bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUN-101 Support for a New Therapeutic Approach of Using a Low-Dose FGFR Tyrosine Kinase Inhibitor (Infigratinib) for Achondroplasia
Authors: Demuynck Benoit , Filipo Justine , Li Gary , Dambkowski Carl L , Legeai-Mallet Laurence 
Published: May 2020

Abstract
Background: Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia. Fibroblast growth factor receptor 3 (FGFR3) plays a crucial role in bone elongation, demonstrated by FGFR3 gain-of-function mutations in individuals with ACH and hypochondroplasia. Multiple therapeutic strategies have been considered for ACH, the most advanced is to employ an analog of C-type Natriuretic Peptide (CNP), which antagonizes the MAP kinase (MAPK) pathway. Here, we evaluated a therapeutic strategy that targets all pathways downstream of FGFR3 (e.g., STAT1), not just MAPK. We hypothesized that a very low dose of the oral selective FGFR1-3 tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) would be able to improve defective bone elongation. We also hypothesized that infigratinib would have greater potency at lower concentrations in an ACH cell line than a CNP analog (e.g., vosoritide) given its effects on multiple downstream pathways. Methods: A mouse model (Fgfr3Y367C/+) mimicking ACH was treated with subcutaneous injections of infigratinib daily (0.2 or 0.5 mg/kg/day) or intermittently (1 mg/kg, every 3 days) for a treatment duration of 15 days (PND1-15). In vivo results were compared with vehicle-treated mutant mice. TAN 4-18-chondrocytes, a human chondrocyte line expressing a heterozygous Y373C FGFR3 mutation, were treated with multiple concentrations of infigratinib and vosoritide and MAPK levels were measured. Results: We observed a significant improvement of the upper (humerus +7%, ulna +11%) and lower (femur +11%, tibia +16%) limbs at 0.5 mg/kg/day, and improvement in the foramen magnum. The effect of infigratinib on bone elongation was reduced with a lower dose (0.2 mg/kg), confirming a dose-response relationship. With intermittent injections of infigratinib (1 mg/kg, every 3 days), gain of growth was significant for all the long bones (+7%) and the size of the foramen magnum was increased. Modification of the growth plate structure, displaying better organization, was also seen. In cell line data, compared with FGF18-treated TAN 4-18-chondrocytes, concentrations of 10-6M to 10-10M infigratinib led to statistically significant (p&lt;0.05) improvements. With vosoritide treatment, a concentration of 10-4M led to statistically significant improvements compared with FGF18-treated chondrocytes (p&lt;0.05), although this was not seen at 10-5M. Conclusions: Preclinical ACH mouse model data indicate that low, as well as intermittent, doses of infigratinib promote growth and can improve the foramen magnum. No apparent toxicity of infigratinib was observed, suggesting that TKI therapy has the potential to be a valuable and relevant option for children with ACH. Furthermore, cell line data indicate that infigratinib showed superior potency over a CNP analog, suggesting that inhibition of multiple FGFR3-related pathways vs MAPK inhibition alone may lead to increased efficacy.
SUN-611 Impact of Existing Heart Failure on Outcomes of Hospitalization of Hyperosmolar Hyperglycemic State. From the National Inpatient Sample
Authors: Ahmed Fatima , Abugroun Ashraf , Elhassan Manar , Seyoum Berhane 
Published: May 2020

Abstract
Introduction: Patients with underlying heart failure (HF) are at increased risk for hyperosmolar hyperglycemic state (HHS). However, no studies have investigated whether the presence of existing HF would impact the outcomes of HHS. Objective: we aimed to study the impact of heart HF on outcomes of HHS among adult patients hospitalized for HHS. Methodology: The National Inpatient Sample (NIS) was queried for all patients who were admitted with a diagnosis of hyperosmolar hyperglycemic state during the years 2005-2014. The primary outcomes of the study were all-cause mortality, acute myocardial infarction (MI), acute stroke. The secondary outcomes were acute kidney injury (AKI), rhabdomyolysis, acute respiratory failure (ARF), need for mechanical ventilation (MV), length of stay (LOS), and total cost of stay. Results: Overall, 188,725 patients were admitted for hyperosmolar hyperglycemic state. Mean age was 55.9 (SEM: 0.1). Females were (43.9%), Caucasians were 37.4% while African American were 35.2%. Total mortality was 1.1%, MI was 1.3% and stroke was 1.1%. Most common secondary outcome was AKI seen in 31.3% followed by ARF seen in 2.9% of total. The mean cost was 7887 $ (SEM: 84.6) and mean LOS was 4.1 days (SEM: 0.03). Patients with heart failure had higher rates for mortality 2% vs 0.9%, p&lt;0.001, MI 3.1% vs 1.1 % p&lt;0.001 and stroke 1.6% vs 1%, p&lt;0.001. In addition, they had higher rates for AKI, ARF, need for mechanical ventilation, length of stay and cost. No significant difference on risk for rhabdomyolysis. On multivariable analysis, patients with heart failure had higher odds for mortality adjusted odd’s ratio (a OR) 1.58 [95%CI: 1.15-2.17] p&lt;0.01 and higher risk for stroke a OR 1.43 [95%CI:1.04-1.95] p=0.03. In addition, presence of heart failure significantly correlated with ARF, need for mechanical ventilation, higher cost and longer LOS. No significant association was demonstrated between heart failure and risk for Rhabdomyolysis, MI and AKI. Conclusion: Diabetic patients with heart failure who develop hyperosmolar hyperglycemic state are at higher risk for stroke and mortality and respiratory failure. Particular attention on fluid balance as well as early recognition for signs of stroke is warranted.
