most prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of death. The symptoms of PHPT can be nonspecific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an underlying heritable form of PHPT that may be associated with extraparathyroidal manifestations, requiring active surveillance for these manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with multiglandular disease, recurrent PHPT, young onset PHPT (age ≤40 years), and those with a family history of parathyroid tumors. However, the underlying genetic cause for the majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for the family. The genes currently known to be associated with heritable forms of PHPT account for approximately half of sporadic parathyroid tumors. But the genetic cause in approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will allow us to identify biomarkers for diagnosis and novel targets for therapy., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)
- Published
- 2023
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9. Specific regulation of mechanical nociception by Gβ5 involves GABA-B receptors.
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Pandey M, Zhang JH, Adikaram PR, Kittock C, Lue N, Awe A, Degner K, Jacob N, Staples J, Thomas R, Kohnen AB, Ganesan S, Kabat J, Chen CK, and Simonds WF
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- Animals, Mice, Receptors, GABA-B genetics, Receptors, GABA-B metabolism, Nociception, Signal Transduction physiology, Pain, GTP-Binding Protein beta Subunits genetics, GTP-Binding Protein beta Subunits metabolism, RGS Proteins genetics, RGS Proteins metabolism
- Abstract
Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gβ5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes Gβ5 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/- Gnb5fl/fl mice but not in Rgs9-Cre+/- Gnb5fl/fl mice, suggesting that Gβ5 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, Gβ5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gβ5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein-coupled receptor Mrgprd agonist β-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/- Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gβ5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.
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- 2023
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10. Expressions of Cushing's syndrome in multiple endocrine neoplasia type 1.
- Author
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Simonds WF
- Subjects
- Humans, Adrenocorticotropic Hormone, Cushing Syndrome complications, Cushing Syndrome diagnosis, Multiple Endocrine Neoplasia Type 1 complications, Multiple Endocrine Neoplasia Type 1 genetics, Pituitary ACTH Hypersecretion complications, Pituitary Neoplasms complications, ACTH Syndrome, Ectopic complications, Neuroendocrine Tumors complications, Neuroendocrine Tumors genetics, Thymus Neoplasms
- Abstract
Cushing's syndrome (CS) resulting from endogenous hypercortisolism can be sporadic or can occur in the context of familial disease because of pituitary or extra-pituitary neuroendocrine tumors. Multiple endocrine neoplasia type 1 (MEN1) is unique among familial endocrine tumor syndromes because hypercortisolism in this context can result from pituitary, adrenal, or thymic neuroendocrine tumors and can therefore reflect either ACTH-dependent or ACTH-independent pathophysiologies. The prominent expressions of MEN1 include primary hyperparathyroidism, tumors of the anterior pituitary, gastroenteropancreatic neuroendocrine tumors, and bronchial carcinoid tumors along with several common non-endocrine manifestations such as cutaneous angiofibromas and leiomyomas. Pituitary tumors are present in about 40% of MEN1 patients, and up to 10% of such tumors secrete ACTH that can result in Cushing's disease. Adrenocortical neoplasms occur frequently in MEN1. Although such adrenal tumors are mostly clinically silent, this category can include benign or malignant tumors causing hypercortisolism and CS. Ectopic tumoral ACTH secretion has also been observed in MEN1, almost exclusively originating from thymic neuroendocrine tumors. The range of clinical presentations, etiologies, and diagnostic challenges of CS in MEN1 are reviewed herein with an emphasis on the medical literature since 1997, when the MEN1 gene was identified., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Simonds.)
- Published
- 2023
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11. Long-Term Outcomes of Parathyroid Autografts in Primary Hyperparathyroidism.
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Chuki E, Graf A, Ninan A, Tora R, Abijo T, Bliss L, Nilubol N, Weinstein LS, Agarwal SK, Simonds WF, and Jha S
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Context: Autologous implantation of parathyroid tissue is frequently utilized after parathyroidectomy in patients with heritable forms of primary hyperparathyroidism (PHPT). Data on long-term functional outcome of these grafts is sparse., Objective: To investigate long-term outcomes of parathyroid autografts., Methods: Retrospective study of patients with PHPT who underwent parathyroid autografts from 1991 to 2020., Results: We identified 115 patients with PHPT who underwent 135 parathyroid autografts. Median follow-up duration since graft was 10 (4-20) years. Of the 111 grafts with known functional outcome, 54 (49%) were fully functional, 13 (12%) partially functional, and 44 (40%) nonfunctional at last follow-up. Age at time of graft, thymectomy prior to autograft, graft type (delayed vs immediate), or duration of cryopreservation did not predict functional outcome. There were 45 (83%) post-graft PHPT recurrences among 54 fully functional grafts at a median duration of 8 (4-15) years after grafting. Surgery was performed in 42/45 recurrences, but cure was attained in 18/42 (43%) only. Twelve of 18 (67%) recurrences were graft-related while remaining 6 (33%) had a neck or mediastinal source. Median time to recurrence was 16 (11-25) years in neck or mediastinal source vs 7 (2-13) years in graft-related recurrences. Median parathyroid hormone (PTH) gradient was significantly higher at 23 (20-27) in graft-related recurrence vs 1.3 (1.2-2.5) in neck or mediastinal source ( P = .03)., Conclusions: Post-graft recurrence of PHPT occurs frequently within the first decade after graft and is challenging to localize. Time to recurrence after graft is significantly shorter and PTH gradient higher for graft-related recurrence. Clinical Trial Number : NCT04969926., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)
- Published
- 2023
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12. Metastatic Grade 3 Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1 Expressing Somatostatin Receptors.
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Graf A, Welch J, Bansal R, Mandl A, Parekh VI, Cochran C, Levy E, Nilubol N, Patel D, Sadowski S, Jha S, Agarwal SK, Millo C, Blau JE, Simonds WF, Weinstein LS, and Del Rivero J
- Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) may occur in 30% to 90% of patients with multiple endocrine neoplasia type 1 (MEN1). However, only 1% of GEP-NETs are grade 3 (G3). Given the rarity of these aggressive tumors, treatment of advanced G3 GEP-NETs in MEN1 is based on the treatment guidelines for sporadic GEP-NETs. We report a 43-year-old male with germline MEN1 followed at our institution, with clinical features including hyperparathyroidism, a nonfunctional pancreatic NET, and Zollinger-Ellison syndrome. On routine surveillance imaging at age 40, computed tomography/positron emission tomography imaging showed 2 arterially enhancing intraluminal masses on the medial aspect of the gastric wall. Anatomical imaging confirmed 2 enhancing masses within the pancreas and a rounded mass-like thickening along the lesser curvature of the stomach. The gastric mass was resected, and pathology reported a well-differentiated G3 NET with a Ki-67 >20%. The patient continued active surveillance. Eighteen months later cross-sectional imaging studies showed findings consistent with metastatic disease within the right hepatic lobe and bland embolization was done. On follow-up scans, including
68 Ga-DOTATATE (68 Ga-DOTA(0)-Tyr(3)-octreotate) imaging, interval increase in number and avidity of metastatic lesions were compatible with disease progression. Given a paucity of treatment recommendations for G3 tumors in MEN1, the patient was counseled based on standard NET treatment guidelines and recommended177 Lu-DOTATATE treatment. PRRT (peptide receptor radionuclide therapy) with177 Lu-DOTATATE (177 Lu-tetraazacyclododecanetetraacetic acid-octreotide) is an important therapeutic modality for patients with somatostatin receptor-positive NETs. However, prospective studies are needed to understand the role of PRRT in G3 NETs., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)- Published
- 2022
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13. Case of Recurrent Primary Hyperparathyroidism, Congenital Granular Cell Tumor, and Aggressive Colorectal Cancer.
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Afreen S, Weinstein LS, Simonds WF, and Jha S
- Abstract
We present the case of a 53-year-old African-American male with recurrent primary hyperparathyroidism (PHPT), multifocal benign granular cell tumor (GCT), and metastatic colon adenocarcinoma. PHPT was diagnosed on routine blood testing (ionized calcium, 1.66 [1.12-1.32] mmol/L; PTH 110 pg/mL, vitamin D-25-OH-D: 18 ng/mL; PTHrP: undetectable). Medical history was notable for 2 reoccurrences of PHPT with persistent disease after most recent parathyroidectomy. Lymph node (LN) dissection during this last surgery showed a 2-mm focus of poorly differentiated adenocarcinoma in 1/5 LNs. Additionally, the patient had a history of multifocal GCTs diagnosed at age 2 years. On examination, there were no Lisch nodules, axillary, or inguinal freckling, neurofibromas, or café-au-lait macules but a prominent abdominal wall nodule was noted. En bloc resection of a tumor in the tracheoesophageal groove, identified by sestamibi scan, and excision of 4.5-cm abdominal wall nodule showed both masses having histology consistent with GCT. Serum calcium and PTH did not decrease, indicating another unsuccessful surgery. Genetic testing was negative for germline variants in PHPT-associated genes, APC, or genes of RAS-MAPK signaling pathway. The LN finding of metastatic adenocarcinoma prompted an endoscopy and transbronchial biopsy leading to the diagnosis of widely metastatic colonic adenocarcinoma, eventually resulting in his death a year later. The source of the patient's persistent PHPT remained unidentified. This is the first case with coassociation of recurrent PHPT, multifocal GCT, and colon cancer. Whether the disparate tumors in this patient share common driver(s) remains unknown. Prospective surveillance of patients for similar associations may provide clues for a novel syndromic form of PHPT., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)
- Published
- 2022
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14. Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives.
