bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT-054 Gigantism and Hypothalamic Obesity: Rare Endocrine Manifestations of Neurofibromatosis Type 1
Authors: Roberts Richard Ogden , Chambers Christina 
Published: May 2020

Abstract
Background: Neurofibromatosis type 1 (NF-1) is a heritable, autosomal dominant, multisystem disorder caused by mutations or deletions in NF1, with approximately 30-50% of cases arising from de novo mutations. In the pediatric population, growth hormone deficiency is among one of the most commonly described endocrine sequelae, although aberrations of pubertal development are also commonly seen.
Clinical Case: A 3-year-old female, who was clinically diagnosed with NF-1 at the age of 4 months based on the presence of multiple café-au-lait macules, underwent screening MRI, which noted a left optic glioma and a hypothalamic mass favored to represent a hypothalamic glioma. Review of her growth chart showed a height much greater than the 99th percentile, with an increase in height velocity beginning 1 year prior. Weight was also noted to be much greater than the 99th percentile, with an increase in weight gain coinciding with the timing of alterations in linear growth. Mid-parental height is at the 95th percentile, and the patient’s height had tracked between the 86th and the 99th percentiles until age 2 years. Weight had tracked between the 68th and the 95th percentiles during that period. Initial laboratory evaluation showed an IGF-1 of 644 ng/mL (26-164 ng/mL). Gonadotropins were prepubertal; prolactin and thyroid studies were normal. ACTH stimulation demonstrated a rise in serum cortisol from 6.8 mcg/dL to 30.2 mcg/dL at 60 minutes. Growth hormone failed to suppress following an oral glucose load with a baseline GH of 4.4 ng/mL and values of 3.7, 6.5, 6.8, and 9.0 ng/mL at time +30, +60, +90, and +120 minutes respectively. Leuprolide stimulation did not show significant rises in gonadotropins. Bone age was advanced by more than 1 year. The patient was started on subcutaneous octreotide with a decrease in IGF-1 to 258 ng/mL after 1 month of therapy. On treatment, linear growth velocity slowed with no interval height gain over the initial 1-month period; however, the patient’s weight continued to increase with a gain of 1.8 kg. Parents additionally reported hyperphagia, which prompted concern for hypothalamic obesity in the setting of her known hypothalamic mass. Thyroid function remained normal on somatostatin therapy. To date, there has been no concern for diabetes insipidus.
Conclusion: Growth hormone excess may rarely complicate a diagnosis of NF-1 in the setting of intracranial gliomas. Increased height velocity and/or tall stature for family should raise clinical suspicion and prompt evaluation. Hyperphagia and significant increases in weight in the setting of hypothalamic gliomas in patients with NF-1 should raise suspicion for hypothalamic obesity and prompt lifestyle modifications to curb ongoing weight gain.
SUN-234 Brain-Selective Estrogen Therapy to Prevent Androgen Deprivation Therapy-Related Hot Flushes
Authors: Merchenthaler Istvan , Lane Malcolm , Stennett Christina , Zhan Min , Prokai Laszlo 
Published: May 2020

Abstract
Synthetic estrogens are used in the clinic to alleviate debilitating neurological symptoms associated with androgen deprivation therapy (ADT), an effective treatment improving survival in prostate cancer patients when administered timely in the course of the cancer. However, this therapy to relieve the symptoms, most commonly hot flushes, causes feminizations that significantly diminishes patients’ compliance because of physical and psychological discomfort. Because only estrogens can provide adequate therapy of hot flushes based on current clinical practices, there is an unmet medical need for an effective, side effect-free and, consequently, compliance-gaining intervention to alleviate these vasomotor symptoms distressing prostate cancer patients on ADT. The goal with our experiments was to show that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED, a brain-selective bioprecursor prodrug of 17β-estradiol (E2) will ease ADT-associated hot flushes without feminizing side-effects.
To evaluate the effect of DHED on hot flushes the pharmacological rat hot flush model was used. Orchiectomized (ORDX) rats were treated orally with three different doses (10, 30, and 100 µg/kg) of DHED or ethynyl estradiol (EE, 200 µg/kg) for ten days. They were addicted to morphine and the tail skin temperature (TST) of saline-treated rats raised by 4.4±0.5 °C when morphine effect was withdrawn with naloxone injection. DHED and EE treatments significantly lowered such TST rise from 4.4 °C to 2.9 ±0.5°C and 1.8 ±0.5°C, respectively.