SUN-361 Cultured Murine Osteoblasts Convert DHEA to Testosterone
Authors: Clines Katrina L , Moon Henry H , O’Day Patrick J , Farber Charles R , Auchus Richard Joseph , Clines Gregory A 
Published: May 2020

Abstract
Androgens have complex effects on the skeleton. Besides gonadal testosterone (T), the adrenal produces the androgen precursor dehydroepiandrosterone (DHEA), using 3β- and 17β-hydroxysteroid dehydrogenases (3βHSD & 17βHSD) to convert to T in target tissues. Microarray analyses of murine calvarial osteoblasts, RT-PCR of long bone osteoblasts, and RNA-Seq of human bone biopsies confirmed that each of the enzyme families is expressed in osteoblasts, suggesting osteoblasts can generate androgens from the adrenal-derived androgen precursor DHEA. Activation of osteoblast androgen receptor (AR) signaling by DHEA was detected using an AR reporter construct, providing evidence that active androgens are generated. To understand how DHEA is converted to T, we treated murine primary osteoblasts with 100 nM and 1 μM DHEA, or vehicle control. Conditioned media were collected 1, 2, and 3 days after DHEA treatment and assayed for intermediate and active androgens by tandem mass spectrometry with two-dimensional chromatography. As DHEA was consumed, the androgen intermediates androstenediol (A5) and androstenedione (A4) were generated and subsequently converted to T. The peak concentrations of T generated by DHEA 100 nM and 1 μM were 22 and 101 pg/ml, respectively. The equilibrium dissociation constant of the AR for T is ~0.2 nM (57.7 pg/ml), indicating sufficient T production to activate AR in androgen-sensitive osteoblasts. Cultured osteoblasts preferentially converted DHEA to A5, via 17βHSD, rather than to A4, signifying that in the conversion of DHEA to T, 3βHSD is the rate-limiting step. Of the 13 17βHSD isoforms, 7 were expressed in these samples. In contrast, only a single gene isoform of Hsd3b—Hsd3b7—was abundantly expressed in mouse osteoblasts and human bone. We investigated the effects of 3βHSD7 in osteoblasts. An Hsd3b7 shRNA knocked-down mRNA and protein expression by &gt;85%, and caused an osteoblast growth defect compared to an shRNA control. 3βHSD7 has known functions in bile acid synthesis, converting 7α-hydroxycholesterol to 7α-hydroxycholestenone (7HC). Treatment of Hsd3b7 knockdown osteoblasts with 7HC rescued the growth defect suggesting that osteoblasts might generate 7HC or a subsequent metabolite as a trophic factor. We now report an unreported function of bone as a source of T, by conversion of the adrenal androgen precursor DHEA, using 3βHSD7 as a common enzyme for androgen and bile acid synthesis, and leading to the activation of osteoblast AR signaling. These data suggest that the skeleton has evolved protective mechanisms against hypogonadal bone loss that exploits the continued production of adrenal DHEA. This concept is especially important in men with prostate cancer bone metastasis undergoing testicular-targeted therapies whereby adrenal DHEA may continue to fuel cancer growth, and in bone maturation during adrenarche before the pubertal rise in gonadal androgens.
SUN-522 A Case of Diabetic Ketoacidosis Associated with Thyroid Storm
Authors: Watanabe Yui , Matoba Keiichiro , Yamazaki Hiroyuki , Nishimura Rimei 
Published: May 2020

Abstract
Background: Thyrotoxic crisis is a rare complication of diabetic ketoacidosis (DKA). We herein report a case of DKA and subsequent thyroid storm which required emergent tracheostomy possibly due to large goiter and post-intubation obstruction.
