bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT-LB59 Functional MRI Study: Weight Loss Induced Changes in Taste Receipt-Induced Activation in the Striatum and Hypothalamus
Authors: Dunn Julia Passyn , Lamicchane Bidhan , Braver Todd , Hershey Tamara , Klein Samuel 
Published: May 2020

Abstract
Background: Reward behaviors including those related to eating are influenced by output from the ventral striatum (VS), dorsal striatal [caudate(Cau) and putamen(Put)]and hypothalamus (HTH). We hypothesized that weight loss would induce modifications in activation in these regions of interest (ROI) during a consummatory reward task. Methods: We recruited metabolic abnormal obese (MAO) from the VA St.Louis Health Care System and Washington University in St.Louis (WUSTL). MAO was screened for by fasting insulin and plasma glucose, 2 hour 75 gram OGTT, and hemoglobin A1c. MAO was defined as prediabetes by ADA criteria and/ or elevated HOMA-IR. Functional magnetic resonance imaging (fMRI) scanning sessions were completed at the WUSTL Center for Clinical Imaging Research. A rapid event-related design was used to randomly deliver taste of chocolate milk (choc) or tasteless water (wat). Each taste receipt was proceeded by a cue of corresponding image of chocolate milk or a glass of water. A total of 5 runs, each with 24 trials were completed. Imaging analyses included preprocessing with fMRIprep including censoring excessive motion ≥ 0.5mm. Single subject GLM analyses were completed in AFNI. ROIs were designated bilaterally (lt and rt) except for HTH. A canonical HRF was applied to the food cue event and the AFNI tent function over 9 TRs was applied to the taste receipt event. To evaluate for an effect of weight loss (WL) on food cue and taste receipt-induced activation, repeated measures ANOVA for each region was completed with condition (choc or wat) as a covariate. Also in the model for taste receipt, repetition time (TR) was included as a covariate. Results reported as F(sign.). Results: Ten participants achieved at least 7% WL, (range 7-15%), 44±8 years, BMI 38±4kg/m2, f/m 4/6, fasting pg 105±11, 2 hour OGTT pg 132 ±49 mg/dL, HOMA-IR 3.9±1.8. One participant fulfilled criteria for T2D. For taste receipt several significant effects were found for WL: Cau_lt WL 5.9(0.02) and WL*TR 4.9(0.03), Cau_rt WL 8.6(0.004) and WL*TR 8(0.005), Put_lt WL 8.5(0.004), HTH WL*condition 5.4(0.02) and a trend for WL 3.3(0.07). All other comparisons were non-significant including all in the VS and all for food cue. Conclusions: Moderate weight loss in MAO modified taste receipt-induced activation in the Cau, Put, and HTH but not in the VS.
SUN-LB34 A Case of BMAH With Aberrant Vasopressin Adrenal Receptors
Authors: Seedat Faheem , Mohamed Nazeer Ahmed , Lutchman Nereshni 
Published: May 2020

Abstract
We report on a 42 - year old woman was referred following an incidental finding of bilateral macronodular (nodules &gt; 1cm) adrenal glands after a computed tomography scan for investigation of an unrelated urological problem. Clear features of Cushing’s syndrome were elicited on initial clincal evaluation and screening tests confirmed the diagnosis biochemically: midnight salivary cortisol 15.4nmol/L (0.2 - 3nmol/L), 24 hour urine free cortisol &gt; 662.4nmol/L (8.3 - 118.7nmol/L per 24 hours) and an 8am serum cortisol measured 951nmol/L following 1mg dexamethasone suppression test (&lt; 50nm/L). A serum adrenocorticotropic hormone (ACTH) measured 0.3pmol/L (1.6 - 13.9pmol/L) suggesting, in light of the CT findings, an adrenal source of the elevated cortisol. Screening for aberrant adrenal receptors to catecholamines, Gastric inhibitory peptide, ACTH, vasopressin and Gonadotropin releasing hormone was performed. A positive biochemical response to ACTH and vasopressin was noted as measured serum cortisol increased to 1600pmol/L (upper limit of the assay). Following a unilateral adrenalectomy, were pathological examination of the respected adrenal gland confirmed adrenal hyperplasia, the patient had both clinical and biochemical resolution of hypercortisolemia. 2 weeks following surgery her midnight salivary cortisol measured 2.1nmol/L (0.2 - 3nmol/L) and 24 hour urine free cortisol 218nmol/L (8.3 - 118.7nmol/L per 24 hours). Her 8am ACTH also increased to 2.9pmol/L (1.6 - 13.9pmol/L). Biochemical screening of her sister showed no evidence of Cushing’s syndrome. Bilateral macronodualr hyperplasia (BMAH) represents a rare cause of Cushing’s syndrome may be diagnosed incidentally and is often associated with an insidious onset. We use this case to highlight the complexities of provocative testing for aberrant adrenal receptors which occur with BMAH and the utilization of unilateral adrenalectomy to achieve clinical and biochemical remission of Cushing’s syndrome thus, removing the need for post - operative steroid replacement following bilateral adrenalectomy.
