bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thyroid Hormone Action in Liver: A Coregulator Shift Rather Than the Canonical Switch
Authors: Shabtai Yehuda , Nagaraj Nagaswaroop K , Batmanov Kirill , Cho Young-Wook , Guan Yuxia , Jiang Chunjie , Remsberg Jarrett , Forrest Douglas , Lazar Mitchell A 
Published: May 2021

Abstract
Thyroid hormone receptors (TR) are transcription factors that mediate the effects of thyroid hormones (TH) in development, physiology, and metabolism. TR canonically activates gene expression via a “switch” whereby TH converts chromatin-bound TR from a transcriptional repressor to an activator. In this model, the unliganded repressed state is mediated by binding of the nuclear receptor corepressor (NCoR), while the TH-activated state is caused by dismissal of NCoR and stabilization of binding of coactivators including CREB-binding protein (CBP). TH also negatively regulates gene expression, although the mechanism is controversial. Elucidation of the TR transcriptional mechanism in vivo has been hampered by the low concentration of endogenous TRs and the unavailability of high quality antibodies. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise analysis at physiological levels, and explored TR function in liver where the actions of TR regulate body weight, cholesterol, and liver fat. ChIP-seq analysis revealed TRβ binding at genomic sites with epigenomic characteristics of enhancers, at sequences enriched for the canonical DR4 motif bound by TR with its RXR partner, at both positively- as well as negatively-regulated genes. The NCoR/HDAC3 corepressor complex was reduced but not completely dismissed by TH at positive enhancers and, surprisingly, at enhancers associated with negatively. CBP binding was also not “all or none” but, rather, shifted toward increased binding at enhancers in their active state, i.e., in the presence of TH for activated genes, but in the absence of TH for repressed genes. Thus, TH action is due to a shift, not an on/off switch, in coregulator association with TRβ-regulated enhancers determines their activity and transcriptional outcomes.
Transcriptional and Genomic Regulation of Pituitary Function by Thyroid Hormone Receptor Beta
Authors: Cho Young-Wook , Huang Chen-Che Jeff , Liu Hong , Fu Yulong , Forrest Douglas 
Published: May 2021

Abstract
Background : The pituitary is a key target for thyroid hormone but underlying transcriptional mechanisms are poorly understood. Thyroid hormone modifies expression of hormones, including growth hormone (GH) and thyroid-stimulating hormone (TSH, thyrotropin). Wider transcriptome responses are undefined. Thyroid hormone receptor beta (TRb) encoded by THRB are expressed in the anterior pituitary and THRB mutations cause human resistance to thyroid hormone. Method: To investigate genomic genomic regulation by TRb, we derived Thrb-HAB knockin mice that express TRb protein with a tag that is biotinylated in vivo in presence of an R26-BirA allele. Specific, sensitive streptavidin pull-down facilitated Chromatin-Affinity-Purification-sequencing (ChAPseq) to identify genomic TRβ binding sites in pituitary of male mice. Hypo- and hyperthyroidism were produced using methimazole (MMI) in drinking water for 4 weeks with/without added thyroid hormone (T3) for the 4th week. Pituitaries from wild type and Thrb-KO mice were also isolated for RNA-sequencing (RNA-seq). Selected expression changes were confirmed by quantitative PCR. Epigenetic changes were determined by ChIPseq for histone acetylation and methylation and open chromatin analysis (ATAC-seq). Results: Transcriptome analysis revealed genes with statistically different expression induced by T3, including known response genes such as Tshb, Hr and Gh. Responses were impaired in Thrb-KO mice. T3 induced recruitment of TRb binding, chromatin opening and specific histone acetylation marks. Conclusion: Most T3 response genes in pituitary depend to some extent upon TRb. T3-dependent chromatin modifications indicate properties of TRb-dependent enhancer regions and a critical role for TRb in transcriptional regulation of pituitary function.
A Case of Carney Triad Complicated by Renal Cell Carcinoma and a Germline SDHA Pathogenic Variant
Authors: Wurth Rachel , Jha Abhishek , Kamilaris Crystal , Gill Anthony J , Poplawski Nicola , Xekouki Paraskevi , Quezado Martha M , Pacak Karel , Hannah-Shmouni Fady , Stratakis Constantine A 
Published: May 2021

