bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUN-485 Combined Treatment with Laser Ablation and Tyrosin Kinase Inhibitors. a Novel Multimodality Approach to Locally Advanced Thyroid Cancer?
Authors: Papini Enrico , Monti Salvatore , Coccaro Carmela , Persichetti Agnese , Presciuttini Federica , Deiana Maria Grazia , Bizzarri Giancarlo , Bianchini Antonio , Guglielmi Rinaldo 
Published: May 2020

Abstract
Background. Direct loco-regional treatments are considered for local control of cervical metastasis of thyroid cancer. In our feasibility study, laser ablation was employed for initial debulking of an unresectable radioiodine-refractory thyroid cancer in a combined treatment with tyrosin kinase inhibitors (TKI).
Clinical case. On June 2016, a 69-year-old woman underwent partial resection of a papillary thyroid cancer with extensive tracheal infiltration. On August 2016, whole body scan performed after 131-I treatment (8140 MBq) demonstrated nearly absent thyroid bed uptake. Due to progressive increase of the cervical mass, the patient experienced dysphonia and dysphagia and, after multidisciplinary consultation, was treated with laser ablation (LTA). After local anesthesia, two 300 nm fiberoptics were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were peformed with a diode-laser source. LTA resulted in rapid mass volume decrease (28 x12 x16 mm, 2.8 mL, vs 52 x 29 x 29 mm, 22.7 mL) and improvement of pressure symptoms that lasted 6 months. In May 2017, due to initial regrowth of the tumor mass, the patient started therapy with Lenvatinib, at 10-24 mg/day. The cervical tumor burden remained controlled until April 2019, when occurred rapid disease progression and death of the patient.
Discussion. These preliminary results suggest that locally-advanced unresectable and radioiodine-refractory thyroid tumors can be managed with preliminary LTA mass debulking, for rapid control of local disease, followed by long-term TKI treatment.
References. Mauri G et al. Cardiovasc Intervent Radiol. 2016 Jul; 39(7):1023-30; Park KW et al. Ann Surg Oncol 2011; 18:2564-2568. Schlumberger M et al. NEJM 2015 12; 372(7):621-30.
OR24-06 USP8 Genetic Variants May Contribute to the Development of Bilateral Adrenal Hyperplasia and ACTH-Independent Cushing Syndrome
Authors: Settas Nikolaos , Kassi Eva , Angelousi Anna , Faucz Fabio Rueda , Stratakis Constantine A 
Published: May 2020

Abstract
Background: Bilateral adrenocortical hyperplasias (BAHs), including primary pigmented nodular adrenocortical disease (PPNAD), isolated micronodular adrenocortical disease (iMAD) and primary macronodular adrenocortical hyperplasia (PMAH), are rare causes of ACTH-independent Cushing syndrome (CS). PPNAD and iMAD usually present in children or adolescents as multiple small (&lt;1cm), cortisol-producing adrenocortical nodules. On the other hand, PMAH is most frequently identified in older patients with multiple large adrenal nodules. Most patients with PPNAD have PRKAR1A mutations whereas patients with PMAH may harbor variants in other genes (ARMC5, MC2R, GNAS, APC, MEN1). Even though several genes have been associated with ACTH-independent CS, there are still cases that the genetic cause has not been elucidated.
Clinical cases: Herein, we present two unrelated patients with ACTH-independent CS that harbor USP8 gene variants. USP8 is mainly known for being mutated in Cushing disease but as a deubiquitinase it may be involved into the Wnt/β-Catenin signaling pathway.
The first patient was diagnosed with BAH on prenatal ultrasound (26 gestational week) and subsequently required bilateral adrenalectomy for CS as she had virilization, hirsutism, hypertension and cardiac hypertrophy 9 weeks old. Adrenalectomy revealed that she had iMAD. She also presented with hemihypertrophy of the right leg, labia and mild newborn hypoglycemia, however she was negative for Beckwith-Wiedemann mutation. Gene analysis of PRKAR1A did not reveal any mutations. After whole exome sequencing (WES), we found a novel heterozygous USP8 variant (c.1387_1393delinsT, p.Ala463_Ile465delinsPhe) at germline level and loss of heterozygosity (LOH) at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in both of her adrenals compared to a control tissue.
The second case is a 59-year old female with osteoporosis who failed to suppress cortisol levels after low dose dexamethasone administration. MRI revealed an adenoma on the right adrenal (2.6cm). She underwent right adrenalectomy and was found to have PMAH. We performed WES in germline level and we detected a novel heterozygous missense USP8 variant (c.287A&gt;G, p.Lys96Arg) that is present also at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in her adrenal tumor compared to the control tissue. No LOH was identified.
Conclusion: This is the first report of the association of USP8 in ACTH-independent CS and the preliminary findings support UPS8 involvement in the development of adrenocortical disease. We are currently performing further in vitro studies to evaluate the effect of these two USP8 variants into the canonical Wnt pathway which is commonly involved in adrenocortical disorders.
SUN-562 Long-Term Mental Stress Implications to Cardiovascular Disease in an Aged Mouse Model
Authors: Carroll Natalie Grace , Amatya Shripa , Kamberov Lilly , Gomez-Torres Oscar , Orr A Wayne , Woolard Matthew D , Bailey Steven , Topete Diana Cruz 
Published: May 2020