SAT-LB68 A Rare De Novo Mutation in LRP5 Gene in an Adolescent Female With Juvenile Onset Primary Osteoporosis
Authors: Shum Betty J , Cheung Clement C , Ryabets-Lienhard Anna 
Published: May 2020

Abstract
Background: Juvenile onset of primary osteoporosis is a rare skeletal disorder with a highly heterogenous clinical presentation and complex poorly understood genetic etiology. Low-density lipoprotein receptor-related protein 5 (LRP5), a Wnt-β-catenin pathway receptor involved in bone mineral density (BMD) regulation, has been reported in children with primary osteoporosis mainly due to missense and frame-shift mutations. To our knowledge, there is only one report of in-frame deletions in exon 21 possibly being implicated in pregnancy related osteoporosis (1). We report the first case of a rare heterozygous de novo in-frame deletion in exon 21 of LRP5 gene in a girl with juvenile onset primary osteoporosis.
Clinical Case: A 7.5 yo previously healthy European-African-American female born to non-consanguineous family, was noted to have left ankle and bilateral wrists fractures during sport activities occurring over the span of 1 y. On exam, she was of normal stature, had normal sclerae and vision, but was found to have hypermobile joints. Initial blood work revealed an elevated iPTH 72 pg/mL (9-59), normal Ca 9.6 mg/dL (8.9-10.4), and low 25OH-Vitamin D 17 ng/mL (30-100), which normalized with supplementation to 30.4 ng/mL. By 10.5 yo, she had sustained multiple sports related and pathologic fractures of long bones with progressive bone pain and functional ambulatory impairment. Radiographic evaluation showed osteopenia, multiple healed long bone fractures with presumed non-ossifying fibroma in the distal right femoral metaphysis, and subtle height loss of T4-5 vertebrae. CT bone densitometry at 12 yo showed low mean cancellous lumbar vertebral BMD of 190 mg/cm3 (ref. 285 ± 45) and normal cortical BMD of the femoral midshaft of 1977 mg/cm3 (ref. 2000 ± 60). Genetic testing for Osteogenesis Imperfecta returned negative for COL1A1 and COL1A2 mutations. Whole exome sequencing (WES) revealed a rare, de novo heterozygous mutation in exon 21 that involved deletion of nucleotides 4454 to 4465 resulting in an in-frame deletion of amino acid 1485 to 1488. This mutation is predicted to be deleterious by in silico analysis.
Conclusion: We present the first case of a young female with progressive pathologic fractures, functional ambulatory impairment, and low BMD in childhood, consistent with juvenile onset primary osteoporosis. WES revealed a rare de novo heterozygous in-frame deletion mutation in LRP5, providing a plausible biological mechanism for her clinical presentation, and further contributing to the increasing genetic heterogeneity of juvenile onset primary osteoporosis and LRP5-related bone disorders.
Reference: (1) Cook, F., Mumm, S., Whyte, M., Wenkert, D. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHRF) polymorphism. JBMR. 2014;29 (4): 922-8.
