bluuebunny/crossref_metadata_2025_split huggingface dataset:
MON-190 Telomere Length as a Novel Prognostic Marker of Cushing Complications
Authors: Tatsi Christina , Faucz Fabio Rueda , Flippo Chelsi , Sinaii Ninet , Stratakis Constantine A 
Published: May 2020

Abstract
Telomeres are small sequences at the end of chromosomes, protecting them from abnormal degradation. Certain conditions, like cancer, have been associated with changes in telomere length (TL), which, in turn, may predict outcomes of the disease. Studies on the effect of cortisol on TL have not led to conclusive results or are limited in stress induced hypercortisolemia. Moreover, no study has focused on effects of persistent endogenous hypercortisolemia during childhood, a known important period for telomere modifications.
We hypothesized that TL is affected in pediatric patients with endogenous Cushing syndrome (CS) and it correlates with markers and complications of hypercortisolemia.
We studied 10 pediatric patients (mean age: 13.3 years, 7 females), diagnosed and treated successfully for Cushing disease. TL of total lymphocytes and their subtypes (Naïve T-cells, Memory T-cells, B-cells and NK-cells) were measured before and 1 year after treatment. TL was compared to age-matched control samples (6-8 per age group) and was correlated with clinical and biochemical characteristics. Paired or two-sample parametric or non-parametric statistical tests were performed, as appropriate.
Lymphocyte TL of patients with active CS did not differ from controls (p=.43). B-cell and NK-cell TLs were shorter after cure compared to active CS [mean B-cell TL difference: -1.44 Kb (-15%), p=.001; mean NK-cell difference: -0.51 Kb (-7%), p=.10] and controls [mean B-cell TL difference: -0.98 (-11%), p=.039; mean NK-cell difference: -1.3 Kb (-16%), p=.005]. Lymphocyte TL in active CS and the change of TL before and after cure did not correlate with measured markers of hypercortisolemia (morning and midnight cortisol, urinary free cortisol or ACTH levels). However, there was a strong inverse correlation between the difference of TL in active disease compared to controls and triglyceride level for all lymphocyte subtypes (range r= -0.74 to -0.86, range p= .003 to p=.022), suggesting that the higher the triglyceride levels, the shorter the TL in patients with CS. Additionally, inverse correlation was observed for weight and BMI SDS and B-cell TL, specifically (r= -0.76, p= .019 and r= -0.76, p= .018, respectively). Furthermore, there appeared to be an implication for shorter TL in CS patients with dyslipidemia compared to those without (mean TL difference from controls: -1.1 Kb in patients with dyslipidemia vs 0.53 Kb in those without, p= .067).
We conclude that although TL in active CS does not seem to differ from controls, B-cell and NK-cell TLs are affected after cure, and this may be related to acute changes that occur in the immune system peri- and post-operatively. Interestingly, the level of TL shortening correlates strongly with several complications of CS, including weight, BMI and dyslipidemia. This suggests that TL may be used as a surrogate prognostic marker of hypercortisolemia-related complications.
SUN-593 Variants in Known Monogenic Causal Genes of Hypertriglyceridemia Are Not Major Contributors for Hypertriglyceridemia in Lipodystrophy Due to a LMNA Mutation
Authors: Ueda Masako , McIntyre Adam D , Remaley Alan T , Hegele Robert A , Rader Daniel J 
Published: May 2020

Abstract
Background: Lipodystrophy is a heterogeneous disorder of adiposity, and one common lipid manifestation is hypertriglyceridemia (HTG). The LMNA gene, which encodes for nuclear envelope proteins, is a known causal gene for heritable lipodystrophy. At present, underlying mechanisms for each clinical manifestation of lipodystrophy due to a LMNA mutation are unknown.
Hypothesis: A likely explanation for HTG in lipodystrophy is the paucity of adipose tissue where excess triglycerides (TGs) are normally stored, thus it may not be due to a specific defect in lipoprotein metabolism. Consequently, rare variants in HTG-associated genes would not be expected to be major contributors for HTG in lipodystrophy with LMNA mutations.
Method: A proband and her father with a clinical diagnosis of lipodystrophy were recruited into an IRB-approved study investigating molecular etiologies of dyslipidemia at the University of Pennsylvania. Next-generation sequencing (NGS) with the LipidSeq panel, targeting causal genes for lipodystrophy, and monogenic HTG was performed, and confirmed by Sanger sequencing. Also, unweighted TG-polygenic scores by summing the number of TG-raising alleles from 14 single nucleotide polymorphisms (SNPs) associated with TG levels were assessed.