Abstract
While clinical evidence indicates that exposure to mental stress is a linked to a two-fold increased risk for coronary heart disease, even independently from traditional risk factors, the underlying direct mechanisms between psychological stress and cardiovascular health status has not been determined. A growing aging population of adults 65 and older represents a particular patient population vulnerable to chronic mental stressors due to a decline in normal physiologic functions. The decrease in function of the cardiovascular system that occurs during aging leads to the activation of pathological processes associated with an increased risk for heart disease. Using a mouse model of mental stress induced by restraint, we mimic the biochemical and physiologic changes observed in chronically stressed humans, which is characterized by an increase in circulating glucocorticoids, such as cortisol. Middle-aged mice (6 months old) as well as old-aged mice (18 months old) were used to differentiate the effects of aging on the burden of mental stress associated cardiovascular disease. Genes implicated in cardiomyopathy and CVD were found to be significantly up-regulated, not only immediately after a two-week stress period, but remained significantly up-regulated after the mice were allowed to recover stress-free for 5 weeks. Gene expression of the glucocorticoid receptor was down-regulated following exposure to chronic stress, suggesting an involvement of the hypothalamic-pituitary axis negative feedback loop. Gene expression of markers for hypertrophy (MHY7, ACTA1, NPPB) were upregulated and persisted in upregulation after mice were allowed to recover. Hypertrophy was further indicated by heart weight to tibia length ratios. Significant changes in aortic samples also implicate an involvement of the vasculature. Chronic stress in humans and mice leads to an increase in inflammatory and pro-coagulant markers. In our study, inflammatory markers (LCN, IL-6, IL-17c, PTGS2) were shown to be significantly increased immediately after the period of chronic stress, however the markers return to non-significant levels when mice were allowed a recovery period. Chronic mental stress has a lasting and direct deleterious effect on the cardiovascular system and it is essential to understand these implications in an aging population.
MON-522 In Silico Analysis of Polymorphism rs2228638 in Neuropillin-1 Demonstrated That This Variant May Hinder EBV Entry into Epithelial Cells
Authors: Teixeira Elisangela Souza , Almeida Jacqueline Fatima Martins , Teodoro Larissa , Peres Karina Colombera , Bufalo Natassia Elena , Ward Laura Sterian 
Published: May 2020

Abstract
The Epstein-Barr virus (EBV) is the first herpesvirus identified to be associated with human cancers and our group has demonstrated its association to thyroid cancer. It infects the vast majority of the world population causing latent and persistent infection, interfering in the metabolism of the host cells and triggering tumorigenic processes. Neuropillin-1 (NRP-1) is a type I transmembrane glycoprotein distributed on the cell surface of the virus, and considered vital for tumorigenesis. It has been demonstrated that EBV infection was increased by NRP1 expression. However, a conformational alteration of NRP1 could interfere with virus internalization into epithelial cells. The rs2228638 polymorphism of NRP1 may modify the molecule tridimensional configuration. In order to better understand the role of this polymorphism, based on NCBI dbSNP and UniProt databases, we evaluated the effect of the amino acid change in the protein structure using bioinformatics tools including SIFT, Align GVGD, PolyPhen-2, SNAP, PANTHER, PredictSNP, nsSNPAnalyzer, PROVEAN, SNP&GO, PMut and MuPRO. PANTHER prediction indicated that the polymorphic variant could produce a change in function. MuPRO indicated that the amino acid exchange produced by the polymorphism decreases protein stability. However, none of these tools showed conformational alteration. In conclusion, the presence of the rs2228638 polymorphism of NRP-1 may cause functional but not morphological changes that hinder EBV entry into the epithelial cells.
OR07-01 Identification of the First Case of Acquired Autoimmune Parathyroid Hormone (PTH) Resistance Due to PTH1 Receptor (PTH1R) Autoantibodies
Authors: Mandl Adel , Burbelo Peter D , DiPasquale Giovanni , Welch James , Simonds William F , Collins Michael T , Agarwal Sunita Kishore , Blau Jenny , Weinstein Lee 
Published: May 2020