MON-LB48 The Genomic Landscape of Sporadic Thyrotrophinomas
Authors: shen Angeline , Wang Paul , De Sousa Sunita M C , Torpy David J , Scott Hamish , King James , Colman Peter Grahame , Yates Christopher James 
Published: May 2020

Abstract
Background: Thyrotrophinoma (TSHoma) is rare and knowledge on the genomic landscape of this tumour type is very limited.
Aim: To perform whole-exome sequencing (WES) in a population of TSHomas to identify recurrent somatic genetic events
Method: WES was performed on paired tumour and germline DNA of 7 patients with TSHomas. Three tissue samples were formalin-fixed paraffin-embedded and 4 fresh frozen tumour samples. Fresh blood samples were also collected from each patient. The average of mean depth of coverage amongst all samples was 129X, and 97% of target bases were covered ≥20X.
Results:Four (57%) of the seven patients were male and median age at diagnosis was 52 years. (IQR 46, 60) Six patients (86%) had macroadenomas. Four patients (57%) had central thyrotoxicosis at diagnosis and three patients’ tumour stained positive for TSH on histology examination. Two patients (29%) had growth hormone co-secreting tumours. In total, 69 somatic variants were identified to be of potential interest, averaging 1.4 variants per million base-pair of DNA read. No variants were observed in more than one individual. According to the GTEx database, 9 of 69 genes (DRC3, HDAC5, KDM1A, POLR21, TCF25, THAP7, TTC13, UNC5D, UNC13A) were highly expressed in the pituitary (top 10%). Four of these genes appear to contribute to tumour development via epigenetic pathway. Specifically, three of these genes (HDAC5, KDM1A, THAP7) either interact with or form part of histone deacetylases whilst POLR21 encodes a subunit of RNA polymerase II which is responsible for mRNA synthesis. On the other hand, TCF25 gene is thought to act as transcriptional repressor and UNC5D plays a role in cell-cell adhesion.
Large scale copy number variations involving gain or loss of whole chromosome or chromosome (chr) arm were observed in six (86%) tumour samples. Chr 5, 9, 13 and 19 were most commonly affected by chromosomal gains. Deletion of chr 1p was seen in two cases and mutations in KDM1A (p.Glu161fs/c.482_491delAGGAAGAAAA) and ADGRB2 gene (p.Leu1565Gln/c.4694T&gt;A) were found in each of the remaining single copy of chr 1p. ADGRB2 gene is thought to be involved in cell adhesion and angiogenesis inhibition. Copy neutral loss-of-heterozygosity were present in two (29%) of the tumour samples (chr 2 and 12q). However, no somatic mutation was found in these regions. Gene level copy number analysis identified a potential deletion in TTI2 gene which encodes for a regulator in DNA damaging response as well as telomere length regulation.
ConclusionOverall, the rate of somatic variant mutations in TSHomas is low, consistent with the relative benign nature of this tumour type. No classical driver mutations were identified by this study however, chromosomal anomalies and epigenetics may play an important part in TSHoma development.
MON-LB77 Inhibitors of XIAP as Novel Therapeutic Agents in Thyroid Cancer
Authors: Chu Simon , Ibrahim Nalian , Chan Rainbow , Tran Trang , Nguyen Trang , Mond Michael , Fuller Peter J 
Published: May 2020

Abstract
Treatment options for radioiodine-refractory epithelial thyroid cancer (ETC) are limited to tyrosine kinase inhibitors (TKIs), which are associated with significant adverse effects and are not curative. The inhibitors of apoptosis (IAP) family have oncogenic properties and overexpression of X-linked IAP (XIAP) in papillary thyroid carcinoma (PTC) is associated with a poor prognosis. Our group has previously reported a synergistic interaction between SMAC mimetics (SM) (IAP antagonists with XIAP and cIAP1 specificity), and PPARgamma agonists in granulosa cell tumors (1). Such an approach has not been explored in ETC.
We hypothesize that SM may be efficacious alone or in combination with a secondary agent to inhibit proliferation, induce cell death and/or promote differentiation to resensitize cells to radioiodine.