Abstract
Background: Carney triad is a rare multiple-neoplasia syndrome presenting as an association of paragangliomas (PGL), gastrointestinal stromal tumors (GIST), and pulmonary chondromas (CHO). Succinate dehydrogenase deficiency has been associated with several neoplasias, including Carney triad, renal cell carcinoma (RCC) and those associated with hereditary PGL/ pheochromocytoma (PHEO) syndromes.
Clinical Case: A 57-year-old male diagnosed with hypertension at age 49, presented with a gradual increase in blood pressure over a period of 12 months. For seven years following his diagnosis of hypertension, the patient experienced episodic increases in blood pressure, to a systolic pressure greater than 180 mmHg associated with a tight band sensation around his forehead lasting half a day. Abdominal computed tomography (CT) revealed a left adrenal adenoma, a 5.1 cm para-aortic mass, and a right renal superior pole lesion measuring 2.5 cm, which was suspicious for a carcinoma. 123I-metaiodobenzylguanidine (123I-MIBG) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) scans were performed, which suggested the para-aortic mass to be consistent with a PGL. Additionally, 18F-FDG uptake was noted in the gastroesophageal region and was suspicious for a GIST. The left adrenal mass was not associated with 123I-MIBG or 18F-FDG activity. Chest CT demonstrated a right middle lobe lung lesion suggestive of a CHO, although no biopsy was performed. A diagnosis of Carney triad was made. The patient underwent surgical resection of the PGL and GIST, as well as a partial right nephrectomy. The PGL and GIST were positive for SDHA and negative for SDHB by immunohistochemical (IHC) staining. Pathology from the renal lesion was consistent with a 2.3 cm conventional clear cell renal carcinoma, with positive staining for SDHA and SDHB by IHC. The patient was found to harbor a germline heterozygous pathogenic variant (c.91 C&gt;T, p.R31X) in SDHA which has been previously reported and results in loss of function of SDHA. SHDC hypermethylation was not detected in the PGL, GIST, or RCC. Additionally, DNA sequencing of the RCC did not indicate loss of heterozygosity at the variant region of interest. Although the SDHA disease-causing variant is responsible for the patients Carney triad phenotype, it is unclear if this variant is causative of the RCC.
Conclusion: This is a novel presentation of a germline inactivating SDHA pathogenic variant in a patient with Carney triad complicated by RCC. However, an SDHA disease-causing variant was previously reported in a patient with comorbid GIST and RCC. This case provides further support to the increasing evidence that SDHx pathogenic variants may predispose patients to develop renal neoplasms.
Clinical Activity of Selpercatinib in RET Mutant Pheochromocytoma-Case Reports
Authors: Konda Bhavana , Massarelli Erminia , Wright Jennifer , Soldatenkova Victoria , Clifton-Bligh Roderick 
Published: May 2021

Abstract
Activating RET gene alterations have been reported in solid tumors including the rare cancer, pheochromocytoma (PHEO) found sporadically and in familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a highly selective and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-altered solid tumors. Described are the initial 3 PHEO patients treated with selpercatinib (LIBRETTO-001/NCT03157128). Case 1: 70-year-old white male with MEN2A and a history of medullary thyroid cancer (MTC) and PHEO s/p thyroidectomy and adrenalectomy, received MIBG in 1991 and 2016 due to symptom reoccurrence. Progressive metastatic disease associated with severe hypertension was treated with Lutate in 2017 and germline RET mutation p.Cys634Phe was confirmed. After developing severe back pain due to a T6 vertebral metastasis, he began selpercatinib treatment. As of Mar 2020, he has a partial response (PR) as assessed by investigator; his back pain resolved, normetanephrine and metanephrine levels decreased, and has ceased alpha and beta blockers. He remains on treatment with only grade 1-2 adverse events, none requiring interruption or dose modification. Case 2: 51-year-old white female with MEN2A and history of MTC and PHEO s/p thyroidectomy and adrenalectomy in 2010. She developed metastatic PHEO in 2013, with multiple bone, omentum, lung, liver, and spleen metastases. Between 2013 and 2018 she was treated with multiple courses of radiation and, additional surgical resections; a PR with sunitinib lasted 13 months followed by temozolomide/capecitabine treatment. A bone lesion biopsy in 2018 confirmed RET C618S mutation and with her disease progression and uncontrolled bone pain, she began selpercatinib treatment, experiencing a PR. After 5.5 months in the study, she discontinued treatment due to disease progression. Case 3: 45-year-old African American female diagnosed with sporadic PHEO in 1996, s/p multiple surgical resections. She received 2 cycles of cyclophosphamide/vincristine/dacarbazine without clinical benefit. I-131-MIBG therapy with autologous stem cell rescue in 2017 improved blood pressure, palpitations, and flushing but without tumor shrinkage while abdominal pain persisted. Somatic M918T RET-mutation was confirmed, and she began selpercatinib treatment in 2018 with symptom resolution and improved plasma metanephrine levels. She required dose reduction for grade 3 palmar-plantar erthrodysesthesia and had stable disease for 22 months until a new bone metastasis was identified. Due to ongoing clinical benefit, she remains on treatment despite disease progression. Conclusion: These are the initial reports of RET-mutant PHEO patients treated with selpercatinib adding to the diversity of RET-altered tumor types that may benefit from a selective RET inhibitor.
What Cut-off Value of 17-Hydroxyprogesterone Should Be an Indication to Perform a 250 µg Cosyntropin Stimulation Test When NCCAH Is Suspected? - a Retrospective Study
Authors: Domagala Bartosz , Trofimiuk-Muldner Malgorzata , Krawczyk Anna , Topor-Kolkowska Joanna , Skalniak Anna , Przybylik-Mazurek Elwira , Pach Dorota , Hubalewska-Dydejczyk Alicja 
Published: May 2021