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Ullah A, Khan J, Waheed A, Sharma N, Pryor EK, Stumpe TR, Velasquez Zarate L, Cason FD, Kumar S, Misra S, Kavuri S, Mesa H, Roper N, Foroutan S, Karki NR, Del Rivero J, Simonds WF, and Karim NA
- Abstract
Introduction: Parathyroid carcinoma (PC) is an extremely rare entity, with a frequency of 0.005% of all malignancies. Most data related to this rare disease are limited to case series and a few database studies. We present a large database study that aims to investigate the demographic, clinical, and pathological factors, prognosis, and survival of PC. Methods: Data of parathyroid carcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) diagnosed between 1975 and 2016. Results: PC had a slightly higher incidence in men (52.2%, p < 0.005), the majority of cases affected Caucasians (75.4%, p < 0.005), and the mean age at diagnosis was 62 years. Histologically, 99.7% were adenocarcinomas not otherwise specified (p < 0.005), well-differentiated (p < 0.005), and 2−4 cm (p < 0.001) in size among the patients with available data. In cases with staging provided, most PC were organ-confined (36.8%, p < 0.001). Lymph nodes were positive in 25.2% of cases where lymph node status was reported. The main treatment modality was surgery (97.2%), followed by radiation alone (2%), and very few received chemotherapy alone (0.8%), p < 0.005. Five-year follow-up was available for 82.7% of the cases. Those who underwent surgery only or radiation alone had 5-year survivals of 83.8% and 72.2%, respectively (p < 0.037). Multivariable analysis identified tumor size >4 cm, age > 40 years, male sex, Caucasian race, distant spread, and poorly differentiated grade as independent risk factors for mortality (p < 0.001). Conclusion: PC is a very rare tumor mostly affecting Caucasian individuals in the fifth decade. Older age, poor histologic differentiation, and distant metastasis are associated with a worse prognosis. Surgical resection offers the best survival outcome. To better understand the pathogenesis and factors affecting survival, all PC patients should be enrolled in national and international registries.
- Published
- 2022
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15. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.
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De Nittis P, Efthymiou S, Sarre A, Guex N, Chrast J, Putoux A, Sultan T, Raza Alvi J, Ur Rahman Z, Zafar F, Rana N, Rahman F, Anwar N, Maqbool S, Zaki MS, Gleeson JG, Murphy D, Galehdari H, Shariati G, Mazaheri N, Sedaghat A, Lesca G, Chatron N, Salpietro V, Christoforou M, Houlden H, Simonds WF, Pedrazzini T, Maroofian R, and Reymond A
- Subjects
- Adolescent, Animals, Arrhythmias, Cardiac physiopathology, Child, Child, Preschool, Developmental Disabilities physiopathology, Female, GTP-Binding Protein beta Subunits metabolism, Gene Expression Profiling methods, Heart Rate genetics, Heart Rate physiology, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Pedigree, Syndrome, Exome Sequencing methods, Young Adult, Mice, Arrhythmias, Cardiac genetics, Developmental Disabilities genetics, GTP-Binding Protein beta Subunits genetics, Heart physiopathology, Mutation, Signal Transduction genetics
- Abstract
Background: Pathogenic variants of GNB5 encoding the β
5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia., Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse., Results: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5 -inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/- , but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients., Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5- /- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2021
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16. Two distinct classes of thymic tumors in patients with MEN1 show LOH at the MEN1 locus.
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Mandl A, Welch JM, Kapoor G, Parekh VI, Schrump DS, Ripley RT, Walter MF, Del Rivero J, Jha S, Simonds WF, Jensen RT, Weinstein LS, Blau JE, and Agarwal SK
- Subjects
- Humans, Loss of Heterozygosity, Retrospective Studies, Multiple Endocrine Neoplasia Type 1 genetics, Multiple Endocrine Neoplasia Type 1 pathology, Thymoma, Thymus Neoplasms genetics
- Abstract
Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to develop various endocrine and non-endocrine tumors. Over 90% of the tumors show loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 locus, due to somatic loss of the wild-type MEN1 allele. Thymic neuroendocrine tumors (NETs) or thymic carcinoids are uncommon in MEN1 patients but are a major cause of mortality. LOH at the MEN1 locus has not been demonstrated in thymic tumors. The goal of this study was to investigate the molecular aspects of MEN1-associated thymic tumors including LOH at the MEN1 locus and RNA-sequencing (RNA-Seq) to identify genes associated with tumor development and potential targeted therapy. A retrospective chart review of 294 patients with MEN1 germline mutations identified 14 patients (4.8%) with thymic tumors (12 thymic NETs and 2 thymomas). LOH at the MEN1 locus was identified in 10 tumors including the 2 thymomas, demonstrating that somatic LOH at the MEN1 locus is also the mechanism for thymic tumor development. Unsupervised principal component analysis and hierarchical clustering of RNA-Seq data showed that thymic NETs formed a homogenous transcriptomic group separate from thymoma and normal thymus. KSR2 (kinase suppressor of Ras 2), that promotes Ras-mediated signaling, was abundantly expressed in thymic NETs, a potential therapeutic target. The molecular insights gained from our study about thymic tumors combined with similar data from other MEN1-associated tumors may lead to better surveillance and treatment of these rare tumors.
- Published
- 2021
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17. Familial Hyperparathyroidism.
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Blau JE and Simonds WF
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- Calcium blood, Humans, Hyperparathyroidism pathology, Mutation, Parathyroid Hormone genetics, Genetic Predisposition to Disease, Hyperparathyroidism genetics, Parathyroid Glands pathology, Parathyroid Hormone blood
- Abstract
Regulation of the serum calcium level in humans is achieved by the endocrine action of parathyroid glands working in concert with vitamin D and a set of critical target cells and tissues including osteoblasts, osteoclasts, the renal tubules, and the small intestine. The parathyroid glands, small highly vascularized endocrine organs located behind the thyroid gland, secrete parathyroid hormone (PTH) into the systemic circulation as is needed to keep the serum free calcium concentration within a tight physiologic range. Primary hyperparathyroidism (HPT), a disorder of mineral metabolism usually associated with abnormally elevated serum calcium, results from the uncontrolled release of PTH from one or several abnormal parathyroid glands. Although in the vast majority of cases HPT is a sporadic disease, it can also present as a manifestation of a familial syndrome. Many benign and malignant sporadic parathyroid neoplasms are caused by loss-of-function mutations in tumor suppressor genes that were initially identified by the study of genomic DNA from patients who developed HPT as a manifestation of an inherited syndrome. Somatic and inherited mutations in certain proto-oncogenes can also result in the development of parathyroid tumors. The clinical and genetic investigation of familial HPT in kindreds found to lack germline variants in the already known HPT-predisposition genes represents a promising future direction for the discovery of novel genes relevant to parathyroid tumor development., Competing Interests: JB is employed by the company AstraZeneca. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the authors JB and WS., (Copyright © 2021 Blau and Simonds.)
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- 2021
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18. Patients With MEN1 Are at an Increased Risk for Venous Thromboembolism.
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Lee ME, Ortega-Sustache YM, Agarwal SK, Tepede A, Welch J, Mandl A, Bansal R, Tirosh A, Piaggi P, Cochran C, Simonds WF, Weinstein LS, and Blau JE
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Anticoagulants therapeutic use, Female, History, 20th Century, History, 21st Century, Humans, Incidence, Male, Middle Aged, Multiple Endocrine Neoplasia Type 1 complications, Multiple Endocrine Neoplasia Type 1 drug therapy, Population Surveillance, Prevalence, Retrospective Studies, Risk Factors, United States epidemiology, Venous Thromboembolism etiology, Venous Thromboembolism prevention & control, Young Adult, Multiple Endocrine Neoplasia Type 1 epidemiology, Venous Thromboembolism epidemiology
- Abstract
Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder predisposing the development of multiple functional and nonfunctional neuroendocrine tumors (NETs). Only uncommon MEN1-associated functional NETs such as glucagonomas (<1%) and adenocorticotropic hormone-producing tumors (<5%) are known to be associated with hypercoagulability. It is unknown if patients with MEN1 generally have an increased risk of venous thromboembolism (VTE)., Methods: We queried a prospective natural history study of germline mutation-positive MEN1 patients (n = 286) between 1991 and 2019 for all lifetime events of VTE. The search terms were: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban, and apixaban. Incidence rates were calculated, accounting for age and sex. Comparisons were made to published incidence rates in healthy populations, different types of cancer, and Cushing's syndrome., Results: Thirty-six subjects (median age 45 years, range 16-75) experienced a VTE event, yielding a prevalence rate of 12.9%. The age-sex adjusted incidence rate of VTE is 9.11 per 1000 patient-years, with a sex-adjusted lifetime incidence rate of 2.81 per 1000 patient-years. MEN1-associated lifetime incidence rates are ~2-fold higher than the estimated annual incidence rate in the general population and are comparable to the known risk in the setting of various types of cancer. Approximately 80% of patients who had a VTE were diagnosed with pancreatic NETs, of which 24% were insulinomas. Fourteen patients (42%) experienced perioperative VTE events., Conclusions: MEN1 patients have an increased risk of VTE. Further mechanistic investigation and validation from other MEN1 cohorts are needed to confirm the increased prevalence of VTE in MEN1., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)
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- 2021
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19. Genotype of CDC73 germline mutation determines risk of parathyroid cancer.