Four ETC-derived cell lines (K1, Nthy-ori 3-1, TPC-1 and SW-1736) were examined for cIAP1, cIAP2 and XIAP expression by RT-PCR. The K-1 and TPC-1 cell lines (PTC origin, BRAFV600E and PI3KCA mutation positive) were chosen to investigate the effects of an SM in combination with either a PPARgamma agonist (rosiglitazone) or a broad-spectrum TKI (sorafenib). Cell proliferation was examined using xCELLigence Real-Time Cell Analysis. Viability was assessed using total cell counts at 24 and 48 hours.
In the four cell lines, we found abundant cIAP1 and XIAP expression and low cIAP2 expression. When an SM was used in combination with either rosiglitazone or sorafenib, we observed significant impairment of cell proliferation and viability with a clear morphological response. These effects appear SM-dependent, as SM treatment alone also showed significant effects on proliferation. However, these effects were enhanced when combined with sorafenib, which was ineffective alone. Markers of differentiation are currently being examined.
Our findings suggest a novel role for SM in treating or redifferentiating radioiodine-refractory ETC. Clinically, this may involve lower doses of individual agents than when used alone, thereby reducing adverse effects.
References1. Leung, D.T.H., et al., Combined PPARgamma Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors. Mol Cancer Ther, 2019. 18(2): p. 364-375.
SAT-LB85 Use of Weekly Levothyroxine Regimen for Rapid Normalization of Thyroid Hormone Levels: A Case Report
Authors: Escudero Jose Renato Martinez , Kirupakaran Johnathan , Yau Alice , Rodriguez Giovanna , Bahtiyar Gul 
Published: May 2020

Abstract
Background: Hypothyroidism affects around 4.6% of the U.S. population1. Non-adherence with thyroid hormone replacement is one of the biggest challenges in treating hypothyroidism1. The half-life of T4 and T3 in hypothyroidism is about 7.5 and 1.4 days respectively2. A large dose once-weekly administration of levothyroxine (Lt4) is possible3, 4. Recent publications suggest that once-weekly Lt4 does not increase the risk of cardiovascular events and is well tolerated by most of patients4. Once weekly Lt4 produces similar results as daily Lt4 as evidenced by thyroid function tests3,4, and potentially improves patient compliance and satisfaction with the treatment4.
Clinical Course: A 29-year-old female with a history of Hashimoto’s hypothyroidism, polycystic ovarian syndrome, depression, presented with irregular menses. Her symptoms included depression, fatigue, increased appetite. Her TSH was grossly elevated at 217 uIU/mL (0.27-4.20 uIU/mL). However upon re-visit, after increasing Lt4 to 100 mcg daily her TSH increased to 280 uIU/mL. She admitted to non-adherence with her daily Lt4 prescription. Physical exam was notable for sinus bradycardia and slow mentation, otherwise unremarkable. Blood count, basic metabolic panel and hemoglobin A1C were within normal limits. Liver function tests showed mild transaminitis, ALT 46 U/L (10-45 U/L). Lt4 was started at 875 mcg per week. At five weeks, her TSH was 6.31 uIU/mL and at seven weeks, the patient was euthyroid with a TSH of 2.53 uIU/mL. Her periods have since normalized.
Conclusion: The current discourse on weekly dosing mainly focuses on its use for non-adherent patients. This case provides a clear time course also demonstrating rapid normalization of TSH using weekly dosing. Weekly Lt4 dosing as first-line therapy in noncompliant depressed patients with severe hypothyroidism should be considered. 1.Hepp, Z., Wyne, K., Manthena, S., Wang, S. and Gossain, V. (2018). Adherence to thyroid hormone replacement therapy: a retrospective, claims database analysis. Current Medical Research and Opinion, 34(9), pp.1673-1678.2.Colucci, P., Yue, C., Ducharme, M. and Benvenga, S. (2010). A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism. European Endocrinology, 9(1), p.40.3.Jayakumari, C., Nair, A., Puthiyaveettil Khadar, J., Das, D., Prasad, N., Jessy, S., Gopi, A. and Guruprasad, P. (2019). Efficacy and Safety of Once-Weekly Thyroxine for Thyroxine-Resistant Hypothyroidism. Journal of the Endocrine Society, 3(12), pp.2184-2193.4.Rajput, R. and Pathak, V. (2017). The Effect of Daily versus Weekly Levothyroxine Replacement on Thyroid Function Test in Hypothyroid Patients at a Tertiary Care Centre in Haryana. European Thyroid Journal, 6(5), pp.250-254.