Results: The proband and her father were diagnosed with lipodystrophy of two different subtypes, generalized in the daughter and partial in the father. The proband reported a gradual loss of subcutaneous fat starting around age 10. A highest reported TG in the proband was19,000 mg/dL with eruptive xanthomas, whereas TG in the father was never &gt;500 mg/dL. Their BMI’s and DEXA body fat% were 12.9 kg/m2 and 7% in the proband, and 25.7 kg/m2 and 25% in the father, corresponding to their fat storage capacities.
The molecular analyses revealed only a lipodystrophy causal mutation in LMNA, c.29C&gt;T, T10I with no other significant findings in18 other lipodystrophy-related genes. No deletion or duplication was identified by a targeted array CGH of LMNA.
As predicted, no rare monogenic variants in HTG-causal genes (LPL, GPIHBP1, APOA5, APOC2, LMF1, GPD1) were identified in either subject. However, TG-polygenic scores were 17/28 (95th %ile) in the proband, and 13/28 (50th %ile) in the father, the same trend as the level of HTG levels seen in them. Apolipoprotein E genotypes were non-contributory, (3/3) in the proband, and (3/4) in the father.
Conclusion:
Our findings support that the pathophysiology of HTG in lipodystrophy is likely to be due to lack of TG-storage space (adipose tissues), and is unlikely due to a defect in lipoprotein metabolism seen in patients with rare monogenic HTG-variants. Although the HTG-polygenic score was higher in the proband, and the accumulative effects of the at-risk alleles may be contributor to the HTG phenotype, it is unlikely to be the leading cause of severe HTG seen in the proband.
SAT-139 STAT5A Regulation by Serine Phosphorylation in Breast Cancer
Authors: Woock Alicia E , Grible Jacqueline M , Zot Patricija , Harrell J Chuck , Michael Idowu , Clevenger Charles V 
Published: May 2020

Abstract
The neuroendocrine hormone prolactin (PRL) and its cognate receptor (PRLr) have been implicated in the pathogenesis of breast cancer. PRL signaling relies on activating kinases such as the tyrosine kinase Jak2 and serine/threonine kinases ERK1/2, Nek3, PI3K, and AKT. In the canonical pathway of PRL signaling, Jak2 phosphorylates the transcription factor Stat5a at tyrosine residue 694 (pY694-Stat5a), preceding Stat5a nuclear translocation and transcriptional activity. However, Stat5a exists with functional duality as a transcription factor, having both pro-differentiative and pro-proliferative target genes. Other Stat family members (Stats 1, 3, and 6) have been shown to have transcriptional activity in the un-phosphorylated (upY) state, distinct from that of pY-Stat activity. This distinction (upY vs. pY) may underlie the duality of Stat5a, coupled with additional regulatory non-canonical post-translational modifications. Within this notion, Stat5a contains two serine residues, S726 and S780, whose phosphorylation are necessary for hematopoietic transformation. However, their functions in PRL-mediated breast cancer pathogenesis have not been examined. We hypothesize that Stat5a serine phosphorylation regulates Stat5a nuclear activity in a non-canonical fashion, contributing to its role in mammary oncogenesis. As shown in a tissue microarray (TMA), human breast cancer tissues express both pS726- and pS780-Stat5a. Nuclear Allred score for pS726-Stat5a increases two-fold with increasing tumor grade, with no difference in staining associated with estrogen or progesterone receptor (ER, PR) status, nor other clinical characteristics. Likewise, patient derived xenograft (PDX) tumors of various molecular subtypes express pS726- and pS780-Stat5a. Phosphorylation of S726-Stat5a is PRL-responsive in vitro. Pharmacologic inhibition of ERK1/2 prevents this phosphorylation, uncovering a novel pathway in which ERK1/2 mediates Stat5a activity in response to PRL in breast cancer. To examine the functional significance of Stat5a serine phosphorylation in vitro, we have performed Stat5a knockdown (KD) in the breast cancer cell line MCF7. Following Stat5a KD, cells were rescued with phospho-site specific Stat5a mutant constructs. Characteristics of breast cancer examined in these mutation-carrying cells, including anchorage-independent growth and proliferation, show distinct phenotypes compared to controls. PRL-induced expression of the CISH gene is significantly decreased up to 65% in the mutation-carrying cells compared to wild type Stat5a. Mechanistic studies will examine the ability of these Stat5a mutants to undergo nuclear translocation and interact with other transcription factors. Collectively, these studies have the potential to provide novel insights into the role of the non-canonical pathway of Stat5a activation in breast cancer pathogenesis.