The conversion of DHED to E2 in the brain was confirmed by measuring the effect of DHED-derived E2 on the expression of progesterone receptors (PR) in the preoptic area of the hypothalamus with in situ hybridization histochemistry. Both DHED and EE treatment stimulated PR expression compared to saline-treatment in ORDX rats.
In our previous studies, we have shown the lack of conversion of DHED to E2 in the periphery in ovariectomized female rats; i.e., DHED treatment did not have uterotrophic, mammotrophic activities and did not stimulate galanin expression in the anterior pituitary. In these studies, the lack of conversion of DHED to E2 was also confirmed in male rats by measuring the expression of galanin, a highly estrogen-regulated gene, in the pituitary with quantitative RT-PCR. Contrary to EE, DHED treatment did not stimulate galanin expression in this estrogen target.
These observations support subsequent translational research focusing on DHED’s therapeutic use to remedy hot flushes and potentially other neurological symptoms in prostate cancer patients undergoing ADT to manage their malignancy. An estrogen therapy with the brain-selective DHED would provide a safe approach to prevent these neurological symptoms without causing peripheral estrogenic side effects such as gynecomastia or deep vein thrombosis.
OR14-01 FSTL3 Neutralizing Antibodies Restore Function to Diabetic Mouse and Human Islets: A New Approach for Treating Diabetes
Authors: Schneyer Alan , Brown Melissa L , Meyer Nolan , Lopez Alexa , Richter Alden 
Published: May 2020

Abstract
Activin, GDF11 and myostatin are structurally related members of the TGFbeta superfamily of growth factors with many biological roles in animal models and humans. Their actions are neutralized by extracellular proteins such as follistatin and follistatin like-3 (FSTL3). We have previously demonstrated that genetic inactivation of Fstl3 results in enlarged pancreatic islets containing increased numbers of beta cells that produce more insulin in response to glucose compared to wild type litter mates. We further discovered that at least some of these new beta cells arise via transdifferentiation from alpha cells. We also demonstrated that functional human islets from normal donors produce very high levels of activin. In contrast, activin biosynthesis is vastly reduced and FSTL3 synthesis is significantly increased in human islets from diabetic donors suggesting that activin is critical for normal insulin production. This was substantiated by direct treatment of human diabetic islets with activin which restored their response to glucose. These observations support the hypothesis that an FSTL3 neutralizing antibody would constitute a novel therapeutic approach to curing diabetes through restoring beta cell function as well as accelerating generation of new beta cells through transdifferentiation. To test this hypothesis, we produced a mouse monoclonal antibody that neutralized hFSTL3 (FP-101), thereby releasing bioactive activin, GDF11, and myostatin. We have now tested this antibody for biological activity in vitro on mouse and human islets. We used islets from high fat diet (HFD) treated mice to model diabetes-inducing effects of obesity as well as 24-hour incubation in hyperglycemic (33 mM glucose) medium to create human islets that lose responsiveness to high glucose as a model for human diabetes. In mouse islets we found that stimulation of normal (chow diet) islets by high glucose produced a stimulation index (SI) of 3.5 that was reduced to 2 in HFD islets. Treatment with activin, FP-101, or a commercial polyclonal antibody to mFSTL3 all increased response of HFD islets to elevated glucose and partially restored SI to normal levels. In human islets, hyperglycemia eliminated the normal (2.5 SI) response to high glucose while activin or FP-101 treatments dose-responsively restored this response. These results demonstrate that anti-FSTL3 therapy can restore function to compromised beta cells from mouse and human diabetes models. The observation that activin has the same action as anti-FSTL3 antibody indicates that FP-101 works through enhancing the activin signaling pathway. Finally, these results demonstrate that the FSTL3-activin pathway is an important regulator of beta cell function in humans as well as mice, supporting further development of this therapy as a diabetes treatment.