SUN-LB39 ATAC-Seq Reveals Dynamic Changes in Chromatin Accessibility Following PKA Activation in NCI-H295R Adrenocortical Cells
Authors: LaPensee Christopher Ryan , Mohan Dipika , Lerario Antonio Marcondes , Hammer Gary D 
Published: May 2020

Abstract
The adrenal cortex is comprised of distinct concentric zones that produce hormones essential for life - the outermost zona glomerulosa (zG) produces aldosterone, and the innermost zona fasciculata (zF) produces cortisol. Adrenal zonation is maintained by a balance between paracrine (Wnt/β-catenin) and endocrine (ACTH/PKA) signaling. Wnt/β-catenin signaling is maintained in the outer cortex (zG, upper zF) by a gradient of Wnt ligands that diminish centripetally, and PKA signaling is maintained in the inner cortex (zF) by ACTH. Recent studies in vivo suggest that sustained PKA signaling promotes zF proliferation, enabling lineage conversion towards zF by inhibiting Wnt/β-catenin transcriptional programming. While these studies were crucial in elucidating mechanisms supporting adrenal zonation, it remains unclear if PKA-mediated repression of Wnt/β-catenin is carried out at the chromatin level or if it is secondary to ligand-dependent modulation of paracrine signaling as may happen in vivo. To address this question, we utilized the adrenocortical cell line (NCI-H295R), which harbors a mutation in CTNNB1 rendering Wnt/β-catenin signaling constitutively active. We stimulated PKA in NCI-H295R using forskolin, and assessed genome-wide chromatin accessibility by ATAC-seq and transcriptome changes by RNA-seq. Motif analysis of ATAC-seq from baseline NCI-H295R revealed that chromatin accessibility is dominated by transcription factors SF1 (master regulator of the adrenal cortex and steroidogenesis), AP1 (effector of PKA) and LEF1 (effector of Wnt/β-catenin). Following forskolin administration, we observed decreased accessibility in chromatin containing LEF1 binding motifs, and increased accessibility in chromatin bearing AP1 and SF1 motifs, suggesting that PKA activation drives AP1/SF1-dependent transcription and inhibits Wnt/β-catenin-dependent transcription at the chromatin level. Indeed, RNA-seq revealed that forskolin administration decreased the expression of zG and Wnt/β-catenin target genes, while simultaneously increasing expression of AP1/SF1 target genes. Collectively, these data demonstrate that PKA activation leads to profound chromatin remodeling that enables zF identity even in the setting of constitutive Wnt/β-catenin signaling. Ongoing studies are aimed at elucidating how chromatin modifiers and transcriptional machinery coordinate the dynamic regulation of differentiation programs required for adrenocortical homeostasis and zonation.