SAT-740 Plasma Glucocorticoids and Mineralocorticoids Are Associated to Metabolic Syndrome Features in Women
Authors: Ostinelli Giada , Adamski Jerzy , Tchernof André 
Published: May 2020

Abstract
Background: Excess visceral adipose tissue accumulation on anatomical structures such as the greater omentum and mesentery are strong predictors of obesity-associated comorbidities (1). High glucocorticoid levels have been associated with body fat distribution and preferential visceral fat accumulation as well as features of the metabolic syndrome (MetS) (2). These effects are thought to be mediated by the glucocorticoid receptor, a nuclear receptor showing affinity for both glucocorticoids and mineralocorticoids. In this study, we examined plasma concentrations of glucocorticoids and mineralocorticoids in women with or without the MetS. In addition, we assessed the ability of these steroids to predict fat accumulation and features of the MetS.
Methods: In a sample of 49 women (age 47 ± 4.99 years; BMI 26.4 ± 4.70 kg/m2), plasma concentrations of cortisol, 11-deoxycortisol, cortisone, aldosterone, corticosterone and 11-deoxycorticosterone were analyzed by electrospray ionization-liquid chromatography-tandem mass spectroscopy (ESI-LC-MS/MS). Metabolic parameters were assessed to establish the presence of the MetS using NCEP-III criteria. Subcutaneous and visceral adipocyte cell size was measured by histomorphometry.
Results: We found HDL-triglycerides to be positively associated with levels of 11-deoxycorticosterone, 11-deoxycortisol, corticosterone, cortisone and cortisol (p&lt;0.05 for all). 11-deoxycorticosterone concentration was also negatively associated with waist circumference (-0.294, p&lt;0.05), LDL-cholesterol and LDL-triglyceride content (-0.264 and -0.362, p&lt;0.05) whereas cortisone level was positively associated with fasting glucose (0.3, p&lt;0.05). Our model including mineralocorticoids predicted systolic blood pressure (R2=0.303), while the one including glucocorticoids predicted HDL-cholesterol (R2=0.495). In addition, as expected, we found that women with the MetS were characterized by significantly higher percentage body fat and displayed subcutaneous and visceral adipocyte hypertrophy (p&lt;0.05). Interestingly, women with the MetS also showed a trend for lower plasma cortisol concentrations (p=0.07).
Conclusion: Our data suggest that glucocorticoids and mineralocorticoids are associated with individual components of the MetS in women.
(1) Tchernof et al.(2013), Physiol Rev, 93(1);
(2) Constantinopoulos et al., (2015), Eur J Endocrinol, 172(1)
SUN-594 Pubertal Timing and Hormonal Correlates in Male Obesity
Authors: De Schepper Jean , Berlanger Evy , Van Helvoirt Monique , De Guchtenaere Ann , Basslé Eddy , Anckaert Ellen , Vanbesien Jesse , Gies Inge 
Published: May 2020

Abstract
An early, normal or delayed pubertal onset have been described in overweight/ obese males(1). A greater prepubertal adiposity has been associated with a greater risk for delayed puberty in males, but an underlying mechanism was not explored(2). We investigated whether an increased testosterone aromatization or an higher degree of low-grade inflammation might be more prevalent in obese males with a delay in genital development. Pubertal status assessment by Tanner staging and measurement of morning serum testosterone, estradiol, leptin, and hSCRP by standard laboratory methods were performed in 191 male adolescents, aged between 10 and 18.6 yr (median 12.8 yr) with overweight (BMI z-score &gt; 1.3), starting an ambulatory (n = 138) or a residential weight loss program (n = 55). Their median (range) BMI z-score was 2.32 (1.34 – 3.38). Delayed / slow and early / rapid genital development was defined by a Tanner genital stage respectively above the 90th or below 10th percentile age distribution (national Flemish standards of 2004). In 3 males pubertal development was advanced, while in 34 it was delayed. In the remaining 154 adolescents genital stage was normally timed. Males with a delayed timing or progression of genital development were older (median(range) age:14.8 (11.6-18.6) yr vs 12.3 (10-18.6) yr; p&lt; 0.005) and shorter (height sds: -0.55 (-1.90- 1.48) vs 0.49 (-3 – 3.19); p &lt; 0.005), and had a higher birthweight (birthweight z-score: 0.15(-3.51-2.75) vs -0.34(-4.7-3.30); p = 0.058), but a similar BMI and waist z-score in comparison with males with a normally timed puberty. Median serum estradiol, leptin, and hSCRP concentrations did not differ significantly between those with a normal or a delayed pubertal onset or progression. In conclusion, pubertal delay is more frequently observed than early puberty in males referred to obesity clinics. Neither low grade inflammation nor increased estradiol production appear to be associated with a later onset of slower progression of genital development in male obesity. References (1) Li W et al. Int J Environ Res Public Health. 2017 Oct 24;14(10) (2) Lee JM et al. Arch Pediatr Adolesc Med. 2010 Feb;164(2):139-44.