Abstract
The Nonclassic Congenital Adrenal Hyperplasia (NCCAH) is a less severe form of CAH in which the activity of the 21-hydroxylase is estimated at about 20% to 50%. Cosyntropin stimulation test is the gold diagnostic standard used to test for this condition. The study was aimed at verifying the currently accepted threshold of 17-hydroxyprogesterone (17OHP) level (≥2.0 ng/mL) at which cosyntropin stimulation test should be performed. Material and methods. The study included 343 patients (328 females and 15 males) referred for a cosyntropin stimulation test due to suspected NCCAH. The median age at the time of evaluation was 27 years. Serum 17-OHP was measured with ELISA assay using Ledect96 Microplate Reader. The NCCAH diagnosis was made if cosyntropin-stimulated 17OHP level exceeded 10.0 ng/mL. The ROC curve was determined, and the cut-off point with the highest sensitivity and specificity was established. The study was approved by the Ethics Board of JUMC. Results:. Symptoms, which prompted testing for NCCAH, most often were: hirsutism in 187 patients, irregular menstrual cycles in 178 patients, and acne in 138 patients. A total of 79 patients (77 females and two males) were diagnosed with NCCAH based on cosyntropin stimulation test results. Seventy-one of them had baseline levels of 17OHP≥2.0 ng/mL. The mean age of patients with confirmed NCCAH was 28.86 years. The baseline 17OHP cut-off value that qualified patients best for testing was 2.79 ng/mL in our group, with sensitivity and specificity of 77.2% and 91.3%, respectively. The sensitivity and specificity for a guideline-recommended cut-off point (17OHP ≥2.0 ng/mL) was 86.1% and 76%, respectively. In five of six patients with secondary amenorrhea and a baseline level of 17OHP ≥2.0 ng/mL, NCCAH was confirmed in a cosyntropin stimulation test. Conclusions:. Our results suggest considering an upward shift in the 17OHP threshold at which patients suspected for NCCAH should be referred for further evaluation. This may reduce the number of unnecessary cosyntropin stimulation tests, mainly that patients with mild phenotype (or asymptomatic) frequently may not require any treatment. However, attention should be paid to patients with coexisting secondary amenorrhea and 17OHP levels ≥2.0 ng/mL, which may be a clinical predictor of NCCAH.
Metastatic Insulinoma Presenting With Post-Prandial Hypoglycemia
Authors: Maher Monique , Desai Dimpi , Bajaj Mandeep 
Published: May 2021