Clinical Case: A 26-year-old woman was admitted to our emergency department complaining fever (38.2℃) and palpitation. There was no history of autoimmune disease. Physiological examination revealed tachycardia (pulse rate 164/min), tachypnea (55/min), impaired consciousness with a GCS score of 13 (E3V4M6) and goiter. Endotracheal intubation was performed. Her laboratory tests showed metabolic acidosis (pH 7.255), marked high plasma glucose of 1,672 mg/dL, elevated HbA1c of 9.2%, elevated FT3 and FT4 with suppressed TSH. She scored 55 on the diagnostic criteria for thyroid storm of Burch & Wartofsky. Based on these findings, she was diagnosed as having DKA and thyroid crisis. The patient responded well to standard treatment which involves intravenous insulin infusion with pump, correction of electrolyte disturbances, use of methimazole, as well as propranolol. Meanwhile, the patient was positive for anti-glutamic acid decarboxylase (GAD) antibody, TSH receptor antibody, as well as thyroid stimulating antibody, indicating type 1 diabetes and Graves’ disease. She underwent extubation on day 5, however, she developed wheezing around day 30. Imaging analysis demonstrated remarkable tracheal stenosis that is possibly due to large goiter and airway injury by intubation. Emergent tracheostomy was performed on day 50, because the dyspnea became progressively worse. Later, she was successfully treated by tracheal stent placement. At the follow-up period, the patient was found to be doing well, with no severe hyperthyroidism or changes in bronchoscopic findings.
Conclusion: Thyroid storm is a rare but serious complication of DKA. Our report highlights the importance of considering airway obstruction due to large goiter especially in patients with a past history of prolonged ventilation.
MON-270 Diagnostic Value of Copeptin in Central Diabetes Insipidus
Authors: Boehm Emma , Sherfan Julie , Smith Joel , King James , Wentworth John , Chiang Cherie 
Published: May 2020

Abstract
Background: The diagnosis of diabetes insipidus (DI) relies on indirect measurement of serum and urine sodium and osmolality. Since the diagnosis can only be made when an inappropriately dilute urine is paired with a significantly concentrated serum, the process is tedious for the clinician and uncomfortable for the patient. Copeptin is the C-terminal portion of the anti-diuretic hormone (ADH) prohormone which correlates with the less stable ADH, therefore providing a direct measurement of posterior pituitary response to hyperosmolar stress. (1,2)
Aim: This study aims to assess the diagnostic accuracy of copeptin in patients with central DI compared with subjects who underwent pituitary surgery without developing DI.
Methods: Serum samples from subjects with central DI, control subjects post pituitary surgery with no DI (NDI) and control subjects with SIADH were collected and analysed on the BRAHMS KRYPTOR copeptin assay. Groups were compared using unpaired T-test and Levene’s test for equal variance.
Results: 56 samples from 22 subjects (13 females, 9 males, mean age 53.9 ± 15.5 y.o.) were analysed. Two subjects had resolved DI (RDI) after copeptin analysis and were successfully weaned off DDAVP and reclassified as NDI. Of the DI subjects, 1 had acute and 5 had chronic DI. Copeptin was lower in DI compared to NDI group (p = 0.013), while serum sodium, osmolality, urine osmolality were similar. Copeptin did not differentiate between the SIADH and NDI groups. After exclusion of NDI samples with serum sodium ≤ 140 mmol/L, the area under the curve was 0.97 (95% CI 0.9 to 1.0), a copeptin cut-off of 2.9 pmol/L predicts DI with a sensitivity of 92% and a specificity of 90%.
Conclusion: Copeptin concentration of &lt; 3.0 pmol/L concurrently with serum sodium concentration of &gt; 140mmol/L predicted central DI when using post pituitary surgery subjects without DI as controls.
1. Winzeler, B., Zweifel, C., Nigro, N., Arici, B., Bally, M., Schuetz, P., Blum, C., Kelly, C., Berkmann, S., Huber, A., Gentili, F., Zadeh, G., Landolt, H., Mariani, L., Müller, B. and Christ-Crain, M. (2015). Postoperative Copeptin Concentration Predicts Diabetes Insipidus After Pituitary Surgery. The Journal of Clinical Endocrinology & Metabolism, 100(6), pp.2275-2282.
