bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUN-738 Establishing the Link Between Genetic Variations of Estrogen Receptor 2 and Unexplained Infertility
Authors: Halassy Sophia , Mikhael Sasha , Chorich Lynn Parson , Tam Kerlene Bertwick , Diamond Michael P , Burkholder Adam B , Hall Janet Elizabeth , Korach Kenneth Steven , Layman Lawrence Clarke 
Published: May 2020

Abstract
Background: Unexplained or idiopathic infertility comprises approximately 30% of couples who present with infertility. This has led to investigations seeking to determine the cause(s) of this important diagnosis of exclusion. Estrogen’s role in reproduction has been well- established. Estrogens bind to two hormone receptors (namely estrogen receptor-alpha and estrogen receptor-beta), which are distributed differentially throughout the body. Specifically, the estrogen receptor-beta, coded by the Estrogen Receptor 2 (ESR2) gene, is highly expressed in granulosa cells and growing follicles. The one female patient reported with an ESR2 mutation presented with hypergonadotropic hypogonadism. However, subfertility with inefficient ovulation and resistance to exogenous ovulatory stimulation is seen in an ESR2 knockout mouse model. We therefore hypothesized that less severe ESR2 variants could lead to a normal female phenotype and pubertal development but could be a cause subfertility.
Methods: DNA samples from 200 women with unexplained infertility were obtained from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial, which investigated optimal ovulation induction medications for unexplained infertility. These samples were subjected to targeted next-generation sequencing (NGS) for the ESR2 gene. Likely pathogenic variants that occurred with a minor allele frequency of &lt; 0.01 in the gnomAD database and a Combined Annotation Dependent Depletion (CADD) score of &gt; 20 were selected for confirmation by Sanger sequencing.
Results: From the 200 patient samples, five heterozygous missense variants and one heterozygous in-frame deletion identified by targeted NGS were confirmed by Sanger sequencing. Further studies will need to be performed in vitro to confirm the likely pathogenicity of these variants.
Conclusion: These studies raise the possibility that If these variants in ESR2 that impair estrogen signaling, they could be a potential newly recognized etiology of unexplained infertility in women with unexplained infertility.
Conclusion: These studies raise the possibility that variants in ESR2 that impair estrogen signaling could be a potential newly recognized etiology of unexplained infertility in women.
SAT-462 Coronary Vasospasm-Induced Myocardial Infarction: An Uncommon Presentation of Thyrotoxicosis
Authors: Ataallah Basma , Buttar Barjinder , Kulina Georgia , Kaell Alan 
Published: May 2020

Abstract
Background: Coronary artery vasospasm-induced myocardial infarction is a rare cardiac complication of untreated thyrotoxicosis. Diagnosis is difficult due to the transient and unpredictable occurrence of coronary spasm [1].
Clinical Case: A 47-year-old Hispanic female smoker presented with a one-week history of severe, intermittent substernal chest pain radiating to the left arm. The pain was associated with palpitations and shortness of breath. She was afebrile with a heart rate of 100, a blood pressure of 119/59, a fine tremor, and brisk reflexes. No lid lag or proptosis was appreciated. The thyroid was enlarged, non-tender, without palpable nodules. ECG showed T- Wave Inversions in leads V1-V2 and ST depressions in V4-V5. Chest pain was relieved by SL nitroglycerin.
Lab results showed a peak Troponin of 0.20 (N &lt; 0.06), TSH 0.01 mU/L (N &gt; 0.45mU/L), free T4 5.54 (N &lt; 1.46 ng/dl), total T3 4.50 pg/mL (N &lt; 1.37 ng/mL), free T3 21.0 ng/mL (N &lt; 4.4 pg/ml), TSI 3.61 IU/L (N &lt; 0.55 IU/L), thyrotropin R Ab 7.47 IU/L (N &lt; 1.75 IU/L) and thyroglobulin Ab 1.3 IU/ml (ULN &lt; 0.9 IU/ml). Thyroid US showed a heterogeneous enlarged thyroid gland with increased vascularity.
For her NSTEMI she was treated with a heparin drip, aspirin, clopidogrel, atorvastatin, propranolol, and isosorbide mononitrate. Methimazole was started to treat thyrotoxicosis. Cardiac catheterization revealed coronary vasospasm without evidence of valvular or coronary artery disease. Methimazole restored euthyroidism and she has not had recurrence of angina.