Abstract
Background: Here we describe a patient who presented with symptomatic hypocalcemia and a biochemical picture suggestive of PTH resistance. PTH resistance is a hallmark of pseudohypoparathyroidism, a heterogeneous group of rare disorders caused by genetic or epigenetic alterations of PTH/PTHrP signaling. However, PTH receptor-related autoimmune etiology has not been identified as the underlying mechanism for PTH resistance. Here we describe the first case of acquired autoimmune PTH resistance that is secondary to PTH1R autoantibodies.
Clinical Case: A 60-year-old African-American woman, who previously had normal calcium homeostasis, presented with acute, symptomatic hypocalcemia, hyperphosphatemia and markedly elevated serum PTH, consistent with parathyroid hormone resistance. She did not have other hormone resistance or a clinical phenotype suggestive of pseudohypoparathyroidism. Whole-exome sequencing and GNAS methylation analysis revealed no genetic or epigenetic defects of the PTH/PTHrP signaling pathway. Treatment with Calcitriol and Calcium supplements was initiated with good clinical response. Within 10 years of follow-up, the patient developed autoimmune hypothyroidism, alopecia and an unusual form of membranous glomerulonephritis, raising the suspicion for an autoimmune etiology for PTH resistance. Luciferase immunoprecipitation system assay identified antibodies against PTH1R with mapping to the N-terminal extracellular ligand-binding domain (amino acids 1- 178). Using an in vitro biological assay in GP-2.3 cells, we found that the antibodies derived from the patient’s serum blocked PTH downstream signaling via Gsalpha/cAMP/protein kinase A pathway in a concentration-dependent manner.
The patient’s autoantibody profile led to the diagnosis of additional autoimmune diseases, including atrophic gastritis and Sjogren syndrome. Lymphocyte immunophenotyping using flow cytometry revealed an overall normal B and T cell profile, but with decreased frequencies and numbers of switched and non-switched memory B cell subsets and an increased frequency and number of the CD8+ naïve cell population. Genes associated with autoimmune inflammatory disorders were sequenced but no pathologic changes were detected.
Conclusions: Identification of the first case of autoimmune PTH resistance secondary to PTH1R autoantibodies extends the etiologic spectrum of hypoparathyroidism and should be considered when a patient presents with findings consistent with pseudohypoparathyroidism, especially in the presence of additional autoimmune diseases.
SAT-065 A Novel De Novo GATA3 Gene Mutation in an Adolescent with HDR Syndrome
Authors: Cruz-Aviles Lisa Michelle , Bale Allen , Carpenter Thomas O 
Published: May 2020

Abstract
Background: GATA3 encodes a transcription factor critical for embryonic development of the parathyroid glands, kidney, inner ear, thymus, and the central nervous system. Heterozygous loss-of-function mutations in GATA3 are associated with hypoparathyroidism, sensorineural deafness and renal disease (HDR syndrome). Clinical Case: A 12 yo male with left hip pain underwent a closed reduction for left slipped capital femoral epiphysis. The pre-op evaluation revealed hypocalcemia (serum Ca 7.7 mg/dL; nl: 8.8-10.2), creatinine 0.46 mg/dL (0.5-1.0), TSH 3.16 uU/mL (0.3-4.2), FT4 1.36 ng/dL (0.8-1.8). Oral calcium and vitamin D supplementation was begun, and 2 wks later, follow-up evaluation revealed serum Ca of 9.4 mg/dL, intact PTH 4.6 pg/mL (10-69), phosphorus 5.9 mg/dL (3.3-5.3), 25-OHD 26 ng/mL (30-100), and a normal chromosomal microarray. Bone density (DXA) Z-scores for hip and spine were -1.7 and 0.8, respectively. At age 13 he underwent bilateral osteotomy due to bilateral hip dysplasia and removal of hardware the next year. At age 15 he underwent left total hip replacement for avascular necrosis. In the post-operative period hypocalcemia recurred (5.9-6.7mg/dL), and he was referred for endocrine evaluation. He was of mixed African American and Puerto-Rican descent. He had difficulties in school and required eyeglasses and hearing aids. Past history included congenital scoliosis (right T11-12 rib fusion, wedged L1 vertebra, and incomplete fusion of posterior elements of L4 and L5), a small right kidney (per ultrasound examination), bilateral orchiopexy for undescended testicles (age 2), diagnoses of ADHD (at age 5); sensorineural hearing loss and psoriasis (age 12), and gastroesophageal reflux (age13). Multiple paternal family members were reported to have abnormal calcium levels and hearing/vision problems, but no known diagnosis. On exam, he had no facial dysmorphism, but left supernumerary nipples, lumbar lordosis and thoracic kyphosis, and clinodactyly. He had achieved Tanner 5 secondary sexual characteristics. There was no Chvostek’s sign. Laboratory investigation revealed Ca 7.9 mg/dL, phosphorus 5.9 mg/dL (3.1-4.7), alkaline phosphatase 123 U/L (50-380), 25-OHD 32 ng/mL, intact PTH 10.2 pg/mL. Treatment with calcium carbonate and calcitriol was begun. Whole exome sequencing identified a heterozygous mutation in GATA3 (c.1061C&gt;T, p.Pro354Leu), predicted to be damaging. This variant has not been reported in literature or public database to our knowledge. Conclusion: This case highlights the importance of genetic testing in the setting of unexplained hypoparathyroidism, and identifies a likely novel mutation in GATA3, providing a basis to counsel the family and encourage medical follow up of suspected family members. References: Barakat, A., et al., Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61-64, 1977
SAT-215 A Case of Polyglandular Autoimmune Syndrome
Authors: Tariq Sarah 
Published: May 2020