2. Fenske, J., Refardt, I., SchnyderI., Winzeler, B., Drummond J., Ribeiro-Oliveira, Jr. A., Drescher, T., Bilz S., Vogt, D.R., Malzahn, U., Kroiss, M., Christ, E., Henzen, C., Fischli S., Tönjes, A., Mueller, B., Schopohl, J., Flitsch, J., Brabant, G., Fassnacht M., Christ-Crain, M. (2018). Copeptin in the Diagnosis of Diabetes Insipidus. New England Journal of Medicine, 379(18), pp.1784-1786.
MON-672 Progesterone Receptor Membrane Component 1 Suppresses Lipid Accumulation and Lipotoxicity in Animal Model of Diabetic Cardiomyopathy (DCM)
Authors: Lee Sang R , Hong Eui-ju 
Published: May 2020

Abstract
Diabetic cardiomyopathy (DCM) is one of the complications triggered by type II diabetes (T2D) (1). When free fatty acids (FFA) are abundant in insulin resistant pre-diabetic patients because of adipose lipolysis, FFA tends to move toward heart (2). Lipid accumulation can cause cardiac lipotoxicity and exacerbate DCM (3). In previous study, Pgrmc1 has been identified to associate with fatty acid synthesis (4). Therefore, we assumed that Pgrmc1 will associate with DCM. By feeding high-fat diet for 8 weeks and injecting streptozotocin (30mg/kg), T2D and DCM were induced. The lipid accumulation was exacerbated in T2D-induced Pgrmc1 KO heart, and FFA level was also high. Levels of lipid metabolic genes showed the tendency for lipid accumulation and lipotoxicity, and glycolysis was induced in T2D-induced Pgrmc1 KO heart. Though glycolysis presents higher efficiency for energy production in cardiomyopathy (5), it did not compensate the impairment of mitochondrial respiration in Pgrmc1 KO heart. High-fat diet and streptozotocin could not be the interfering factors, because suppression of fatty acid oxidation, induction of glycolysis, and impairment of mitochondrial respiration were observed similarly in post-prandial mice which were fed with normal chow. Insulin was excluded for interfering factor as cell line with serum starvation showed mitochondrial suppression and glycolytic induction in flux analyzer analysis in Pgrmc1 knockdown. Conversely, induction of fatty acid oxidation and suppression of glycolysis were observed in 72 h fasting of Pgrmc1 KO heart, suggesting the nutrition is closely associated with the metabolic modulation of Pgrmc1 on heart. This metabolic phenotype of Pgrmc1 KO heart consequently exacerbated DCM by showing high levels of fibrosis, inflammation, endoplasmic reticulum stress, and oxidative stress.
References: (1) Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circulation research. 2018;122:624-38. (2) Noll C, Carpentier AC. Dietary fatty acid metabolism in prediabetes. Current opinion in lipidology. 2017;28:1-10. (3) Goldberg IJ, Trent CM, Schulze PC. Lipid metabolism and toxicity in the heart. Cell metabolism. 2012;15:805-12. (4) Lee SR, Kwon SW, Kaya P, Lee YH, Lee JG, Kim G, et al. Loss of progesterone receptor membrane component 1 promotes hepatic steatosis via the induced de novo lipogenesis. Scientific reports. 2018;8:15711. (5) Nagoshi T, Yoshimura M, Rosano GM, Lopaschuk GD, Mochizuki S. Optimization of cardiac metabolism in heart failure. Current pharmaceutical design. 2011;17:3846-53.
SAT-164 Pattern and Spectrum of Adrenal Disorders Seen Among Adults in Southern Iraq. A Tertiary Center Experiences
Authors: Mansour Abbas Ali , Ali Alhamza Ali Hussain , Abdullah Almomin Ammar Mohammed Saeed , Zaboon Ibrahim Abbood , Alibrahim Nassar Taha Yaseen , Hussein Rudha Naser , Kadhim Muayad Baheer , Mohammed Adel Gassab , Al-Waeli Dheyaa Kadhim Jabbar , Nwayyir Hussein Ali , Alidrisi Haider Ayad Yassin , Hussein Ibrahim Hani , Odhaib Samih Abed , Altemimi Mahmood Thamer Jallod , Imran Husam Jihad 
Published: May 2020

Abstract
Background: Adrenal disorders is rare life-threatening conditions needed high awareness for earlier diagnosis. The aim of this study is to see the pattern and spectrum of adrenal disorders in Southern Iraq.
Methods: Retrospective electronic database analysis of Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah, the largest tertiary referring Center in the Southern Iraq. Only adults 18 years and above analysed.