SAT-006 A New Concept for the Endocrinology of Pre-Eclampsia: The Role of Spiral Steroids
Authors: Chasalow Fred I , Bochner Ron 
Published: May 2020

Abstract
Background: In 1987, Graves observed that during the 3rd trimester, some patients with pre-eclampsia had high levels of unknown materials that could be detected with assays for digoxin (DLM). In 2018, we characterized a new candidate for the DLM, Ionotropin. It is a phosphocholine (PC) ester of a novel steroid with 23 carbon atoms. As Ionotropin shares structural features (a) with spironolactone (both have spiral lactones in the E-ring) and (b) with digoxin (E-ring lactone and 3α-5β configuration), we have proposed that Ionotropin may function as a potassium (K+) sparing diuretic. This suggestion is supported by the observations that [1] patients who cannot make Ionotropin (7-dehydrosterol reductase deficiency) are K+ wasting and [2] breast cyst fluids with high K+ levels also have high Ionotropin levels.
Hypothesis: During the 3rd trimester, fetal requirements for K+ reach a maximum, fetal blood pressure increases and aldosterone signaling is blocked. This blockage leads to fetal sodium (Na+) wasting and is essential for formation of amniotic fluid. These events are consistent with a normal role for an unknown endogenous K+ sparing hormone and would be the basis for a modest elevation of maternal DLM during the 3rd trimester. Our hypothesis is that if any of the functions were inadequate, then the fetal-placental unit would synthesize excess PC-spiral steroids; the woman would exhibit symptoms of K+ sparing hormone excess (hypertension and proteinuria) and would be diagnosed with pre-eclampsia.
Experimental Results: We have just reported a pilot study associating elevated PC esters of spiral steroids in women with pre-eclampsia. In brief, 12 of 19 women had elevated levels of at least one of the PC steroids (Z-score &gt; 2) when compared to the levels in 20 pregnant women matched for gestational age and fetal sex. There are two basic mechanisms for this dichotomy: (a) there may be episodic secretion with of a DLM with a short half-life or (b) there may be two different underlying biochemical causes. In prior studies, there has been no indication of episodic secretion of DLM similar to that observed with glucocorticoids, Ionotropin or other PC spiral steroids.
Discussion: There are two basic types of K+ sparing diuretics. Type A: Spironolactone functions by regulating the NaK-ATPase. Type B: Triamterene functions by blocking synthesis of epithelial Na+ channels. Thus, Type A would have high levels of spiral steroids and Type B would have low levels of spiral steroids. Type A patients would be expected to have higher risk of long-term consequences when compared to the Type B patients.
Conclusion: The recognition of the division of pre-eclampsia into two separate diseases might be the key observation for developing Type-specific diagnosis and therapy. For example, a Type A patient might benefit from a low salt diet but that diet would not be expected to benefit a patient with Type B disease.
MON-205 Effectiveness of Pre-Op α-Blockade on Intra-Op Blood Pressure Control in Patients with Pheochromocytoma
Authors: Lake Julia Caroline Wingate , Comi Richard J 
Published: May 2020

Abstract
Pheochromocytoma are rare tumors arising from catecholamine producing chromaffin tissue. Surgical manipulation of pheochromocytoma inevitably leads to supraphysiologic levels of circulating catecholamines. Such manipulation has the potential to lead to an intra-operative hypertensive crisis, cardiac arrhythmia, myocardial infarction, or pulmonary edema. When inadequately primed pre-operatively, a patient exposed to such surges may experience life-threatening consequences.
Phenoxybenzamine is a non-competitive, non-selective α 1 and α 2 receptor antagonist that prevents blood pressure liability during surgical resection of pheochromocytoma. Previous literature has suggested that phenoxybenzamine affords more pronounced peri-operative systolic blood pressure control as compared to selective alpha-blockers. This superior control potentially is at the cost of postoperative hypotension owing to the irreversible nature of phenoxybenzamine.1
Our study compares the effects of pre-operative phenoxybenzamine on perioperative outcomes at a single tertiary medical center from 2004 to 2019. The cumulative pre-operative phenoxybenzamine dose was compared to the maximum intra-operative blood pressure, need for IV blood pressure lowering medications, duration of vasopressor need, volume replacement need, duration of time in the OR, duration of hospital stay, and pre-operative catecholamine levels. We speculate that increased phenoxybenzamine exposure will result in reduced peak intra-operative blood pressure and need for IV blood pressure lowering medications but may increase the need for post-resection intra-operative vasopressors and post-resection volume replacement.