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Li Y, Zhang J, Adikaram PR, Welch J, Guan B, Weinstein LS, Chen H, and Simonds WF
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- Female, Genotype, Humans, Male, Models, Molecular, Germ-Line Mutation genetics, Parathyroid Neoplasms genetics, Tumor Suppressor Proteins genetics
- Abstract
Mutation of the CDC73 gene, which encodes parafibromin, has been linked with parathyroid cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of parathyroid cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as 'high-impact mutations') were significantly higher among the subjects with parathyroid cancers compared to all other subjects. The Kaplan-Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperparathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of parathyroid carcinoma by disrupting the CTD of parafibromin.
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- 2020
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20. Pitfalls of using denosumab preoperatively to treat refractory severe hypercalcaemia.
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Li Y, Fan CY, Manni A, and Simonds WF
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- Adult, Calcium therapeutic use, Humans, Hypocalcemia drug therapy, Lung Neoplasms secondary, Lung Neoplasms surgery, Male, Parathyroid Neoplasms pathology, Parathyroid Neoplasms surgery, Preoperative Care, Vitamin D therapeutic use, Denosumab administration & dosage, Denosumab adverse effects, Hypercalcemia drug therapy, Hypocalcemia chemically induced
- Abstract
A 40-year-old man, with a history of metastatic parathyroid carcinoma, status post primary tumour resection and lung metastasectomy, was hospitalised for persistent severe hypercalcaemia and elevated parathyroid hormone levels despite conventional management and escalating doses of cinacalcet. A single dose (120 mg) of denosumab was given and his calcium level plummeted from 14.8 mg/dL to 5.5 mg/dL. After second lung metastasectomy, he developed prolonged hypocalcaemia that required calcium and vitamin D supplements for more than 3 years. In patients with severe hypercalcaemia refractory to conventional therapies, denosumab has been used off-label with some success. A known side effect of denosumab is hypocalcaemia, which is often short-lived. The risk of prolonged hypocalcaemia should be fully evaluated before using denosumab preoperatively, especially in patients with renal insufficiency, prolonged hyperparathyroidism or anticipated tumour debulking surgery., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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21. 18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma.
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Tepede AA, Welch J, Lee M, Mandl A, Agarwal SK, Nilubol N, Patel D, Cochran C, Simonds WF, Weinstein LS, Jha A, Millo C, Pacak K, and Blau JE
- Abstract
Summary: Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients., Learning Points: 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients. Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions. MEN1 is implicated in the tumorigenesis of PHEO in this patient.
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- 2020
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22. Development of R7BP inhibitors through cross-linking coupled mass spectrometry and integrated modeling.
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Adikaram PR, Zhang JH, Kittock CM, Pandey M, Hassan SA, Lue NG, Wang G, Gucek M, and Simonds WF
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- Amino Acid Sequence, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal pharmacology, Binding Sites, Drug Discovery, Humans, Ligands, Molecular Conformation, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, Structure-Activity Relationship, Surface Plasmon Resonance, Drug Design, Models, Molecular, RGS Proteins antagonists & inhibitors, RGS Proteins chemistry
- Abstract
Protein-protein interaction (PPI) networks are known to be valuable targets for therapeutic intervention; yet the development of PPI modulators as next-generation drugs to target specific vertices, edges, and hubs has been impeded by the lack of structural information of many of the proteins and complexes involved. Building on recent advancements in cross-linking mass spectrometry (XL-MS), we describe an effective approach to obtain relevant structural data on R7BP, a master regulator of itch sensation, and its interfaces with other proteins in its network. This approach integrates XL-MS with a variety of modeling techniques to successfully develop antibody inhibitors of the R7BP and RGS7/Gβ5 duplex interaction. Binding and inhibitory efficiency are studied by surface plasmon resonance spectroscopy and through an R7BP-derived dominant negative construct. This approach may have broader applications as a tool to facilitate the development of PPI modulators in the absence of crystal structures or when structural information is limited., Competing Interests: Competing interestsThe authors declare no competing interests.
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- 2019
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23. Clinical presentation and management of primary ovarian neuroendocrine tumor in multiple endocrine neoplasia type 1.
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Jhawar S, Lakhotia R, Suzuki M, Welch J, Agarwal SK, Sharretts J, Merino M, Ahlman M, Blau JE, Simonds WF, and Del Rivero J
- Abstract
Summary: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5-15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF)., Learning Points: Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET. Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins. Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence. Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.
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- 2019
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24. Retrospective study of inpatient diabetes management service, length of stay and 30-day readmission rate of patients with diabetes at a community hospital.
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Mandel SR, Langan S, Mathioudakis NN, Sidhaye AR, Bashura H, Bie JY, Mackay P, Tucker C, Demidowich AP, Simonds WF, Jha S, Ebenuwa I, Kantsiper M, Howell EE, Wachter P, Golden SH, and Zilbermint M
- Abstract
Background : Hospitalized patients with diabetes are at risk of complications and longer length of stay (LOS). Inpatient Diabetes Management Services (IDMS) are known to be beneficial; however, their impact on patient care measures in community, non-teaching hospitals, is unknown. Objectives : To evaluate whether co-managing patients with diabetes by the IDMS team reduces LOS and 30-day readmission rate (30DR). Methods : This retrospective quality improvement cohort study analyzed LOS and 30DR among patients with diabetes admitted to a community hospital. The IDMS medical team consisted of an endocrinologist, nurse practitioner, and diabetes educator. The comparison group consisted of hospitalized patients with diabetes under standard care of attending physicians (mostly internal medicine-trained hospitalists). The relationship between study groups and outcome variables was assessed using Generalized Estimating Equation models. Results : 4,654 patients with diabetes (70.8 ± 0.2 years old) were admitted between January 2016 and May 2017. The IDMS team co-managed 18.3% of patients, mostly with higher severity of illness scores (p < 0.0001). Mean LOS in patients co-managed by the IDMS team decreased by 27%. Median LOS decreased over time in the IDMS group (p = 0.046), while no significant decrease was seen in the comparison group. Mean 30DR in patients co-managed by the IDMS decreased by 10.71%. Median 30DR decreased among patients co-managed by the IDMS (p = 0.048). Conclusions : In a community hospital setting, LOS and 30DR significantly decreased in patients co-managed by a specialized diabetes team. These changes may be translated into considerable cost savings.
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- 2019
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25. Frequency and consequence of the recurrent YY1 p.T372R mutation in sporadic insulinomas.
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Parekh VI, Modali SD, Welch J, Simonds WF, Weinstein LS, Kebebew E, and Agarwal SK
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- Female, Humans, Insulinoma pathology, Male, Pancreatic Neoplasms pathology, Insulinoma genetics, Mutation, Pancreatic Neoplasms genetics, YY1 Transcription Factor genetics
- Published
- 2018
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26. Ethnicity of Patients With Germline GCM2 -Activating Variants and Primary Hyperparathyroidism.
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Guan B, Welch JM, Vemulapalli M, Li Y, Ling H, Kebebew E, Simonds WF, Marx SJ, and Agarwal SK
- Abstract
Context: Germline gain-of-function variants in the transcription factor GCM2 were found in 18% of kindreds with familial isolated hyperparathyroidism (FIHP). These variants [c.1136T>A (p.Leu379Gln) and c.1181A>C (p.Tyr394Ser)] were located in a 17-amino acid transcriptional inhibitory domain named C-terminal conserved inhibitory domain (CCID)., Objective: We investigated the ethnicity of individuals with germline variants in the GCM2 CCID in our primary hyperparathyroidism (PHPT) patient samples and in the Genome Aggregation Database., Design: Ethnicity information was obtained from an in-house clinical database and genetic counseling. Sanger sequencing of blood DNA was used to determine the genotype of the GCM2 CCID region. Luciferase reporter assays were performed to determine the functional impact of GCM2 variants., Setting and Patients: National Institute of Diabetes and Digestive and Kidney Diseases endocrine clinic is a service that accepts PHPT referral patients., Results: The GCM2 p.Tyr394Ser variant was found in 41% [95% confidence interval (CI), 22% to 64%] of Ashkenazi Jewish (AJ) kindreds with FIHP and in 27% (95% CI, 17% to 40%) of AJ patients with sporadic PHPT. The p.Tyr394Ser variant was also found in sporadic PHPT patients of European ancestry, but at a lower prevalence. The p.Leu379Gln variant was found in 8% (95% CI, 1% to 26%) of European kindreds with FIHP and 0.5% (95% CI, 0% to 3.0%) of sporadic PHPT cases of European ancestry. The sporadic PHPT patients with GCM2 -activating variants often had multigland involvement or postoperative recurrent or persistent disease., Conclusions: Specific GCM2 -activating variants enriched among various ethnic backgrounds could contribute to a large number of cases with FIHP or sporadic PHPT.