SUN-653 Bypassing Skeletal Muscle Lipid Handling Deficiencies as a Therapy for Metabolic Disease
Authors: Fan Liyan , Sweet David R , Prosdocimo Domenick A , Keerthy Komal S , Jain Mukesh K 
Published: May 2020

Abstract
Metabolic diseases and their serious sequelae such as non-alcoholic fatty liver disease (NAFLD) pose a substantial clinical burden. It is now well recognized that skeletal muscle is a major site for the metabolism of all major macronutrients, and derangements in these muscle processes significantly contribute to metabolic disease. Studies over the last 15 years have identified the transcription factor Krüppel-like factor 15 (KLF15) as an important regulator and effector of metabolic processes across various tissues, and furthermore, genome-wide studies have identified human KLF15 variants with increased body mass index and diabetes. Given the importance of skeletal muscle in maintaining metabolic homeostasis, we generated a skeletal muscle specific KLF15 knockout (K15-SKO) mouse to study the role of skeletal muscle KLF15 in regulating systemic metabolism. We found that this animal is prone to developing obesity and insulin resistance at baseline, a phenotype that is greatly exacerbated in response to high fat diet (HFD). Strikingly, K15-SKO mice show a propensity toward developing NAFLD, as demonstrated by increased micro- and macrovesicular steatosis, hepatocellular ballooning, increased hepatic fatty acid and triglyceride deposition, and elevated Cd36 expression. A potential cause of NAFLD is the accumulation of excess lipids and lipid intermediates due to defects in the lipid flux pathway in extrahepatic tissues. Indeed, we see defects in the expression of genes involved in the carnitine shuttle and a paucity of long-chain acylcarnitines in K15-SKO skeletal muscle. Furthermore, RNA sequencing of skeletal muscle from K15-SKO mice shows downregulation in a number of pathways involved in lipid handling. This indicates that KLF15 serves as a novel extrahepatic molecular regulator of hepatic health. It has been previously shown that a diet rich in short-chain fatty acids (SCFA) can bypass defects in lipid handling and ultimately improve metabolic health. To explore this therapeutic avenue, we gave K15-SKO mice either normal chow (NC) or a SCFA-rich diet for 7 weeks. We observed decreased weight gain and improved glucose homeostasis in SCFA-rich diet fed mice. In addition to being a preventative strategy, SCFA-rich diets may also serve as a potential therapy to rescue from metabolic disease. To this end, we gave K15-SKO mice HFD for 5 weeks followed by 7 weeks of either NC or SCFA-rich diet. We observed that providing SCFAs can improve metabolic health and ameliorate the phenotype seen due to defects in skeletal muscle lipid handling: mice given SCFA-rich diet following HFD had significantly decreased weight gain and improved insulin sensitivity. These studies demonstrate that skeletal muscle KLF15 serves as an important regulator of lipid flux and hepatic health, and that SCFA-rich diets are a promising candidate for metabolic disease resultant of impaired lipid handling.
SAT-641 Self-Reported Psychological Stress and Glucose Variability in Type 1 Diabetes on Sensor Augmented Pump over 5 Weeks
Authors: Kaur Ravinder Jeet , Pinsker Jordan E , Dadlani Vikash , Thapa Prabin , Batthula Sreedhar , Church Mei Mei , Reid Corey , Spitzer Shelly McCrady , Kremers Walter K , Dassau Eyal , Kudva Yogish C 
Published: May 2020

Abstract
Introduction: Patients and their families and medical providers have assumed that psychologic stress impacts glucose control in T1D (Type 1 Diabetes) though studies providing confirmatory evidence in real world settings are, to our knowledge, lacking. We hypothesized that self-reported psychologic stress worsens glucose control in T1D.
Method: We studied 20 adults with T1D on continuous glucose monitor (CGM), sensor augmented insulin pump (SAP) prospectively at 2 clinical research centers. Patients reported psychological stress through stress diaries for 5 weeks on a severity scale of 1-7 using hard copy logs including time of onset and offset of stress and severity. For analytic purpose, grades 1-4 are classified as mild and grades 5-7 as severe.
Results: Baseline characteristics were age 44.9±15.0 years, F/M 12/8, HbA1c 6.8 ± 0.7%, and diabetes duration of 22.9±15.9 years. We analyzed glucose variability during days of stress versus days without stress. During a 24 hour period, patients experienced less hypoglycemia during days with stress versus days without stress (p value 0.03). During the 5 week period, patients reported 23 ± 19.5 events. We analyzed the impact of self-reported stress on CGM data streams after excluding stress events associated with missing CGM data, nocturnal events (from 12 MN to 6 AM, too few events) and events for which subjects did not provide duration of stress. Thus, we analyzed 19.5 ± 17 events per patient from 6AM to 12MN. From 6 AM to 12 MN, the episodes lasted 179 ± 255 minutes with 83 % episodes being mild/moderate and 17% moderate/ severe. Number of CGM readings during daytime stress episodes were 717± 1120 compared to 8768± 1238 during non-stress periods. Impact of stress from 6 AM to 12 MN (Mid-Night) on CGM glucose was analyzed using matched paired t test. Mean glucose (160.6±41.9 vs 148.3± 28.6) and SD (53.2 ±17.7 vs 56.1±14.6) did not show a difference; however % of time spent below 70 mg/dl was less (4 ± 5) in patients during stressful periods compared to times without stress (6.3± 5.5, P value 0.02).