Abstract
Background: Polyglandular autoimmune syndrome is defined by the presence of Addison’s disease, Autoimmune thyroid disease and Type 1 Diabetes Mellitus.
Clinical Case: This is a case presentation of a 56 year old female with a multitude of endocrine disorders, classified as polyglandular autoimmune syndrome, type 2, persistently elevated ACTH levels.
Over the years, the diagnoses of Primary Adrenal Insufficiency, Type 1 Diabetes, and Hypothyroidism, had revealed themselves, in this patient.
Her initial diagnosis upon establishment into our clinic was Addison’s disease and hypothyroidism for which she was getting adequate treatment. Her clinical course had been complicated by multiple admissions for DKA, along with adrenal crises.
Following the adrenal crisis, her ACTH levels had been noted to be persistently elevated, at 3362, despite hydrocortisone replacement at optimal dosing and normal AM cortisol levels. Her hyperpigmentation continued to worsen. A 1mg dexamethasone suppression test failed to lower the ACTH levels.
Concern for a possible ectopic ACTH secretion prompted further investigation with imaging studies such as an abdominal Cat scan which showed no adrenal pathology. Pituitary MRI was ultimately performed which showed no evidence of pituitary lesions.
These were following by an 8mg Dexamethasone suppression test which adequately decreased the ACTH level. However re-check of ACTH levels, after weeks of being on her physiological hydrocortisone dosing, showed that her ACTH levels had started to rise again. Given she had also had multiple admissions for adrenal crises, the concern was raised for possible malabsorption.
Given her risk for auto-antibody development, there was concern for another autoimmune process such as Celiac disease, as a potential cause for malabsorption. Her TTG IgA antibodies were checked, however they were absent.
At this point, the decision was made to use prednisone as a means of suppression of ACTH, and she was given three days of 40mg Prednisone daily, followed by ACTH level testing, which showed a decrease from 2009 to 708. These results prompted us to change her hydrocortisone to prednisone daily dosing instead, and we converted her to a slightly higher dose of Prednisone.
In the setting of underlying DM, this may pose an additional challenge with glycemic control, but we plan for close clinic follow up and repeat ACTH levels a few weeks after she has been on the new prednisone regimen.
Conclusion: This is a rare case of a patient with polyglandular autoimmune syndrome, type 2, with a persistently elevated ACTH level, requiring Prednisone, instead of hydrocortisone for treatment of primary adrenal insufficiency in efforts to reduce ACTH levels.
References: Neufeld M, Maclaren NK, Blizzard RM, Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). 1981;60(5):355.
SUN-221 Subclinical Alpha-1 Antitrypsin Deficiency Is Associated with Increased Free Cortisol Fraction in Plasma and Altered Glucocorticoid Delivery to Tissues
Authors: Boyle Luke David , Nixon Mark , Underhill Caroline M , Hill Lesley A , Homer Natalie Z M , Andrew Ruth , Hammond Geoffrey L , Lewis John G , Stimson Roland H , Walker Brian Robert 
Published: May 2020