Discussion: Rarely, hyperthyroidism can present with transient myocardial ischemia secondary to coronary artery vasospasm in patients with normal coronary arteries. The etiopathogenesis is unclear and may relate to a direct metabolic effect of excess thyroid hormone on the myocardium. In a Korean study evaluating chest pain in patients who underwent coronary angiography, the incidence of coronary vasospasm was 5%, occurring most frequently in women under 50 years of age with thyrotoxicosis [2].
Conclusion: Patients who present with angina and are thyrotoxic should be evaluated for vasospasm. Females under 50 years old with Graves’ disease are at highest risk. Treatment includes antithyroid medications along with nitroglycerin, and we can consider calcium channel blockers including diltiazem. Treatment of thyrotoxicosis eliminates recurrence of vasospasm [3].
References
1. Chudleigh RA, Davies JS: Grave’s thyrotoxicosis and coronary artery spasm. Postgrad Med J. 2007, 83(985):e1-e2.
2. Zheng W, Zhang YJ, Li SY, et al: Painless thyroiditis-induced acute myocardial infarction with normal coronary arteries. Am J Emerg Med. 2015, 33:5-10.
3. Marah N, Bryant K, Haq S, Khan M: Graves’ disease-induced coronary vasospasm. JACC: Cardiovascular Interventions. 2016, 9(23):2452-2453.
OR09-05 Expression of SLC35F1 in the Plasma Membrane of Cells of Aldosterone Producing Cell Clusters (APCCs) and Its Possible Role in Aldosterone Synthesis
Authors: Goodchild Emily , Stoetaert Jan , Drake William , Linton Kenneth , Brown Morris Jonathan 
Published: May 2020

Abstract
Background Genetic mutations and histological appearances suggest that APCCs are precursors to some aldosterone producing adenomas (APA). They are hypothesised to contribute to post-operative non-cure and recurrence of primary aldosteronism (PA) but are currently undetectable pre-operatively. SLC35F1 is a possible nucleotide sugar transporter. On microarray it is highly expressed in APCCs, but not in the rest of the adrenal cortex (1). Our aim was to investigate the role of SLC35F1 in APCCs, determine its subcellular localisation and establish whether expression is consistent with pathological APCC subtypes (as suggested by recent evidence from in situ metabolomic studies (2)). Methods Comparative bioinformatic analysis of the SLC35F1 amino acid sequence was carried out. Ex vivo 4uM adrenal sections, from 6 PA patients in the MATCH study, were stained on serial sections with anti-CYP11B2 (Gomez-Sanchez) or anti-SLC35F1 (Novus NBP1-86755). In vitro, H295R cells were transfected with SLC35F1 cDNA. Subcellular localisation of SLC35F1-GFP was studied by comparison to organelle markers (golgin 97, RAB11, wheat germ agglutinin, calnexin and Tom20) using confocal microscopy. Overexpression and siRNA knock-down in H295R cells was correlated to aldosterone production. Results SLC35F1 is a decamembrane-spanning transporter molecule predicted to have a negatively charged pocket in the substrate binding site, implying a transport substrate with a positive charge. Strong staining of CYP11B2 in clusters of cells in adrenal cortex, consistent with APCCs, were present in all six adrenal glands (25 APCCs). Serial sections showed specific SLC35F1 staining of APCCs, in cytoplasm and plasma membrane. SLC35F1 staining was absent from normal cortex. 12 APCCs (48%) were SLC35F1-negative. Visualisation of transiently expressed SLC35F1 demonstrated localisation to the endoplasmic reticulum in H295R cells (Pearson’s coefficient r=0.758) with no plasma membrane localisation (r=-0.07). Preliminary transfection data suggest direct involvement in aldosterone production. Conclusions Expression of SLC35F1 in the plasma membrane and cytosol of APCC cells supports a role in pathological aldosterone production by APCCs. The inferred transport substrate of SLC35F1 is the NAD(P)(H) precursor, nicotinamide riboside, a positively-charged nucleotide sugar. If confirmed, the essential requirement for NAD(P)H in steroidogenesis, and heterogeneity of SLC35F1-staining in APCCs, is consistent with a metabolically active, possibly pathological, subtype of APCCs. Detection of SLC35F1 in vivo may therefore facilitate sub-classification of PA patients.
1). Nishimoto et. al. PNAS. 2015 Aug 18;112(33):E4591-9. 2). Murakami et. al. 2019 Hypertension. In press.