Conclusions: To our knowledge, this is the first study attempting to analyze the impact of self-reported stress using daily stress diaries on CGM data streams in T1D patients on SAP. The study revealed significant challenges experienced by patients in reporting adequate data. Self-reported stress was not associated with hyperglycemia. However, days of self-reported stress and periods during patients reported stress were characterized by less hypoglycemia on CGM data streams.
OR05-02 The IGFBP-3/IGFBP-3 Receptor Axis Is a New Therapeutic Target for Triple Negative Breast Cancer
Authors: Cai Qing , Harrell J Chuck , Koblinski Jennifer , Oh Youngman 
Published: May 2020

Abstract
Insulin-like growth factor binding proteins (IGFBPs) are components of the IGF signaling system, which is comprised of ligands IGF-I and IGF-II as well as a family of transmembrane receptors including the IGF-IR and IGF-IIR. IGFBPs bind to both IGF-I and IGF-II with high affinity and are essential for transporting IGFs. This prolongs their half-lives and regulates the availability of free IGFs for interaction with IGF receptors, thereby modulating the effects of IGFs on growth and differentiation. Amongst the six IGFBPs, IGFBP-3, the only IGFBP species regulated by the p53 tumor suppressor, is a well-documented potent tumor suppressor in a variety of human cancer. IGFBP-3 has been further suggested as a potent anti-metastatic factor. Recently, more direct evidence for antitumor effect of IGFBP-3 has been reported in various cancer cells including triple negative breast cancer (TNBC) cells in vitro and in vivo, but the underlying mechanisms of antitumor action of IGFBP-3 are largely unknown.
We have identified a new class of cell death receptor called IGFBP-3R, which constitutes a novel cell-death receptor that mediates the anticancer effects of IGFBP-3 in human cancer. IGFBP-3 is significantly reduced whereas IGFBP-3R is broadly expressed in many human cancer types such as breast, prostate, lung and colon cancer. In order to discover novel IGFBP-3/IGFBP-3R antitumor signaling as a therapeutic target, a panel of IGFBP-3R specific monoclonal antibodies (mAbs) have been generated and further identified IGFBP-3R agonistic mAbs acting like IGFBP-3 showing anticancer effects in human cancer cells. Further in vivo studies using a bioluminescent orthotopic TNBC mouse model and Patient Derived Xenograft (PDX) TNBC mouse models demonstrated that administration of IGFBP-3R agonistic mAbs results in significant shrinkage of primary and metastatic tumors up to 75%, accompanying induction of caspase-dependent apoptosis and suppression of tumor-activated NF-κB signaling. More importantly, IGFBP-3R agonistic mAbs have synergistic anticancer effects with therapeutic agents such as carboplatin and Bcl-2 family inhibitors in a variety of human cancer including TNBC, and it was further identified molecular mechanisms involved in its synergy in vitro.
These findings clearly demonstrate the IGFBP-3/IGFBP-3R system as a new target and the IGFBP-3R agonists such as IGFBP-3R agonistic mAbs as a new monotherapy and a combination therapy with therapeutic agents for TNBC.
SAT-354 Isolated Hypoparathyroidism: A Rare Initial Manifestation of Hereditary Hemochromatosis (HH)
Authors: Shaheen Zainab , McCann Kevin , Khthir Rodhan Abass 
Published: May 2020

Abstract
Background:
We present a case of hypoparathyroidism diagnosed in a patient as initial manifestation of hereditary hemochromatosis. As per our literature search, it is very rarely reported as an isolated abnormality in HH.
Case:
A 27 year old male with history of seizure disorder, well controlled on Oxcarbazepine, referred for evaluation of chronic hypocalcemia. His PMH includes cerebral palsy, with good functional capacity and mild cognitive impairment. He denied muscle spasm, perioral numbness, bone pain, muscle weakness or fracture. He was taking calcium carbonate 600mg bid and vitamin D 50,000 IU q2monthly.
There was no family history of any Ca disorders. Physical exam was unremarkable.