Abstract
Background
Corticosteroid Binding Globulin (CBG) binds &gt;85% of plasma cortisol and controls the circulating free cortisol pool. Proteolytic cleavage by neutrophil elastase is proposed to reduce CBG binding affinity and increase free cortisol availability to inflamed tissues. The CORtisol NETwork (CORNET) consortium found that genetic variation at a locus spanning SERPINA1 (encoding alpha-1 antitrypsin, A1AT, the endogenous inhibitor of neutrophil elastase) and SERPINA6 (CBG) contributes to morning total plasma cortisol variation. We hypothesised that A1AT deficiency increases CBG cleavage and hence free plasma cortisol, resulting in increased tissue cortisol delivery in adipose and in HPA axis negative feedback. We tested this in recall-by-genotype studies of people who are heterozygous for inactivating mutations in SERPINA1.
Methods
16 healthy carriers of one of the two most common A1AT-deficiency single nucleotide polymorphisms (rs17580 & rs28929474) and 16 age-, gender- and BMI-matched controls were recruited from the Generation Scotland Biobank. Participants underwent combined receptor antagonist stimulation of the HPA axis (‘CRASH’) testing using RU486 400mg and spironolactone 200mg, or placebo in a double blind randomised crossover design. Plasma free cortisol was measured by isotopic dilution and ultrafiltration, total cortisol by LC-MS/MS, total CBG by ELISA, CBG binding capacity by radioligand displacement assay, and ACTH by immunoassay. Serum A1AT was measured by ELISA. Tissue cortisol (LC-MS/MS) and expression of glucocorticoid dependent transcripts (qPCR) were measured in subcutaneous adipose samples collected by needle biopsy.
Results
Serum A1AT was confirmed lower in those with heterozygous mutations vs wild type controls (411.3 +/- 27.44 vs 565.1 +/- 23.38 mg/dL, p=0.0002). No measurable differences in total CBG or CBG binding capacity were observed. However, plasma free cortisol fraction was higher in those carrying A1AT mutations (16.13 +/- 0.2 vs 13.88 +/- 0.04 %, p&lt;0.0001). Adipose cortisol concentrations were not significantly different but expression of glucocorticoid responsive genes e.g. PER1 was 54% higher (p=0.014) in A1AT-deficient subjects. Plasma cortisol was elevated during CRASH testing in both groups, with the increment versus placebo tending to be lower in A1AT-deficient subjects (82.5 +/- 6.7 vs 126.7 +/- 6.8 nM).
Conclusion
Alpha-1 antitrypsin mutation heterozygosity, common in the general population, is associated with higher free cortisol fraction, consistent with enhanced cleavage of CBG. This is associated with evidence of enhanced delivery of glucocorticoid to adipose tissues but reduced HPA negative feedback, suggesting tissue-specific control of cortisol delivery by CBG.
SAT-719 Prenatal Exposure to Bisphenol A, S and F Increases Blood Pressure in Female Rats
Authors: Al Mansi Maryam H , Chuang YenJun , MohanKumar Puliyur S , MohanKumar Sheba M J 
Published: May 2020

Abstract
Cardiovascular diseases are the leading causes of mortality among men and women. With the new blood pressure guidelines from the American Heart Association, almost half of the United States population has hypertension (45.6%). The reasons for this high prevalence of hypertension in our population could be several, but the effect of emerging contaminants are overlooked and understudied. Bisphenol-A (BPA) is a widely used plasticizing agent that contaminates the environment. Most humans are exposed to BPA on a daily basis and urine levels of this endocrine disrupting chemical (EDC) are positively correlated with hypertension. The FDA banned the use of BPA in baby bottles in 2012, however, it is still being used in food containers and plastics. Currently, several BPA analogs such as bisphenol-S (BPS) and bisphenol-F (BPF) are used to replace BPA in the plastic industry. But their physiological effects are not clear. In order to study the effects of these EDCs on the development of hypertension, we exposed pregnant Sprague Dawley (SD) rats to saline, 5 µg/Kg BW of BPA, BPS or 1µg/kg BW of BPF. The offspring were allowed to reach adulthood before implantation with a radiotelemeter (Data Sciences International; HD-S10) in the femoral artery for undisturbed monitoring of systolic, diastolic and mean arterial blood pressure and heart rate. Recordings were measured once a week for 11 weeks over 24 hours to establish day and night readings. Night-time systolic BP was significantly elevated in BPA, BPF and BPS exposed rats compared to control. During the day, systolic BP was significantly higher in the BPA group compared to control. Diastolic BP was elevated in the BPS and BPF groups. Heart rate was elevated the most in the BPS group. These results indicate that prenatal exposure to low levels of BPA analogs has a profound effect on hypertension.