Abstract
Background: Patients with an insulinoma, a type of pancreatic neuroendocrine tumor, typically present with fasting hypoglycemia (1). Occurrence of exclusively postprandial hypoglycemia as a result of a predominantly proinsulin-secreting metastatic neuroendocrine tumor is rare (2).
Clinical Case: A 69-year-old man presented with episodes of postprandial blurry vision, sweating and confusion for the last two years that were becoming more frequent over the last several weeks. Self-monitoring of blood glucose at home revealed postprandial hypoglycemia (45-70mg/dl) and symptoms were consistent with Whipple’s triad. Continuous glucose monitoring over 14-days via Dexcom G6 showed no nocturnal or fasting hypoglycemia and revealed only postprandial hypoglycemia within one-two hours after meals. Laboratory measurements were performed at 8am in fasting state which revealed a blood glucose of 97mg/dl, insulin level 7.8 µIU/ml (2-21 µIU/ml), c-peptide 1.67 ng/ml (1.1-4.4 ng/ml) and elevated proinsulin level of 39 pmol/l (&lt;8.0 pmol/l). An outpatient fast was conducted in the clinic, and when serum blood glucose dropped to 47mg/dL (21 hours after the initiation of the fast), insulin (6 µIU/ml) and c-peptide (2.0ng/ml) levels were detectable with an elevated proinsulin (20.8pmol/L) level. CT abdomen and pelvis showed a 1.6cm hyperenhancing lesion in the distal body of the pancreas. He underwent endoscopic ultrasonography with fine-needle aspiration, confirming the diagnosis of a pancreatic neuroendocrine tumor. Distal pancreatectomy and splenectomy were performed to resect the tumor which led to resolution of his symptoms. Pathology revealed a low grade well-differentiated neuroendocrine tumor with lymphovascular invasion and regional lymph node metastases.
Conclusion: Pancreatic neuroendocrine tumor should be considered in post-prandial hypoglycemia, even in the absence of fasting hypoglycemia. Measuring proinsulin is essential in the diagnostic workup of insulinoma causing hypoglycemia
References: 1. Placzkowski KA, Vella A, Thompson GB, Grant CS, Reading CC, Charboneau JW, et al. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab. 2009;94(4):1069-73.2. Murtha TD, Lupsa BC, Majumdar S, Jain D, Salem RR. A Systematic Review of Proinsulin-Secreting Pancreatic Neuroendocrine Tumors. J Gastrointest Surg. 2017;21(8):1335-41.
Assessment of Steroid Hormones in Both Saliva and Blood During a Phase 2 Clinical Trial for the Use of Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia
Authors: Keevil Brian , Sarafoglou Kyriakie , Moriarty David , Huang Michael , Barnes Chris , Arlt Wiebke 
Published: May 2021

Abstract
Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder characterized by an inability to synthesize endogenous cortisol resulting in overproduction of 17-hydroxyprogesterone (17-OHP) and androgens such as androstenedione (A4). Serum-based methods to measure steroid hormones typically require clinic visits and are not amenable to frequent, serial measurements when patient daily glucocorticoid doses are adjusted. Reliable, non-invasive new methodologies that can easily be adopted in a clinical trial setting are needed to complement existing measures of disease control. Here we report on the correlation between salivary and serum steroid hormone data from a Phase 2 proof-of-concept study for tildacerfont, a second generation corticotropin-releasing factor-1 (CRF1) receptor antagonist, which previously showed an ability to reduce excess adrenocorticotropic hormone (ACTH), 17-OHP, and A4 concentrations. Methods: Subjects with CAH under evaluation for tildacerfont underwent concurrent salivary and serum concentration measurements of androstenedione (A4), 17-hydroxyprogesterone (17-OHP) and testosterone (T) at approximately 8 am every 2 weeks for up to 6 weeks. Both serum and saliva samples were measured using liquid chromatography-tandem mass spectrometry. Results: 25 subjects (16 females) with a median age of 31 years (range 19-67) participated; median body mass index (BMI) was 27.8 kg/m2 (22-62 kg/m2). The number of matched samples across time points were: n=106 (17-OHP), n=106 (A4) and n=98 (T). 17-OHP and A4 were well correlated between serum and salivary assessments, r=0.80 (p&lt;0.001) and r=0.80 (p&lt;0.001), respectively, using kendall rank tests. T measurements had a lower correlation, r=0.67 (p&lt;0.001). Over the duration of treatment, correlations between saliva and serum for 17-OHP and A4 were generally stable with only small differences across sex and clinic visit. Correlations between saliva and serum for T showed a moderate degree variability in women and a high degree of variability in men across visits. While correlations were high for A4 and 17-OHP, the magnitude of change, as a percentage of baseline across time points, was less pronounced with saliva as compared to serum. Conclusions: The ability to employ salivary steroid hormone measurements in CAH patients was demonstrated in a clinical trial setting. These data show that the measurement of the hormones 17-OHP and A4 in saliva may offer a promising, non-invasive approach to more frequently assessing response to therapy in patients with CAH.
A Huge Adrenal Incidentaloma With Suspicious Features and a Complete Cure!
Authors: Saeed Farheen , Chemitiganti Ramachandra Rahul V 
Published: May 2021