After IRB approval, (ID #00031606), we performed a data warehouse query for the ICD 9 and 10 codes of “pheochromocytoma” and “paraganglioma”. Patients who did not have confirmed pheochromocytoma on pathology were excluded. Data was collected retrospectively on 30 patients who underwent adrenalectomy for pheochromocytoma. 14 charts were excluded due to incomplete intra-operative anesthetic documentation.
Our results suggest that there is no significant correlation between peak intra-operative MAP and cumulative phenoxybenzamine exposure. The cumulative dose of pre-operative phenoxybenzamine did not correlate with the number of anti-hypertensive medications used intra-operatively. An increased cumulative dose of pre-operative phenoxybenzamine was not associated with an increased duration of intra-operative vasopressor medications. Intra-operative volume replacement needs were surprisingly reduced with increased cumulative pre-operative phenoxybenzamine exposure.
1 P.A. van der Zee, A. de Boer. Pheochromocytoma: A review on preoperative treatment with phenoxybenzamine or doxazosin. The Netherlands Journal of Medicine. May 2014; Vol. 72 No 4, 190-201.
SAT-184 Silent Pheochromocytoma Complicated by Adrenal Insufficiency After Unilateral Adrenalectomy
Authors: Aftab Hassaan B , Madhavan Parvathy , Dulipsingh Latha 
Published: May 2020

Abstract
Background: Adrenal insufficiency (AI) following unilateral adrenalectomy for pheochromocytoma (PCC) is an exceedingly rare occurrence described previously in 1 study in only 4 out of 13 patients with unilateral PCC. We discuss an unusual case of a patient with incidentally discovered PCC who underwent unilateral adrenalectomy and subsequently developed AI.
Clinical Case: 61-year-old male in overall good health taking no medications presented with left flank and groin pain after a handlebar injury in a bicycle crash. CT angiogram Abdomen & Pelvis revealed a complex enhancing left adrenal mass with internal necrosis measuring 13 x 12 cm. He denied history of headaches, diaphoresis, chest pain or hypertensive crisis. He did endorse palpitations which had resolved with reduced caffeine intake. Labs showed plasma free metanephrine 3,295 pg/mL (ref range &lt;57) and normetanephrine 68,472 pg/mL (&lt;148), 24hr urine metanephrine 192,677 ug (52-341), 24hr urine normetanephrine 171,880 ug (88-444), 24hr urine vanillylmandelic acid (VMA) 182 mg (1.8-6.7), serum aldosterone 8.1 ng/dL (&lt;39.2), serum free cortisol 0.47 ug/dL (0.07-0.93), 24hr urine cortisol 41.6 ug (&lt;60), DHEA sulfate 37 ug/dL (42-290). He was started on phenoxybenzamine and underwent left adrenalectomy. Of note patient remained only minimally hypertensive with tumor manipulation intraoperatively. Pathology was consistent with PCC with no evidence of regional or distant metastases. Postop-labs showed plasma free metanephrine &lt;25 pg/mL and normetanephrine 122 pg/mL. Calcitonin and parathyroid hormone levels were normal. Patient was evaluated in endocrinology clinic 4 weeks after surgery for complaint of severe fatigue, weight loss, anorexia and myalgias. Adrenocorticotropic hormone (ACTH) level was 31 pg/mL (7.2-63) with AM cortisol of 2.1 ug/dL (5-23) which increased to 7.4 ug/dL 1 hour after Cosyntoprin 250 mcg stimulation. He was started on prednisone 10 mg once daily with significant improvement in his symptoms.
Conclusion: PCCs typically manifest as sustained or paroxysmal hypertension, episodic headaches, palpitations or diaphoresis. Our patient was found to have a PCC with strikingly elevated levels of catecholamines without typical signs and symptoms of PCC. To the best of our knowledge this is the 5th reported case where a patient developed AI after unilateral adrenalectomy for PCC. There are case reports describing PCCs which secrete both catecholamines and ACTH. However, our patient lacked clinical or biochemical evidence of hypercortisolism preoperatively and his tumor cells in path sample stained negative for ACTH. Other possible pathophysiologic mechanisms include ectopic corticotropin releasing factor production leading to subclinical Cushing syndrome (SCS). Clinicians should have a high suspicion for SCS in the setting of PCC to promptly diagnose and treat AI after unilateral adrenalectomy.