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- 2017
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27. GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism.
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Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, Kebebew E, Biesecker LG, Simonds WF, Marx SJ, and Agarwal SK
- Subjects
- Adenoma diagnosis, Adolescent, Adult, Aged, Amino Acid Sequence, Exome, Female, Fibroma diagnosis, Genetic Variation, Humans, Hyperparathyroidism diagnosis, Hyperparathyroidism, Primary diagnosis, Jaw Neoplasms diagnosis, Male, Middle Aged, Multiple Endocrine Neoplasia Type 1 diagnosis, Parathyroid Hormone, Pedigree, Proto-Oncogene Mas, Proto-Oncogenes genetics, Sequence Analysis, DNA, Young Adult, Adenoma genetics, Fibroma genetics, Germ-Line Mutation, Hyperparathyroidism genetics, Hyperparathyroidism, Primary genetics, Jaw Neoplasms genetics, Multiple Endocrine Neoplasia Type 1 genetics, Nuclear Proteins genetics, Transcription Factors genetics
- Abstract
Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP., (Published by Elsevier Inc.)
- Published
- 2016
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28. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.
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Lodder EM, De Nittis P, Koopman CD, Wiszniewski W, Moura de Souza CF, Lahrouchi N, Guex N, Napolioni V, Tessadori F, Beekman L, Nannenberg EA, Boualla L, Blom NA, de Graaff W, Kamermans M, Cocciadiferro D, Malerba N, Mandriani B, Akdemir ZHC, Fish RJ, Eldomery MK, Ratbi I, Wilde AAM, de Boer T, Simonds WF, Neerman-Arbez M, Sutton VR, Kok F, Lupski JR, Reymond A, Bezzina CR, Bakkers J, and Merla G
- Subjects
- Adolescent, Animals, Child, Developmental Disabilities physiopathology, Female, GTP-Binding Protein beta Subunits deficiency, Gastroesophageal Reflux genetics, Gastroesophageal Reflux physiopathology, Gene Deletion, Heart Rate genetics, Heterozygote, Humans, Male, Muscle Hypotonia genetics, Mutation, Missense genetics, Pedigree, Phenotype, Retinal Diseases genetics, Retinal Diseases physiopathology, Seizures genetics, Syndrome, Young Adult, Zebrafish genetics, Zebrafish physiology, Zebrafish Proteins, Bradycardia genetics, Bradycardia physiopathology, Developmental Disabilities genetics, GTP-Binding Protein beta Subunits genetics, Genes, Recessive genetics, Mutation genetics, Sinoatrial Node physiopathology
- Abstract
GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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29. Endocrine neoplasms in familial syndromes of hyperparathyroidism.
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Li Y and Simonds WF
- Subjects
- Humans, Syndrome, Endocrine Gland Neoplasms diagnosis, Endocrine Gland Neoplasms epidemiology, Endocrine Gland Neoplasms genetics, Endocrine Gland Neoplasms therapy, Hyperparathyroidism diagnosis, Hyperparathyroidism epidemiology, Hyperparathyroidism genetics, Hyperparathyroidism therapy
- Abstract
Familial syndromes of hyperparathyroidism, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), and the hyperparathyroidism-jaw tumor (HPT-JT), comprise 2-5% of primary hyperparathyroidism cases. Familial syndromes of hyperparathyroidism are also associated with a range of endocrine and nonendocrine tumors, including potential malignancies. Complications of the associated neoplasms are the major causes of morbidities and mortalities in these familial syndromes, e.g., parathyroid carcinoma in HPT-JT syndrome; thymic, bronchial, and enteropancreatic neuroendocrine tumors in MEN1; and medullary thyroid cancer and pheochromocytoma in MEN2A. Because of the different underlying mechanisms of neoplasia, these familial tumors may have different characteristics compared with their sporadic counterparts. Large-scale clinical trials are frequently lacking due to the rarity of these diseases. With technological advances and the development of new medications, the natural history, diagnosis, and management of these syndromes are also evolving. In this article, we summarize the recent knowledge on endocrine neoplasms in three familial hyperparathyroidism syndromes, with an emphasis on disease characteristics, molecular pathogenesis, recent developments in biochemical and radiological evaluation, and expert opinions on surgical and medical therapies. Because these familial hyperparathyroidism syndromes are associated with a wide variety of tumors in different organs, this review is focused on those endocrine neoplasms with malignant potential., (© 2016 Society for Endocrinology.)
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- 2016
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30. Optimization of genome editing through CRISPR-Cas9 engineering.
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Zhang JH, Adikaram P, Pandey M, Genis A, and Simonds WF
- Subjects
- Animals, Bacterial Proteins metabolism, CRISPR-Associated Protein 9, DNA chemistry, DNA genetics, DNA metabolism, DNA End-Joining Repair, Endonucleases metabolism, Humans, Models, Molecular, Nucleotide Motifs, RNA, Guide, CRISPR-Cas Systems metabolism, Recombinational DNA Repair, Bacterial Proteins genetics, CRISPR-Cas Systems, Clustered Regularly Interspaced Short Palindromic Repeats, Endonucleases genetics, Gene Editing methods, Genome, RNA, Guide, CRISPR-Cas Systems genetics
- Abstract
CRISPR (Clustered Regularly-Interspaced Short Palindromic Repeats)-Cas9 (CRISPR associated protein 9) has rapidly become the most promising genome editing tool with great potential to revolutionize medicine. Through guidance of a 20 nucleotide RNA (gRNA), CRISPR-Cas9 finds and cuts target protospacer DNA precisely 3 base pairs upstream of a PAM (Protospacer Adjacent Motif). The broken DNA ends are repaired by either NHEJ (Non-Homologous End Joining) resulting in small indels, or by HDR (Homology Directed Repair) for precise gene or nucleotide replacement. Theoretically, CRISPR-Cas9 could be used to modify any genomic sequences, thereby providing a simple, easy, and cost effective means of genome wide gene editing. However, the off-target activity of CRISPR-Cas9 that cuts DNA sites with imperfect matches with gRNA have been of significant concern because clinical applications require 100% accuracy. Additionally, CRISPR-Cas9 has unpredictable efficiency among different DNA target sites and the PAM requirements greatly restrict its genome editing frequency. A large number of efforts have been made to address these impeding issues, but much more is needed to fully realize the medical potential of CRISPR-Cas9. In this article, we summarize the existing problems and current advances of the CRISPR-Cas9 technology and provide perspectives for the ultimate perfection of Cas9-mediated genome editing.
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- 2016
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31. Improving the specificity and efficacy of CRISPR/CAS9 and gRNA through target specific DNA reporter.
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Zhang JH, Pandey M, Kahler JF, Loshakov A, Harris B, Dagur PK, Mo YY, and Simonds WF
- Subjects
- Animals, High-Throughput Nucleotide Sequencing, Humans, Clustered Regularly Interspaced Short Palindromic Repeats genetics, DNA genetics, RNA, Guide, CRISPR-Cas Systems genetics
- Abstract
Genomic engineering by the guide RNA (gRNA)-directed CRISPR/CAS9 is rapidly becoming a method of choice for various biological systems. However, pressing concerns remain regarding its off-target activities and wide variations in efficacies. While next generation sequencing (NGS) has been primarily used to evaluate the efficacies and off-target activities of gRNAs, it only detects the imperfectly repaired double strand DNA breaks (DSB) by the error-prone non-homologous end joining (NHEJ) mechanism and may not faithfully represent the DSB activities because the efficiency of NHEJ-mediated repair varies depending on the local chromatin environment. Here we describe a reporter system for unbiased detection and comparison of DSB activities that promises to improve the chance of success in genomic engineering and to facilitate large-scale screening of CAS9 activities and gRNA libraries. Additionally, we demonstrated that the tolerances to mismatches between a gRNA and the corresponding target DNA can occur at any position of the gRNA, and depend on both specific gRNA sequences and CAS9 constructs used., (Published by Elsevier B.V.)
- Published
- 2014
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32. Association of type-O blood with neuroendocrine tumors in multiple endocrine neoplasia type 1.