Laboratory evaluation revealed Ca levels ranging from 7.6 to 8.5mg/dl with intact PTH values ranging from 11 to 22pg/ml. His ionized calcium was also low. Patient’s 24 hr urinary Ca was 122mg/24hrs. In this case, he did initially have hypomagnesemia and vitamin d deficiency, which could potentially explain low calcium. But even after supplementing Vitamin D and Mg, patient’s Ca remained low. His kidney function was normal. Hemoglobin was in range of 14-15g/dl. To further evaluate the cause of hypoparathyroidism, iron saturation and iron levels were also sent. His iron saturation % was high at 89% with iron level of 286 ug/dl. His ferritin was 224 ng/ml and TIBC was 265 ug/dl. A sample was sent for genetic analysis to rule out hemochromatosis. Homozygous mutations in C282Y gene were found. A diagnosis of hereditary hemochromatosis was made. His other entire hormonal axis was intact. In this case, patient’s hypoparathyroidism is likely an initial manifestation of his HH.
Discussion:
Hereditary Hemochromatosis (HH) is a genetic disease characterized by an excessive (unregulated) entry of iron into the bloodstream with increased iron deposition in the parenchymal cells of a variety of organs leading to their failure. A defect in the hemochromatosis gene (HFE) is the most common form of HH, also known as the classic form or type 1 HH, where the principal mutation is represented by a substitution of tyrosine for cysteine at position 282 of the HFE gene (C282Y) as seen in our case. According to the genetic forms, the clinical manifestation usually ranges from simple biochemical abnormalities to severe organ damage and disease such as liver cirrhosis, arthritis, DM, cardiomyopathy and hypogonadism.
There are reports of hypoparathyroidism from iron overload seen in thalassemia patients and patients who receive long term blood transfusions. In our literature review, this is the first documented case of HH initially manifesting as hypoparathyroidism. As HH is not uncommon in Caucasians, the work up for hemochromatosis as a possible cause of endocrinopathies should be kept in the differential diagnosis. It will help in early diagnosis & treatment which can reverse the effects of the disease leading to better outcomes.
SAT-659 Micro/Nanoparticles from Antidiabetic Chinese Herbal Medicine Soup Increase Bioavailability of Phytochemicals and Regulate Glucose and Lipid Metabolism
Authors: Ke Lijing , Rao Pingfan 
Published: May 2020

Abstract
Herbal soups have always been a popular option for treating oxidative stress-related chronic diseases including diabetes. Various components of these soups have been studied in the hope to identify the active principles, mainly focusing on the individual phytochemicals. As we have revealed previously, the micro/nanoparticles (MNPs) formed incidentally during the boiling water extraction of herbal soups may be bioactive and functional. This study aims to elucidate the underlying mechanism of the biological functions of these MNPs. A Chinese herbal medicine soup prepared by Radix Puerariae lobatae, ginger and other three herbs, namely Ge-Gen-Qin-Lian-Tang, was employed here, as it was proven to be effective in treating type 2 diabetes clinically.
The soup was separated with high-speed centrifuge (15600×g) to obtain the supernatant (solutes and nanoparticles) and sediments (MNPs), and determined for the content of three bioactive phytochemicals, e.g. puerarin, berberine and baicalin. Their hypoglycemic, hypolipidemic and antioxidant effects were determined on streptozotocin (STZ)-induced Type 2 diabetic Wistar male rats fed on high fat-high sugar diet. The animals were divided into six groups (normal control, diabetic model, whole soup, supernatant, MNPs and metformin, 8 rats each), recording weight, diet, excretion, mental status, etc. The fasting blood glucose and oral glucose tolerance test were conducted regularly. Eight weeks after the administration, the rats were sacrificed after anesthesia. Abdominal aorta blood and tissue samples of pancreas, heart, skeletal muscle, liver, kidney, spleen were collected. The glycated hemoglobin, glucose, lipid, insulin, glucagon, AMPK, SOD, puerarin, berberine, baicalin in blood plasma, insulin in pancreas, SOD in tissues, AMPK in skeletal muscle were measured. Liver tissue sections were observed with HE staining. Statistical analysis (t-test) were performed.
The MNPs reduced blood glucose, ameliorated glucose tolerance, elevated insulin secretion and significantly improve glucose and lipid metabolism (P &lt;0.05), showing stronger effects than the supernatant components. Notably, MNPs elevated the AMPK level in skeletal muscle, even more potently than the whole soup. The therapeutic effects of MNPs on the liver damage were even stronger than metformin. Meanwhile, MNPs promoted absorption of puerarin, berberine and baicalin and increase their concentration in blood (P &lt;0.05). Therefore, the MNPs from the herbal soup exhibited more potent effects than the soluble components on ameliorating glucose and lipid metabolism and pancreatic functions of diabetic rats. The actions of these MNPs provide a new perspective for understanding the antidiabetic effects of herbal soups and serve as a vehicle for the multiple phytochemicals to synergistically possess therapeutic effects.