OR25-01 Durable CYP21A2 Gene Therapy in Non-Human Primates for Treatment of Congenital Adrenal Hyperplasia
Authors: Eclov Rachel J , Lewis Terra E W , Kapadia Mayank , Scott David W , McCoy Daniel D , Rouse Jeremy L , Romero Kirsten B , Beard Clayton W , Mansfield Gary S 
Published: May 2020

Abstract
Severe Congenital Adrenal Hyperplasia (CAH) is most commonly caused by genetic defects in the CYP21A2 gene, which leads to a deficiency of 21-hydroxylase enzyme and disruption in the biosynthesis of Adrenal corticosteriods. Despite treatment with corticosteroids, patients remain at significant risk for adrenal crisis, experiencing a 3-fold higher mortality rate than age matched controls. They also suffer from significant infertility, bone, metabolic, and cardiovascular disease, and hyperandrogenism in women leading to genital abnormalities, hirsutism, and other complications. We are developing an AAV5- based gene therapy (BBP-631) that will provide a functional copy of the CYP21A2 gene to the adrenal glands of CAH patients. To determine the durability of this therapy we treated cynomolgus monkeys with increasing doses of BBP-631 via intravenous injection. At 4-, 12- and 24-weeks post treatment, expression of hCYP21A2 mRNA and vector genome copies (VGC) in the adrenals and other peripheral tissues was measured. VGC was present in the liver and adrenals at 4 weeks, with durable detection through 24 weeks and total vg levels were dose dependent. hCYP21A2 RNA expression in adrenal and liver tissues was also dose dependent and continued to increase from 4 weeks through 12 weeks. There were no adverse safety signals in any of the treated animals. This data combined with efficacy data of BBP-631 in a Cyp21-/- mouse model supports our continued clinical development of BBP-631 as a treatment for congenital adrenal hyperplasia.
OR04-05 MYOD1 Is Associated with Eosinophil-Mediated Browning of Subcutaneous Adipose Tissue
Authors: Li Ting , Masuda Mia Y , LeSuer William E , Stubblefield Tianna M , Hernandez James D , Jacobsen Elizabeth A , De Filippis Eleanna 
Published: May 2020

Abstract
A novel role for adipose tissue (AT)-resident eosinophils (EOS) in metabolism has been suggested. These data were obtained using genetic animal models with either whole-body overexpression of Interleukin-5 (IL-5Tg) leading to eosinophilia or gene ablation resulting in complete lack of EOS. These models limit the specificity of the findings. We hypothesized that AT-resident EOS play a specific role in whole-body metabolism. To this end, we generated a transgenic mouse model overexpressing human eotaxin-2 (hE2) under the control of a fat-specific aP2 promoter, which would exclusively recruit circulating EOS into AT (hEo2Tg), without any changes in the overall EOS numbers. Compared with wild type (WT) mice, AT-EOS numbers were markedly increased in multiple fat depots from hEo2Tg mice, including subcutaneous white adipose tissue (sWAT). After 12 weeks of high-fat diet (HFD), hEo2Tg mice showed significantly less body weight gain and fat mass compared with WT littermates. These changes were associated with an improvement in glucose tolerance. We also found increased oxygen consumption and heat production in hEo2Tg mice under room temperature conditions. The increased thermogenesis was accompanied with an increased expression of browning genes such as Ucp1, Prdm16, Dio2 in sWAT from hEo2Tg HFD mice. So far, our data suggest that AT-resident EOS promote browning of sWAT. This, in turn, protects our animals against development of HFD-induced obesity and insulin resistance. Next, whole transcriptome mRNA sequencing and bioinformatic analyses were performed and showed a significant increase of myogenic differentiation 1 (Myod1) gene expression in hEo2Tg sWAT mice. This was confirmed by qRT-PCR. Myod1 is a key regulator of skeletal muscle differentiation. Given the shared features between brown fat and skeletal muscle, we speculate that by increasing Myod1 gene expression, (AT)-resident EOS mediate sWAT browning. Additional studies are needed to determine the molecular mechanism(s) underling the regulation of Myod1 gene expression by AT-resident EOS and its effect on sWAT browning.