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Weisbrod AB, Nilubol N, Weinstein LS, Simonds WF, Libutti SK, Jensen RT, Marx SJ, and Kebebew E
- Subjects
- ABO Blood-Group System genetics, Adult, Aged, Cohort Studies, Female, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia Type 1 complications, Multiple Endocrine Neoplasia Type 1 mortality, Multiple Endocrine Neoplasia Type 1 pathology, Neuroendocrine Tumors complications, Neuroendocrine Tumors mortality, Neuroendocrine Tumors pathology, Pancreatic Neoplasms complications, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Retrospective Studies, Survival Analysis, Young Adult, ABO Blood-Group System physiology, Multiple Endocrine Neoplasia Type 1 blood, Neuroendocrine Tumors blood, Pancreatic Neoplasms blood
- Abstract
Context: The ABO blood type system describes the expression of human blood group antigens found on both erythrocytes and normal tissue throughout the body. We recently reported an association between O blood type and the manifestation of pancreatic neuroendocrine tumors in a cohort of patients with Von Hippel-Lindau syndrome., Objective: The aim of the study was to determine whether there is an association of ABO blood type with the development of neuroendocrine tumors in patients with multiple endocrine neoplasia, type 1 (MEN-1)., Design: A retrospective analysis of 105 patients with MEN-1 was performed. Demographic, clinical, and biochemical data were analyzed by ABO blood type. Fisher's exact test was used to determine association between ABO blood type and manifestation of neuroendocrine tumor., Results: Demographic and clinical characteristics were similar amongst blood type cohorts. We found an association between O blood type and the manifestation of a primary neuroendocrine tumor of the gastrointestinal tract, lung, pancreas, and thymus in patients with MEN-1 (P = 0.01). Sixteen of 17 (94%) metastatic tumors had type-O blood, compared to 32 of 43 (74%) with a benign tumor who had non-O blood type., Conclusions: Our findings suggest an association between O blood type and the manifestation of a primary neuroendocrine tumor in patients with MEN-1. Prospective clinical studies are warranted to see whether patient blood type status may be a useful addition to current screening and surveillance practices.
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- 2013
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33. Cerebellar abnormalities in mice lacking type 3 deiodinase and partial reversal of phenotype by deletion of thyroid hormone receptor α1.
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Peeters RP, Hernandez A, Ng L, Ma M, Sharlin DS, Pandey M, Simonds WF, St Germain DL, and Forrest D
- Subjects
- Animals, Cerebellum abnormalities, Female, Immunohistochemistry, In Situ Hybridization, Iodide Peroxidase genetics, Male, Mice, Mice, Knockout, Motor Activity genetics, Motor Activity physiology, Thyroid Hormone Receptors alpha genetics, Thyroid Hormones metabolism, Cerebellum enzymology, Cerebellum metabolism, Iodide Peroxidase metabolism, Thyroid Hormone Receptors alpha metabolism
- Abstract
Thyroid hormone serves many functions throughout brain development, but the mechanisms that control the timing of its actions in specific brain regions are poorly understood. In the cerebellum, thyroid hormone controls formation of the transient external germinal layer, which contains proliferative granule cell precursors, subsequent granule cell migration, and cerebellar foliation. We report that the thyroid hormone-inactivating type 3 deiodinase (encoded by Dio3) is expressed in the mouse cerebellum at embryonic and neonatal stages, suggesting a need to protect cerebellar tissues from premature stimulation by thyroid hormone. Dio3(-/-) mice displayed reduced foliation, accelerated disappearance of the external germinal layer, and premature expansion of the molecular layer at juvenile ages. Furthermore, Dio3(-/-) mice exhibited locomotor behavioral abnormalities and impaired ability in descending a vertical pole. To ascertain that these phenotypes resulted from inappropriate exposure to thyroid hormone, thyroid hormone receptor α1 (TRα1) was removed from Dio3(-/-) mice, which substantially corrected the cerebellar and behavioral phenotypes. Deletion of TRα1 did not correct the previously reported small thyroid gland or deafness in Dio3(-/-) mice, indicating that Dio3 controls the activation of specific receptor isoforms in different tissues. These findings suggest that type 3 deiodinase constrains the timing of thyroid hormone action during cerebellar development.
- Published
- 2013
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34. Sleeping parathyroid tumor: rapid hyperfunction after removal of the dominant tumor.
- Author
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Yavuz S, Simonds WF, Weinstein LS, Collins MT, Kebebew E, Nilubol N, Phan GQ, Libutti SK, Remaley AT, Van Deventer M, and Marx SJ
- Subjects
- Adolescent, False Positive Reactions, Humans, Hypercalcemia blood, Hypercalcemia physiopathology, Hyperparathyroidism, Primary blood, Hyperparathyroidism, Primary physiopathology, Hyperparathyroidism, Primary surgery, Male, Multiple Endocrine Neoplasia Type 1 blood, Multiple Endocrine Neoplasia Type 1 physiopathology, Parathyroid Hormone blood, Parathyroid Neoplasms blood, Parathyroid Neoplasms physiopathology, Postoperative Complications blood, Young Adult, Multiple Endocrine Neoplasia Type 1 surgery, Parathyroid Neoplasms surgery, Parathyroidectomy adverse effects, Postoperative Complications physiopathology
- Abstract
Context: Due to frequent multiplicity of tumors in multiple endocrine neoplasia type 1, it may be difficult to decide when to stop a parathyroid exploration. A fall of intraoperative serum PTH by a certain percentage during parathyroid surgery is often used as one criterion for ending the operation., Results: We report two patients with primary hyperparathyroidism due to multiple endocrine neoplasia type 1 who had their first parathyroidectomy at the National Institutes of Health. In both cases, two and a half glands were removed, an extensive search was done for an occult parathyroid tumor, and intraoperative PTH decreased markedly to the lower limits of normal, suggesting a successful operation. Despite this, both patients became hypercalcemic within 3 d after the operation and showed persistent primary hyperparathyroidism. Detailed findings suggest the following course: chronic hypercalcemia had caused near total suppression of PTH secretion by an undiscovered parathyroid tumor (sleeping parathyroid tumor). When the hypercalcemia decreased after surgery due to the removal of the dominant parathyroid tumor(s), the abnormal yet previously suppressed tumor rapidly began to oversecrete PTH and thus caused postoperative hypercalcemia., Conclusions: Even a fall of the intraoperative PTH to the lower limits of the normal range cannot guarantee that removal of all parathyroid tumors has been complete in cases with multiple tumors. These findings likely reflect strikingly differing PTH secretory functions among distinct tumors in the same patient, with hypercalcemia at least from a dominant tumor suppressing PTH secretion by one or more other parathyroid tumors.
- Published
- 2012
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35. The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome.
- Author
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Zhang JH, Seigneur EM, Pandey M, Loshakov A, Dagur PK, Connelly PS, Koo L, Panicker LM, and Simonds WF
- Subjects
- Animals, Autophagy, Biomarkers metabolism, Carboxy-Lyases genetics, Carboxy-Lyases metabolism, Carrier Proteins metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster, Germ-Line Mutation, Haploinsufficiency, Heterozygote, Humans, Parathyroid Glands pathology, Parathyroid Neoplasms metabolism, Parathyroid Neoplasms pathology, Protein Biosynthesis, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Sequence Homology, Amino Acid, Signal Transduction, Syndrome, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Tumor Suppressor Proteins metabolism, Carrier Proteins genetics, Parathyroid Glands metabolism, Parathyroid Neoplasms genetics, Tumor Suppressor Proteins genetics
- Abstract
Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome associated with a high risk of parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. The molecular pathways that distinguish malignant from benign parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye phenotype of lobe, encoding the fly homolog of Akt1s1/ PRAS40. We report now an interaction between hyx and Tor, a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein (EIF4EBP), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to parathyroid malignant transformation.
- Published
- 2012
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36. A new look at vitamin D metabolism and "idiopathic" hypercalcemia.
- Author
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Simonds WF
- Subjects
- Humans, Male, Vitamin D3 24-Hydroxylase, Hypercalcemia genetics, Steroid Hydroxylases genetics
- Published
- 2012
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37. Cytoplasmic polyadenylation element binding protein is a conserved target of tumor suppressor HRPT2/CDC73.
- Author
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Zhang JH, Panicker LM, Seigneur EM, Lin L, House CD, Morgan W, Chen WC, Mehta H, Haj-Ali M, Yu ZX, and Simonds WF
- Subjects
- Animals, Carboxy-Lyases genetics, Carboxy-Lyases metabolism, Cell Line, Chromatin Immunoprecipitation, Drosophila growth & development, Drosophila metabolism, Drosophila Proteins genetics, Humans, Larva metabolism, Mutation, RNA Interference, RNA, Small Interfering, Signal Transduction, Transcription Factors genetics, Tumor Suppressor Proteins genetics, Wnt Proteins metabolism, mRNA Cleavage and Polyadenylation Factors genetics, Drosophila Proteins metabolism, Transcription Factors metabolism, Tumor Suppressor Proteins metabolism, mRNA Cleavage and Polyadenylation Factors metabolism
- Abstract
Parafibromin, a tumor suppressor protein encoded by HRPT2/CDC73 and implicated in parathyroid cancer and the hyperparathyroidism-jaw tumor (HPT-JT) familial cancer syndrome, is part of the PAF1 transcriptional regulatory complex. Parafibromin has been implicated in apoptosis and growth arrest, but the mechanism by which its loss of function promotes neoplasia is poorly understood. In this study we report that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of HRPT2/CDC73, rescues the loss-of-ventral-eye phenotype of lobe (Akt1s1). Such rescue is consistent with previous reports that hyx/parafibromin is required for the nuclear transduction of Wingless (Wg)/Wnt signals and that Wg signaling antagonizes lobe function. A screen using double hyx/lobe heterozygotes identified an additional interaction with orb and orb2, the homologs of mammalian cytoplasmic polyadenylation element binding protein (CPEB), a translational regulatory protein. Hyx and orb2 heterozygotes lived longer and were more resistant to starvation than controls. In mammalian cells, knockdown of parafibromin expression reduced levels of CPEB1. Chromatin immunoprecipitation (ChIP) showed occupancy of CPEB1 by endogenous parafibromin. Bioinformatic analysis revealed a significant overlap between human transcripts potentially regulated by parafibromin and CPEB. These results show that parafibromin may exert both transcriptional and, through CPEB, translational control over a subset of target genes and that loss of parafibromin (and CPEB) function may promote tumorigenesis in part by conferring resistance to nutritional stress.