Results: The total referred patients for presumed adrenal disorders were 5064(6%) of 83473 new patients seen over 11 years for the period of August 2008 to August 2019.The commonest adrenal disease were due to glucocorticoids misuse in 2407/5064 (47.5%),followed by adrenal endocrine hypertension in 883/5064 (17.4%),than adrenal insufficiency in 340/5064 (6.7%), hirsutism in 264/5064 (5.2%), hypopituitarism 85/5064 (1.6%) and congenital adrenal hyperplasia in 78/5064 (1.5%).Rare causes of adrenal disorder were primary aldosteronism in 30/5064 (0.5%), Addison disease in 26/5064 (0.5%), pheochromocytoma in 19/5064 (0.4%), autoimmune polyendocrine syndromes in 19/5064 (0.4%), ACTH independent Cushing syndrome in 17(0.3%), ACTH dependent Cushing syndrome in 4(0.07%), subclinical Cushing syndrome in 4(0.07%), ectopic ACTH syndrome in 1(0.01%), adrenal cyst in 9(0.1%), adrenal myelolipoma in 5(0.09%), adrenocortical carcinoma in 3(0.05%),and paraganglioma in 2(0.04%).One of the paraganglioma were secretory. Patients characteristics for those with glucocorticoids misuse showed that female forming the bulk of cases in 1708/2407 (70.9%), and mean age of 39.5±12.3 years. Urban constitutes 1306/2407 (54.3%),and 629/2407 (26.1%) were illiterates. There were 706/2407 (29.3%) with established type 2 diabetes mellitus(with all the risks of loss of glycemic control) and glucocorticoids misuse causes 105/2407 (4.3%) incident diabetes.
Conclusion: Glucocorticoids misuse constituted the bulk of referral for adrenal disorders in Basrah. A lot of work needed to reduce the prevalence of this new high-risk iatrogenic disease.
SUN-084 A Quantitative-PCR Based Rapid and Cost-Effective Diagnostic Method for Turner Syndrome and Its Variants
Authors: Mondal Sunetra , Saha Chinmay , Bhattacharyya Nitai P , Mukhopadhyay Satinath 
Published: May 2020

Abstract
Turner’s syndrome (TS) is a common aneuploidy diagnosed by peripheral blood karyotyping in patients. Karyotyping involves manual labour, time and costs. Quantitative real-time PCR (qPCR) is a rapid molecular diagnostic test for TS that yields results of upto 48 samples within two hours at low cost with reasonable accuracy. To assess the sensitivity and specificity of qPCR in the rapid diagnosis of TS, genomic DNA was isolated and estimated from peripheral blood from 50 TS patients(45,XO-23, XO/XX mosaics - 10, Isochromosome Xq-12, XO/XY mosaics - 5), 25 normal females(46,XX) and 5 normal males(46,XY). qPCR was done using 96 well plates, fast real-time PCR. 4 primers were used - two on Xp [SHOX and ARSE] and two on Xq (VAMP7 and XIST). Autosomal gene HBB was used as housekeeping gene. The ΔΔ CT method was used for calculation of the ‘X gene dose’ with respect to the housekeeping gene and X genes from normal females. Differences of doses of the four X-chromosomal primers in different karyotypes were analysed. ROC curves were plotted to determine cut-offs to discriminate the different karyotypes of TS from normal females. qPCR could distinguish classical TS from normal females with &gt;95% sensitivity and specificity. SHOX gene primer was the best to diagnose TS of all karyotypes combined and also classical TS(XO) from normal females. qPCR could also identify non-classical TS with &gt;92% sensitivity and specificity,the best primer being ARSE, for detecting both mosaics and isochromosomes. The cut-offs determined from our study corroborates with past similar studies.1,2 qPCR using an appropriate panel of primers on the short and long arms of X chromosomes can be a rapid and cheaper alternative to karyotyping to diagnose TS of different karyotypes. The choice of primers should be guided by the need for a more sensitive or specific test depending on the clinical scenario. If used as a neonatal screening test, SHOX should be the best primer. For diagnostic purposes, when the pre-test probability is low, a more specific primer like SHOX would be more appropriate. However, when the pre-test probability is high, a sensitive primer for ruling out TS like VAMP7 is better. In case there is a high pre test probability of the patient having a non-classic TS rather than classic TS, ARSE should be used. This is the first study to show good sensitivity of qPCR in detecting non-classic TS of different karyotypes in addition to classic TS. References: 1. Ibarra-Ramírez M, Martínez-de-Villarreal LE. Clinical and genetic aspects of Turner’s syndrome. Medicina universitaria. 2016 Jan 1;18(70):42-8. 2 .Rocha MN et al. Applicability of real-time PCR methodology in the neonatal detection of Turner syndrome. Hormone and metabolic research. 2010 Aug;42(09):677-81.