SAT-197 Unilateral Adrenalectomy Can Induce Control in ARMC5 Mutations Patients
Authors: Ferreira Maria João , Castedo José Luis , Costa Maria Manuel , Carvalho Davide M 
Published: May 2020

Abstract
Primary macronodular hyperplasia (PMAH) is a rare cause of endogenous Cushing’s syndrome characterized by functioning adrenal macronodules and variable cortisol secretion. ARMC5 is the most frequent gene responsible for PMAH. Genetic mutations including inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene have been identified. The occurrence of several other non adrenal tumors (meningioma, breast, colon, thyroid and parathyroid) has also been associated with PBMAH, suggesting a possible role of ARMC5 for the development of other neoplasias. The best treatment to this condition is not established. Clinical case: 64-year-old man, referred due to bilateral adrenal incidentalomas on a CT scan with characteristics of adenoma/hyperplasia. He had type-2 diabetes, hypertension and dyslipidemia for about 4 years. He was being treated with 4 different anti-hypertensive medications, gliclazide and simvastatin. Physical examination revealed thin and dry skin, obesity with centripetal fat distribution, multiple ecchymosis and facial erythrosis. He had a son and a daughter. No known familial relevant diseases. His laboratory workup revealed ACTH-independent hypercortisolism: failure to suppress on the overnight dexametasone suppression test - cortisol 27.6ug/dL- and on the low-dose dexamethasone test- cortisol 24ug/dL- associated to morning ACTH &lt;1ng/L. He underwent stimulation tests with tetracosactide, LHRH, TRH, vasopressin, metoclopramide, glucagon anddeambulation test, which were overall negative. It was decided to proceed to bilateral adrenalectomy. Due to surgical complications, only right adenalectomy was performed. Histology revealed adrenal nodular hyperplasia. Molecular study in DNA extracted from peripheral blood leucocyte and in the adrenal gland revealed the presence in heterozygosity of the pathogenic mutation c.1379T&gt;C in the ARMC5 gene. The patient underwent a cerebral CT scan which showed a meningioma in the posterior left temporal convexity. Genetic testing was also performed on the daughter and son of the patient, which revealed the same mutation. They were also tested for hypercortisolism and underwent adrenal and cerebral CT scan, which showed no abnormality. The adrenal CT scan of the daughter showed enlargement of the left adrenal gland, with aspects suggestive of nodular hyperplasia. Her blood tests revealed no sign of hypercortisolism - overnight dexametasone test- cortisol 1.0 ug/dL, morning ACTH 19.1 ng/L. The patient is currently with cortisol hypersecretion controlled. Conclusion: All patients with PMAH should be tested for ARMC5 mutations and if they are found, family screening is mandatory in this autosomal dominant disorder. Unilateral adrenalectomy could control the cortisol hypersecretion, however some of these patients can have subclinical Cushing Syndrome.
SUN-507 Fueling the Fire: A Case of Hypokalemic Periodic Paralysis Associated with Type I Renal Tubular Acidosis and Thyrotoxicosis in Pregnancy
Authors: Mathew Jilcy Joy , Pichardo-Lowden Ariana R 
Published: May 2020

Abstract
Background: Hypokalemic periodic paralysis (HPP) related to thyrotoxicosis, though rare, is more often seen in Asian males. Type 1 renal tubular acidosis (T1 RTA), which can also cause HPP, is typically managed with alkali therapy and potassium supplementation, though there are no well-established guidelines for management in pregnancy.
Clinical Case: A 27-year-old Puerto Rican woman, at 32 weeks gestation, presented to the hospital with sudden onset muscle weakness, and was found to have 1/5 muscle strength in her lower extremities. She had no personal or family history of similar illness. Laboratory analysis revealed hypokalemia (potassium 2.0 mmol/L, range: 3.5 – 5); non-gap metabolic acidosis (sodium 137mmol/L, range 136 – 145; chloride 113 mmol/L, range 98- 107; and bicarbonate 8 mmol/L, range 22 – 29); and an arterial pH of 7.09. Urine studies demonstrated a urine pH of 6.5 and a urine sodium of 32 mmol/L which was diagnostic of T1 RTA in the context of her metabolic derangements. She was treated emergently with potassium and bicarbonate infusions, with improvement in her symptoms. Subsequent thyroid function testing revealed: a low TSH of 0.01 uIU/ml, normal free T4 of 1.66 (range: 0.9 - 1.7) ng/dl, normal free of T3 3.7 (range: 2.0 -4.4) pg/ml and elevated total T4 of 16.5 (range: 4.5 - 11.7) ug/dl. Renal ultrasound demonstrated medullary nephrocalcinosis. She was discharged on potassium and sodium citrate tablets. At 37 weeks, the patient was readmitted for induction of labor due to pre-eclampsia, and delivered a healthy male baby. Several months later, she presented to the Endocrinology clinic with symptoms of increased frequency bowel movements, palpitations and heat intolerance, which had been ongoing since pregnancy. On review, a metabolic panel prior to pregnancy had demonstrated non-gap acidosis and mild hypokalemia. Further testing demonstrated the following: TSH &lt; 0.01 uIU/ml, Free T4 1.71 ng/dl, Free T3 4.8 pg/ml, TSI 280%, and a thyroid uptake scan with homogenous radiotracer uptake, with a 24-hour uptake of 40%. She was started on methimazole therapy, and continued on potassium and sodium citrate tablets with clinical and biochemical improvement.