Abstract
Introduction: Adrenal hemangioma is an extremely rare benign vascular tumor occurring in adrenal glands (~0.01%). Its clinical presentation is usually vague and is frequently discovered as an incidentaloma. These tumors are mostly encountered at 40–70 years of age and are twice as common in women. We report a case of a nonfunctioning large adrenal incidentaloma with suspicious features on imaging. This in fact was an adrenal hemangioma diagnosed postoperatively with histopathology. Case Description: Our patient was 76 year old Hispanic male, active smoker, with medical history significant for well controlled Type 2 diabetes, hyperlipidemia and hypertension. He was seen for evaluation and management of an adrenal incidentaloma discovered on iv contrast enhanced CT performed to investigate recurrent hematuria. Imaging of the abdomen and pelvis revealed a posterior bladder mass measuring up to 2.6 cm and 20.1 cm x 17.1 cm x 20.5 cm left adrenal mass with few punctuate calcifications displacing the left kidney and spleen- findings concerning for adrenal cortical carcinoma. The right adrenal gland unremarkable. Given the size of mass and suspicious features hormonal workup was initiated in preparation for surgery. Workup was unremarkable for Pheochromocytoma {24 hour urine metanephrine 124 (nl: 0–300), normetanephrine 440 (nl: 0–400)}, Cushing syndrome {(negative 1 mg overnight dexamethasone suppression test), ACTH 22 (nl: 7—63)} and hyperaldosteronism (Aldosterone 5, renin 0.7). Patient underwent an uncomplicated total radical left adrenalectomy, he had no evidence of invasive disease. Pathology showed a large entirely encapsulated heterogenous adrenal mass weighing 2300 grams with largely solid (80%) and cystic components. There was hemorrhage and extensive infarcts- findings consistent with a Hemangioma. He recovered well. No evidence of adrenal insufficiency was noted on subsequent follow-ups. He had a normal surveillance CT scan at 6 months. Discussion: Adrenal hemangiomas are difficult to differentiate clinically and radiographically from adrenal cortical cancer. They must be evaluated to exclude hormonal hypersecretion and malignancy. Previous case reports hypothesized that adrenal hemangiomas may have functional hypersecretion due to mass effect on the adrenal parenchyma. There was no evidence of this in our patient. These tumors increase in size overtime. Surgical resection is often necessary to rule out any malignant potential and alleviate symptoms secondary to mass effect. Adrenal hemangiomas though rare and must be considered in the differential diagnosis.
Evaluation of a Nep-Score Threshold and the Derived Nep-D Score in Predicting Survival of Patients With Typical and Atypical Bronchial Carcinoids
Authors: Gagliardi Irene , Tarquini Mario , Giannetta Elisa , de Souza Patricia Borges , Lanza Giovanni , Bondanelli Marta , Carnevale Aldo , Franceschetti Paola , Ambrosio Maria Rosaria , Zatelli Maria Chiara 
Published: May 2021

Abstract
Background: Typical and atypical bronchial carcinoids (TBC and ABC) display a wide range of clinical presentations and may behave very differently. Survival prognostic markers are necessary to better define therapeutic strategies. AIM: verify that the NEP-Score, recently proposed as prognostic score, can be applied in a homogeneous TBC and ABC cohort and identify a derivate prognostic marker taking into account clinical and pathological characteristics at diagnosis. Methods: Age, site of primary tumor, primary tumor surgery, symptoms, Ki67, timing of metastases of 64 patients including TBC and ABC were evaluated to calculate the NEP-Score at the end of follow-up (NEP-T). We then assessed a derivative score considering the NEP-Score at diagnosis (NEP-D): this score does not consider the appearance of new metastases during follow-up. We then considered the patients that were alive or dead at the end of follow-up (EOF). A NEP-Score threshold to predict survival was investigated. Results: live patients at EOF displayed a mean NEP-T and mean NEP-D significantly lower as compared to those that were dead. A NEP-T threshold &gt;138 significantly predicts survival. ABC relapsed more frequently as compared to TBC. Male gender as well as previous malignancy were negative prognostic factors for survival. Conclusions: We found that NEP-Score is applicable to a series of bronchial neuroendocrine neoplasms. In addition, we propose NEP-D as a simple, quick and cheap prognostic score that can help clinicians in decision making. Moreover, the use of a NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy. Furthermore we found additional prognostic factors that together with the NEP-Score could improve prognosis evaluation at diagnosis by using easily accessible information.