- Published
- 2010
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38. Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism-jaw tumor syndrome.
- Author
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Panicker LM, Zhang JH, Dagur PK, Gastinger MJ, and Simonds WF
- Subjects
- Amino Acid Sequence, Amino Acid Substitution genetics, Amino Acid Substitution physiology, Animals, Carcinoma complications, Carcinoma metabolism, Cells, Cultured, Genes, Dominant, Humans, Hyperparathyroidism complications, Hyperparathyroidism metabolism, Jaw Neoplasms complications, Jaw Neoplasms metabolism, Leucine genetics, Mice, Molecular Sequence Data, Mutant Proteins genetics, Mutant Proteins metabolism, Mutant Proteins physiology, NIH 3T3 Cells, Pedigree, Phenylalanine genetics, Protein Transport genetics, Sequence Homology, Amino Acid, Syndrome, Tumor Suppressor Proteins physiology, Carcinoma genetics, Cell Nucleolus metabolism, Hyperparathyroidism genetics, Jaw Neoplasms genetics, Mutation, Missense physiology, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism
- Abstract
The hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a familial cancer syndrome that can result from germline inactivation of HRPT2/CDC73, a putative tumor suppressor gene that encodes parafibromin, a component of the transcriptional regulatory PAF1 complex with homology to the yeast protein Cdc73p. The vast majority of HRPT2/CDC73 germline mutations identified have been truncation or frameshift mutations, and loss of function due to missense mutation is rare. We report here a kindred with HPT-JT due to a germline L95P missense mutation in parafibromin. The mutant parafibromin was studied in vitro to understand the basis of its presumed loss-of-function. When transfected in cultured cells, the L95P mutant was expressed to a lower level than wild-type (wt) parafibromin, a difference that was not overcome by inhibition of the proteasomal degradation pathway. The L95P mutant parafibromin retained the ability to assemble with endogenous PAF1 complex components as evidenced by co-immunoprecipitation. Analysis of subcellular localization showed that the L95P mutant was markedly deficient in nucleolar localization compared to the wt, an impairment likely resulting from disruption of a putative nucleolar localization signal immediately upstream of the L95P mutation. Transfection of the L95P parafibromin mutant, but not the wt, enhanced cell cycle progression and increased cell survival in NIH-3T3 and HEK 293 cells, resulting apparently from dominant interference with endogenous parafibromin action. The simultaneous loss of nucleolar localization and acquisition of a growth stimulatory phenotype with the L95P mutation raise the possibility that parafibromin must interact with targets in the nucleolus to fully execute its tumor suppressor functions.
- Published
- 2010
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39. The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene.
- Author
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Lin L, Zhang JH, Panicker LM, and Simonds WF
- Subjects
- Chromatin Immunoprecipitation, DNA Primers genetics, Flow Cytometry, Half-Life, Humans, Immunoblotting, Luciferases, Proto-Oncogene Mas, RNA Interference, Tumor Suppressor Proteins genetics, Cell Proliferation, Cell Transformation, Neoplastic metabolism, Gene Expression Regulation, Neoplastic physiology, Genes, myc physiology, Models, Biological, Tumor Suppressor Proteins metabolism
- Abstract
Parafibromin is a tumor suppressor protein encoded by HRPT2, a gene recently implicated in the hereditary hyperparathyroidism-jaw tumor syndrome, parathyroid cancer, and a subset of kindreds with familial isolated hyperparathyroidism. Human parafibromin binds to RNA polymerase II as part of a PAF1 transcriptional regulatory complex. The physiologic targets of parafibromin and the mechanism by which its loss of function can lead to neoplastic transformation are poorly understood. We show here that RNA interference with the expression of parafibromin or Paf1 stimulates cell proliferation and increases levels of the c-myc proto-oncogene product, a DNA-binding protein and established regulator of cell growth. This effect results from both c-myc protein stabilization and activation of the c-myc promoter, without alleviation of the c-myc transcriptional pause. Chromatin immunoprecipitation demonstrates the occupancy of the c-myc promoter by parafibromin and other PAF1 complex subunits in native cells. Knockdown of c-myc blocks the proliferative effect of RNA interference with parafibromin or Paf1 expression. These experiments provide a previously uncharacterized mechanism for the anti-proliferative action of the parafibromin tumor suppressor protein resulting from PAF1 complex-mediated inhibition of the c-myc proto-oncogene.
- Published
- 2008
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40. The parafibromin tumor suppressor protein interacts with actin-binding proteins actinin-2 and actinin-3.
- Author
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Agarwal SK, Simonds WF, and Marx SJ
- Subjects
- Animals, Cell Nucleus metabolism, Cells, Cultured, Cytoplasm metabolism, Fluorescent Antibody Technique, Gene Library, HeLa Cells, Humans, Mice, Parathyroid Neoplasms metabolism, Transfection, Two-Hybrid System Techniques, Actinin metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Background: Germline and somatic inactivating mutations in the HRPT2 gene occur in the inherited hyperparathyroidism-jaw tumor syndrome, in some cases of parathyroid cancer and in some cases of familial hyperparathyroidism. HRPT2 encodes parafibromin. To identify parafibromin interacting proteins we used the yeast two-hybrid system for screening a heart cDNA library with parafibromin as the bait., Results: Fourteen parafibromin interaction positive preys representing 10 independent clones encoding actinin-2 were isolated. Parafibromin interacted with muscle alpha-actinins (actinin-2 and actinin-3), but not with non-muscle alpha-actinins (actinin-1 and actinin-4). The parafibromin-actinin interaction was verified by yeast two-hybrid, GST pull-down, and co-immunoprecipitation. Yeast two-hybrid analysis revealed that the N-terminal region of parafibromin interacted with actinins. In actin sedimentation assays parafibromin did not dissociate skeletal muscle actinins from actin filaments, but interestingly, parafibromin could also bundle/cross-link actin filaments. Parafibromin was predominantly nuclear in undifferentiated proliferating myoblasts (C2C12 cells), but in differentiated C2C12 myotubes parafibromin co-localized with actinins in the cytoplasmic compartment., Conclusion: These data support a possible contribution of parafibromin outside the nucleus through its interaction with actinins and actin bundling/cross-linking. These data also suggest that actinins (and actin) participate in sequestering parafibromin in the cytoplasmic compartment.
- Published
- 2008
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41. R7-binding protein targets the G protein beta 5/R7-regulator of G protein signaling complex to lipid rafts in neuronal cells and brain.
- Author
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Nini L, Waheed AA, Panicker LM, Czapiga M, Zhang JH, and Simonds WF
- Subjects
- Animals, Kinetics, Mice, PC12 Cells, Palmitic Acid metabolism, Protein Binding, Rats, Brain metabolism, Heterotrimeric GTP-Binding Proteins metabolism, Membrane Microdomains metabolism, Neurons metabolism, RGS Proteins metabolism, Signal Transduction
- Abstract
Background: Heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins), composed of G alpha, G beta, and G gamma subunits, are positioned at the inner face of the plasma membrane and relay signals from activated G protein-coupled cell surface receptors to various signaling pathways. G beta 5 is the most structurally divergent G beta isoform and forms tight heterodimers with regulator of G protein signalling (RGS) proteins of the R7 subfamily (R7-RGS). The subcellular localization of G beta 5/R7-RGS protein complexes is regulated by the palmitoylation status of the associated R7-binding protein (R7BP), a recently discovered SNARE-like protein. We investigate here whether R7BP controls the targeting of G beta 5/R7-RGS complexes to lipid rafts, cholesterol-rich membrane microdomains where conventional heterotrimeric G proteins and some effector proteins are concentrated in neurons and brain., Results: We show that endogenous G beta 5/R7-RGS/R7BP protein complexes are present in native neuron-like PC12 cells and that a fraction is targeted to low-density, detergent-resistant membrane lipid rafts. The buoyant density of endogenous raft-associated G beta 5/R7-RGS protein complexes in PC12 cells was similar to that of lipid rafts containing the palmitoylated marker proteins PSD-95 and LAT, but distinct from that of the membrane microdomain where flotillin was localized. Overexpression of wild-type R7BP, but not its palmitoylation-deficient mutant, greatly enriched the fraction of endogenous G beta 5/R7-RGS protein complexes in the lipid rafts. In HEK-293 cells the palmitoylation status of R7BP also regulated the lipid raft targeting of co-expressed G beta 5/R7-RGS/R7BP proteins. A fraction of endogenous G beta 5/R7-RGS/R7BP complexes was also present in lipid rafts in mouse brain., Conclusion: A fraction of G beta 5/R7-RGS/R7BP protein complexes is targeted to low-density, detergent-resistant membrane lipid rafts in PC12 cells and brain. In cultured cells, the palmitoylation status of R7BP regulated the lipid raft targeting of endogenous or co-expressed G beta 5/R7-RGS proteins. Taken together with recent evidence that the kinetic effects of the G beta 5 complex on GPCR signaling are greatly enhanced by R7BP palmitoylation through a membrane-anchoring mechanism, our data suggest the targeting of the G beta 5/R7-RGS/R7BP complex to lipid rafts in neurons and brain, where G proteins and their effectors are concentrated, may be central to the G protein regulatory function of the complex.