Conclusion: Thyrotoxicosis can augment hypokalemia in T1 RTA, and can increase the risk of HPP. Our patient had biochemical evidence of RTA prior to pregnancy, though without episodes of HPP, and we believe that her hyperthyroidism, triggered by pregnancy, may have been the additional insult that precipitated her paralysis. This is the first reported case of HPP related to co-existing thyrotoxicosis and T1 RTA in a pregnant individual.
Reference:1. Tu ML, Fang YW, Leu JG, Tsai MH. An atypical presentation of high potassium renal secretion rate in a patient with thyrotoxic periodic paralysis: a case report. BMC Nephrol. 2018;19(1):160. Published 2018 Jul 4. doi:10.1186/s12882-018-0971-9
OR01-01 Human Type 1 Iodothyronine Deiodinase (DIO1) Mutations Cause Abnormal Thyroid Hormone Metabolism
Authors: França Monica Malheiros , Liao Xiao Hui , Fernandes Gustavo Werpel , German Alina , Bianco Antonio C , Refetoff Samuel , Dumitrescu Alexandra 
Published: May 2020

Abstract
Iodothyronine deiodinases (Ds) mediate thyroid hormone (TH) action. They catalyze triiodothyronine (T3) production and degradation via, respectively; outer (ORD) and inner (IRD) ring deiodination. Type 1 D (D1) has a relatively high Km for substrates thyroxine (T4) and reverse T3 (rT3), catalyzes both ORD and IRD and is inhibited by propylthiouracil (PTU). Although no mutations in DIO1 gene have been reported so far in humans, based on the D1-deficient C3H mouse and the heterozygous Dio1 knockout mice, the expected phenotype of D1 loss-of-function is higher serum rT3 and slightly elevated T4. Our objective was to identify new gene defects causing unexplained and discrepant thyroid function tests using whole-exome sequencing (WES). Exons and splice sites are captured with Agilent SureSelectXT and sequenced in Illumina HiSeq2500. Data are analyzed with BWA, GATK, and ANNOVAR applications for alignment, variant calling and annotation, respectively. Sanger sequencing is used to confirm and segregate WES variants in families. A heterozygous pathogenic missense variant in the DIO1 gene (c.282C&gt;A:p.N94K; N-linker) was identified in four family members with relatively higher serum rT3, T4, and free T4 than unaffected relatives, and normal TSH. We identified a second heterozygous pathogenic mutation in the DIO1 (c.603G&gt;A:p.M201I; thioredoxin-fold) in a second family. Two affected individuals presented slightly elevated TSH, higher serum rT3, normal T4 levels, while the T3/T4 ratio was lower compared to unaffected members. To assess the functional activity of the mutant D1 protein, human embryonic kidney epithelial cells (HEK293) were transiently co-transfected with pcDNA3 plasmids expressing pD1-WT, pD1-N94K or pD1-M201I, and pGFP as transfection control. In assays performed with 1μM 125I-T4, the catalytic activities of pD1-N94K and pD1-M201I were 44.7% and 54.1% lower as compared to pD1-WT, respectively. To study the enzyme kinetics, the D1 assay was repeated in the presence of increasing 125I-T4 concentrations (0.1-20μM). The enzymatic activity assays revealed similar Vmax for pD1-N94K and pD1-M201I mutants compared to pD1-WT (VmaxpD1-N94K=53.7 vs VmaxpD1-WT=40.9 and VmaxpD1-M201I=58.8 vs VmaxpD1-WT=42), but higher Michaelis constant (Km) than pD1-WT (KmpD1-N94K=16.4 vs KmpD1-WT=6 and KmpD1-M201I=21.4 vs KmpD1-WT=6.9), which demonstrates a reduced affinity for T4. In conclusion, we report the first DIO1 mutations in humans with serum thyroid tests suggestive of TH metabolism defects. These mutations affect the catalytic activity of the D1, demonstrating impaired functional activity of the mutant enzymes and consequently altering TH metabolism.