SUN-LB35 Using Chromogranin A to Unmask the Great Masquerader: A Case Reportof a Minimally Symptomatic Pheochromocytoma
Authors: Goukassian Ilona , Randle Reese , McClain Donald A 
Published: May 2020

Abstract
Introduction/Background: Pheochromocytomas are rare neoplasms, occurring in less than 0.2% of the population. The classic triad of symptoms includes hypertension, headaches and sweating. An increasing number of patients with pheochromocytomas that are diagnosed at a pre-symptomatic stage.Clinical Case A 69 yo male being worked up for hematuria and possible bladder cancer was referred to endocrinology due to a 3 cm x 3 cm right adrenal “incidentaloma.” The mass was noted to be heterogeneously enhancing on CT adrenal protocol, suggesting pheochromocytoma, adrenal carcinoma or metastasis. He endorsed no clinical symptoms of hormone excess and blood pressure was controlled HCTZ. He was found to have elevated serum metanephrines (184 pg/mL, nl &lt;57) and noremetanephrine (608 pg/dL, nl &lt;148) and total metanephrines (792 pg/dL, nl &lt;205). Other hormonal determinations were normal including cortisol (9AM, 8.97 ug/dL, nl 3-22), DHEAS 66 mcg/dL (25-240), estradiol 23 pg/mL (&lt;39), 17 OHD 60 ng/dL, ACTH 37 (6-50), free testosterone 43.6, total testosterone 396, androstenedione 63 (20-220). Further testing revealed 24 hour urine metanephrine and catecholeamines; urinary metanehrine 2025, noremetanephrine 1729, total 2442 and epinephrine 48, norepinephrine 336 and dopamine 112 which were 2-3 times the upper limit of normal. Because the patient consumed significant amount of caffeine (10 cups of coffee and cola daily), these studies were repeated after caffeine washout. Repeat serum testing revealed metanephrine at the upper limit of normal (metanephrine 47, noremetanphrine 146, respectively). Chromogranin A levels were elevated before (626 units) and after PPI discontinuation, (539 units, nl 25-140). Given the biochemical results and size of mass, he was referred him surgical resection. He was treated pre-operatively with doxazosin and underwent an uncomplicated right adrenalectomy via posterior right retroperitoneoscopic. Pathology was consistent with pheochromocytoma without capsular invasion. Immunohistochemical stains were characteristic of pheochromocytoma, positive for synaptophysin, chromogranin, and S100 but negative for Cytokeratin AE1/AE3 and calretinin. Conclusion: We present the case of a patient with a clinically asymptomatic pheochromocytoma. The diagnosis was supported by elevations in chromogranin and catecholamine metabolites, although the latter results were mixed and clouded by potential confounding factors such as heavy caffeine intake. The case demonstrates that with early detection, screening should include patients with no symptoms and otherwise low risk of disease. Decisions on surgical resection should be based on clinical suspicion, symptoms, imaging, tumor size and biochemical findings given the aggressive nature of these tumors and their malignant potential.
SUN-LB124 Novel Elisa Assays Demonstrate Specificity of Islet and Intestinal Processing of Proglucagon
Authors: D’Alessio David A , Kumar Ajay , Kalra Bhanu , Mistry Shivani , Tong Jenny 
Published: May 2020

Abstract
Circulating proglucagon peptides (PGP) are produced in islet α-cells, enteroendocrine L-cells. Release of PGP is thought to be tissue specific, e.g. α-cells make glucagon and L-cells make GLP-1 through predominant actions of proconvertases 2 and 1/3 (PC2 and PC1/3). However, this dichotomous model has recently been challenged. To address the contribution of the gut and pancreas to plasma PGP we developed 4 novel sandwich ELISA assays and applied them in studies with PGP stimulation from the islet (IV arginine) and intestine (meal). Monoclonal antibodies were raised in mice with genetic ablation of proglucagon transcription. Clones were screened and selected for affinity and specificity, and assays for glucagon, GLP-1, glicentin and oxyntomodulin developed. Eight healthy humans received 5 g arginine intravenously after a 12 hour fast and had blood sampled for 15 minutes; an additional 10 consumed a liquid mixed nutrient meal and prandial blood was taken for 180 minutes. None of the assays registered signal in plasma from proglucagon null mice, and specificity, background and cross-reactivity were acceptable in each. In response to IV arginine plasma glucagon increased 4-fold, and GLP-1 1.5-fold, with significant increases in 15-minute AUC; there was no significant change in either glicentin or oxyntomodulin. In response to meal ingestion there was no change in circulating glucagon, but oxyntomodulin, GLP-1 and glicentin increased 2, 3, and 4-fold respectively. These findings are generally compatible with PC1/3 dominant processing of PGP in the gut, but raise the possibility that α-cells produce both PC2 (glucagon) and PC1/3 (GLP-1) products.