- Published
- 2007
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42. The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27Kip1 mutations.
- Author
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Ozawa A, Agarwal SK, Mateo CM, Burns AL, Rice TS, Kennedy PA, Quigley CM, Simonds WF, Weinstein LS, Chandrasekharappa SC, Collins FS, Spiegel AM, and Marx SJ
- Subjects
- Adult, DNA, Neoplasm genetics, Female, Gene Frequency, Germ-Line Mutation genetics, Hormones metabolism, Humans, Male, Middle Aged, Parathyroid Neoplasms pathology, Pituitary Neoplasms pathology, Polymorphism, Genetic genetics, Cyclin-Dependent Kinase Inhibitor p27 genetics, Multiple Endocrine Neoplasia Type 1 genetics, Parathyroid Neoplasms genetics, Pituitary Neoplasms genetics
- Abstract
Context: One variant of multiple endocrine neoplasia type 1 (MEN1) is defined by sporadic tumors of both the parathyroids and pituitary. The prevalence of identified MEN1 mutations in this variant is lower than in familial MEN1 (7% vs. 90%), suggesting different causes. Recently, one case of this variant had a germline mutation of p27(Kip1)/CDKN1B., Objective: The objective was to test p27 in germline DNA from cases with tumors of both the parathyroids and pituitary., Design: Medical record review and sequence analysis in DNA were performed., Setting: This study involved an inpatient and outpatient referral program for cases of endocrine tumors., Patients: Sixteen index cases had sporadic tumors of two organs, both the parathyroids and the pituitary. There were 18 additional index cases with related features of familial tumors. Five subjects were normal controls. No case had an identified MEN1 mutation., Interventions: Clinical status of endocrine tumors was tabulated. Sequencing of germline DNA from index cases and control cases for the p27 gene was performed by PCR., Main Outcome Measures: Endocrine tumor types and their expressions were measured, as were sequence changes in the p27 gene., Results: Tumor features were documented in index cases and families. One p27 germline single nucleotide change was identified. This predicted a silent substitution of Thr142Thr. Furthermore, there was a normal prevalence of heterozygosity for a common p27 polymorphism, making a large p27 deletion unlikely in all or most of these cases., Conclusions: The MEN1 variant with sporadic parathyroid tumors, sporadic pituitary tumor, and no identified MEN1 mutation is usually not caused by p27 germline mutations. It is usually caused by as yet unknown process(es).
- Published
- 2007
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43. Ruling out a suspect: the role of beta-catenin mutation in benign parathyroid neoplasia.
- Author
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Simonds WF
- Subjects
- Adenoma genetics, Exons, Humans, Mutation, Parathyroid Neoplasms genetics, beta Catenin genetics
- Published
- 2007
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44. Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function.
- Author
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Lin L, Czapiga M, Nini L, Zhang JH, and Simonds WF
- Subjects
- Amino Acid Sequence, Animals, Apoptosis, Cell Line, Tumor, Humans, Hyperparathyroidism genetics, Jaw Neoplasms genetics, Mice, Molecular Sequence Data, Transfection, Tumor Suppressor Proteins metabolism, Cell Nucleus metabolism, Hyperparathyroidism metabolism, Jaw Neoplasms metabolism, Nuclear Localization Signals genetics, Tumor Suppressor Proteins genetics
- Abstract
Parafibromin is a tumor suppressor protein encoded by HRPT2, a gene recently implicated in the hereditary hyperparathyroidism-jaw tumor syndrome, parathyroid cancer, and a subset of kindreds with familial isolated hyperparathyroidism. Human parafibromin binds to RNA polymerase II as part of a PAF1 transcriptional regulatory complex. The mechanism by which loss of parafibromin function can lead to neoplastic transformation is poorly understood. Because the subcellular localization of parafibromin is likely to be critical for its function with the nuclear PAF1 complex, we sought to experimentally define the nuclear localization signal (NLS) of parafibromin and examine its potential role in parafibromin function. Using site-directed mutagenesis, we define a dominant bipartite NLS and a secondary NLS, both in the NH(2)-terminal region of parafibromin whose combined mutation nearly abolishes nuclear targeting. The NLS-mutant parafibromin is significantly impaired in its association with endogenous Paf1 and Leo1. We further report that overexpression of wild-type but not NLS-mutant parafibromin induces apoptosis in transfected cells. Inhibition of endogenous parafibromin expression by RNA interference inhibits the basal rate of apoptosis and apoptosis resulting from DNA damage induced by camptothecin, a topoisomerase I inhibitor. These experiments identify for the first time a proapoptotic activity of endogenous parafibromin likely to be important in its role as a tumor suppressor and show a functional role for the NLS of parafibromin in this activity.
- Published
- 2007
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45. Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation.
- Author
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Kelly TG, Shattuck TM, Reyes-Mugica M, Stewart AF, Simonds WF, Udelsman R, Arnold A, and Carpenter TO
- Subjects
- Adenoma genetics, Adenoma surgery, Base Sequence, Carcinoma genetics, Carcinoma surgery, Child, Genetic Testing, Humans, Hyperparathyroidism, Primary diagnosis, Male, Molecular Sequence Data, Parathyroid Neoplasms genetics, Parathyroid Neoplasms surgery, Tumor Suppressor Proteins metabolism, Adenoma diagnosis, Carcinoma diagnosis, Germ-Line Mutation, Hyperparathyroidism, Primary genetics, Parathyroid Neoplasms diagnosis, Tumor Suppressor Proteins genetics
- Abstract
Unlabelled: Familial hyperparathyroid syndromes involving mutations of HRPT2 (also CDC73), a tumor suppressor, are important to identify because the relatively high incidence of parathyroid malignancy associated with such mutations warrants a specific surveillance strategy. However, there is a dearth of reports describing experience with surveillance and early detection informed by genetic insight into this disorder., Introduction: Familial isolated hyperparathyroidism (FIHP) is a rare cause of parathyroid (PT) tumors without other neoplasms or endocrinopathies. Germline mutations in CASR, MEN1, and rarely, HRPT2 have been identified in kindreds with FIHP. HRPT2 mutations may be enriched in FIHP families with PT carcinoma, underscoring the importance of identifying causative mutations., Materials and Methods: A 13-year-old boy, whose father had died of PT carcinoma, developed primary hyperparathyroidism. A left superior PT mass was identified by ultrasonography and removed surgically. Aggressive histological features of the boy's tumor included fibrous trabeculae, mitoses, and microscopic capsular infiltration. Two years later, under close biochemical surveillance, primary hyperparathyroidism recurred 5 months after documentation of normocalcemia and normal parathyroid status. Ultrasound and MRI identified a newly enlarged right superior PT gland but indicated no recurrent disease in the left neck. Histologic features typical of a benign adenoma were evident after surgical extirpation of the gland., Results: Leukocyte DNA analysis revealed a frameshift mutation in exon 2 of HRPT2. The initial tumor manifested the expected germline HRPT2 mutation, plus a distinct somatic frameshift mutation, consistent with the Knudson "two hit" concept of biallelic inactivation of a classic tumor suppressor gene. Genetic screening of the patient's 7 asymptomatic and previously normocalcemic siblings revealed three with the same germline HRPT2 mutation. One of the siblings newly identified as mutation-positive was noted to be hypercalcemic at the time of the genetic screening. He was found to have a PT adenoma with aggressive features. Two of the five children of another mutation-positive sibling also carry the same HRPT2 mutation., Conclusions: Despite the reported rarity of HRPT2 mutations in FIHP, a personal or family history of PT carcinoma in FIHP mandates serious consideration of germline HRPT2 mutation status. This information can be used in diagnostic and management considerations, leading to early detection and removal of potentially malignant parathyroid tumors.
- Published
- 2006
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46. Editorial: Imaging to detect early endocrine cancers.
- Author
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Marx SJ and Simonds WF
- Subjects
- Adult, Calcium blood, Germ-Line Mutation, Humans, Male, Parathyroid Hormone blood, Parathyroid Neoplasms diagnosis, Parathyroid Neoplasms genetics, Time Factors, Tumor Suppressor Proteins genetics, Diagnostic Imaging, Endocrine Gland Neoplasms diagnosis
- Published
- 2006
- Full Text
- View/download PDF
47. Hereditary hormone excess: genes, molecular pathways, and syndromes.
- Author
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Marx SJ and Simonds WF
- Subjects
- Endocrine Gland Neoplasms metabolism, Endocrine Gland Neoplasms pathology, Humans, Hyperparathyroidism genetics, Hyperparathyroidism metabolism, Hyperparathyroidism pathology, Neoplastic Syndromes, Hereditary metabolism, Neoplastic Syndromes, Hereditary pathology, von Hippel-Lindau Disease genetics, von Hippel-Lindau Disease metabolism, von Hippel-Lindau Disease pathology, Endocrine Gland Neoplasms genetics, Neoplastic Syndromes, Hereditary genetics
- Abstract
Hereditary origin of a tumor helps toward early discovery of its mutated gene; for example, it supports the compilation of a DNA panel from index cases to identify that gene by finding mutations in it. The gene for a hereditary tumor may contribute also to common tumors. For some syndromes, such as hereditary paraganglioma, several genes can cause a similar syndrome. For other syndromes, such as multiple endocrine neoplasia 2, one gene supports variants of a syndrome. Onset usually begins earlier and in more locations with hereditary than sporadic tumors. Mono- or oligoclonal ("clonal") tumor usually implies a postnatal delay, albeit less delay than for sporadic tumor, to onset and potential for cancer. Hormone excess from a polyclonal tissue shows onset at birth and no benefit from subtotal ablation of the secreting organ. Genes can cause neoplasms through stepwise loss of function, gain of function, or combinations of these. Polyclonal hormonal excess reflects abnormal gene dosage or effect, such as activation or haploinsufficiency. Polyclonal hyperplasia can cause the main endpoint of clinical expression in some syndromes or can be a precursor to clonal progression in others. Gene discovery is usually the first step toward clarifying the molecule and pathway mutated in a syndrome. Most mutated pathways in hormone excess states are only partly understood. The bases for tissue specificity of hormone excess syndromes are usually uncertain. In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter. Polyclonal excess of a hormone is usually from a defect in the sensor system for an extracellular ligand (e.g., calcium, glucose, TSH). The final connections of any of these polyclonal or clonal pathways to hormone secretion have not been identified. In many cases, monoclonal proliferation causes hormone excess, probably as a secondary consequence of accumulation of cells with coincidental hormone-secretory ability.
- Published
- 2005
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48. topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage.
- Author
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Lin L, Ozaki T, Takada Y, Kageyama H, Nakamura Y, Hata A, Zhang JH, Simonds WF, Nakagawara A, and Koseki H
- Subjects
- Amino Acid Sequence, Animals, Antineoplastic Agents toxicity, Antineoplastic Agents, Phytogenic toxicity, Bone Neoplasms pathology, Camptothecin toxicity, Cell Cycle, Cisplatin toxicity, DNA Topoisomerases, Type I, Genes, Tumor Suppressor, Humans, Mice, Molecular Sequence Data, Neoplasms genetics, Neoplasms physiopathology, Osteosarcoma pathology, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Ubiquitin-Protein Ligases, Zinc Fingers, Apoptosis genetics, Carrier Proteins genetics, Carrier Proteins pharmacology, DNA Damage, DNA-Binding Proteins genetics, DNA-Binding Proteins pharmacology, Gene Expression Regulation, Neoplasm Proteins genetics, Neoplasm Proteins pharmacology, Nuclear Proteins genetics, Nuclear Proteins pharmacology, Transcription Factors genetics, Transcription Factors pharmacology, Tumor Suppressor Protein p53 biosynthesis, Tumor Suppressor Protein p53 pharmacology
- Abstract
The RING family zinc-finger protein topors (topoisomerase I-binding protein) binds not only topoisomerase I, but also p53 and the AAV-2 Rep78/68 proteins. topors maps to human chromosome 9p21, which contains candidate tumor suppressor genes implicated in small cell lung cancers. In this study, we isolated the murine counterpart of topors and investigated its impact on p53 function. The deduced amino-acid sequence of mouse topors exhibits extensive similarity to human topors. Overexpressed myc-tagged topors associates with and stabilizes p53, and enhances the p53-dependent transcriptional activities of p21(Waf1), MDM2 and Bax promoters and elevates endogenous p21(Waf1) mRNA levels. Overexpression of topors consequently results in the suppression of cell growth by cell cycle arrest and/or by the induction of apoptosis. Taken together, these studies identify topors as a positive regulator of p53. The expression of topors is induced by exposure to the genotoxic reagents cisplatin and camptothecin, a DNA topoisomerase I inhibitor. We therefore postulate that topors mediates p53-dependent cellular responses induced by DNA damage, suggesting its physiological role as a tumor suppressor.
- Published
- 2005
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49. Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression.
- Author
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Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ, and Simonds WF
- Subjects
- Adenoma immunology, Animals, COS Cells, Carcinoma immunology, Cell Nucleus immunology, Cell Proliferation, Chlorocebus aethiops, Cytoplasm immunology, Humans, Mice, Mutation, Missense genetics, Parathyroid Glands immunology, Parathyroid Glands metabolism, Parathyroid Neoplasms immunology, Proteins analysis, Proteins genetics, Transfection, Tumor Suppressor Proteins analysis, Tumor Suppressor Proteins genetics, Adenoma metabolism, Carcinoma metabolism, Cyclin D1 biosynthesis, Down-Regulation, Parathyroid Neoplasms metabolism, Proteins physiology, Tumor Suppressor Proteins physiology
- Abstract
Parafibromin is the 531-amino-acid protein product encoded by HRPT2, a putative tumor suppressor gene recently implicated in the autosomal dominant hyperparathyroidism-jaw tumor familial cancer syndrome, sporadic parathyroid cancer, and a minority of families with isolated hyperparathyroidism. Parafibromin contains no identified functional domains but bears sequence homology to Cdc73p, a budding yeast protein component of the RNA polymerase II-associated Paf1 complex. This study addressed the expression and functional properties of human parafibromin. A survey of human and mouse tissues analysed with polyclonal antibodies to parafibromin showed specific immunoreactivity in adrenal and parathyroid glands, kidney, heart, and skeletal muscle. Subcellular fractionation and laser confocal microscopy of normal human parathyroid gland demonstrated expression of parafibromin in both the cytoplasmic and nuclear compartments. Parafibromin was expressed in four parathyroid adenomas but was absent from two parathyroid carcinomas. Transient overexpression of wild-type parafibromin, but not its Leu64Pro missense mutant implicated in parathyroid cancer and familial isolated hyperparathyroidism, inhibited cell proliferation, and blocked expression of cyclin D1, a key cell cycle regulator previously implicated in parathyroid neoplasia. These results demonstrate that human parafibromin is a nucleocytoplasmic protein with functions consistent with its postulated role as a tumor suppressor protein.
- Published
- 2005
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50. Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma.
- Author
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Hao W, Skarulis MC, Simonds WF, Weinstein LS, Agarwal SK, Mateo C, James-Newton L, Hobbs GR, Gibril F, Jensen RT, and Marx SJ
- Subjects
- Adenoma complications, Adenoma genetics, Adolescent, Adult, Age Distribution, Cohort Studies, Female, Gastrinoma epidemiology, Heterozygote, Humans, Longitudinal Studies, Male, Middle Aged, Pancreatic Neoplasms epidemiology, Parathyroid Neoplasms complications, Parathyroid Neoplasms genetics, Pedigree, Pituitary Neoplasms complications, Pituitary Neoplasms epidemiology, Prevalence, Prolactinoma complications, Prolactinoma epidemiology, Gastrinoma genetics, Genetic Variation, Multiple Endocrine Neoplasia Type 1 genetics, Pancreatic Neoplasms genetics, Pituitary Neoplasms genetics, Prolactinoma genetics
- Abstract
No variant of multiple endocrine neoplasia type 1 (MEN1) has been reproducible among families. We examined two large kindreds with MEN1 variants, and we compared these to past reports. The two kindreds were followed up for 20-30 yr with MEN1 tumors in 30 members. Results in cases from two kindreds were that 93% showed parathyroid adenoma, 40% pituitary tumor (always prolactinoma), and 27% enteropancreatic endocrine tumor. The latter included 10% insulinoma, 7% nonfunctioning islet tumor, but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs. 42%, P < 0.01) and higher prevalence of prolactinoma (40% vs. 22%, P < 0.01) define this variant. Many possible biases of retrospective analyses were excluded as possible explanations. Previously sequenced DNA showed no characteristic MEN1 mutation in these two kindreds and in a third, reported previously; the lack of any shared MEN1 mutation also excluded common ancestry for MEN1 among the three kindreds. The causes for differences between this variant and typical MEN1 are unknown. In conclusion, this variant shows more frequent prolactinoma and less frequent gastrinoma than typical MEN1; the variant is reproducible among kindreds. MEN1 carriers in such families should have periodic monitoring adjusted for the expected penetrance of tumors.
- Published
- 2004
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