bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT-LB95 Low Density Lipoprotein Receptor and Proprotein Convertase Subtilisin/Kexin Type 9 Kinetics Using Heavy Water (2H2O) Labeling and Mass Spectrometry
Authors: Dandan Mohamad , Hellerstein Marc 
Published: May 2020

Abstract
Abnormally high blood cholesterol levels in low density lipoprotein (LDL) increases the risk of heart disease. Cell surface receptors such as LDL-receptors (LDLr) regulate the clearance of LDL from blood circulation. As cholesterol levels decrease, cells promote cholesterol synthesis and cholesterol uptake by increasing LDLr expression. Another regulatory protein of plasma cholesterol clearance is proprotein convertase subtilisin/kexin type 9 (PCSK9). It is secreted from the liver into circulation where it can bind to and target LDLr to the lysosome for subsequent degradation. The current model of cholesterol regulation describes how increased cholesterol content down-regulates the number of LDLr promoted by PCSK9 mediated degradation, however minimal knowledge is not known about LDLr and PCSK9 kinetics using heavy water labeling, and how cholesterol enriched diet affects LDLr and PCSK9 kinetics in vivo. Therefore, our objective(s) were to establish a method 1) to measure the kinetics of LDLr and PCSK9 via stable isotopic metabolic labeling with heavy water (2H2O) in vivo 2) to further test established models of cholesterol metabolic regulation on LDLr and PCSK9 turnover after feeding mice a cholesterol enriched diet. We hypothesize that a cholesterol enriched diet will decrease both LDLr and PCSK9 synthesis rates. In order to test this, mice were fed a cholesterol enrich diet for 1 week and metabolically labeled with heavy water (2H2O) up to 36 hours. LDLr and PCSK9 were immunoprecipitated from liver and deuterium incorporation into LDLr and PCSK9 were measured via mass spectrometry. Our results revealed high cholesterol feeding down-regulated cholesterol synthesis and LDLr fractional synthesis rate decreased from 10.0% to 6% per hour. PCSK9 concentration also decreased from 1 to 0.2 (ng/ml / total mg protein), but the synthesis rate increased from 9.0%/day in control mice to 19.5%/day in high cholesterol diet. These results suggest high cholesterol feeding increases PCSK9 synthesis that potentially depletes the intracellular pool to target LDLr to the lysosome thus decreasing LDLr turnover. This research provides a flux-based approach to measure the kinetics of LDLr and PCSK9 for a molecular based kinetic insight of their functions in physiology, disease and therapy.
OR28-07 Increased BMI Is Associated With Anti PD-1/PD-L1-Induced Thyroid Immune-Related Adverse Events
Authors: Pollack Rena , Ashash Amit , Cahn Avivit , Dresner-Pollak Rivka 
Published: May 2020

Abstract
Background: Immune checkpoint inhibitors have revolutionized cancer therapy, however, are associated with immune related adverse events (irAEs). Obesity is a pro-inflammatory metabolic state that may play a role in the development of irAEs. Hypothesis: We hypothesized that likelihood of developing thyroid irAEs following anti-PD-1/L1 therapy increases with increasing body mass index (BMI). Methods: We retrospectively analyzed data of 187 cancer patients who initiated anti-PD-1/L1 at our institution between 01/2014-12/2018, had normal thyroid function tests at baseline and had baseline BMI data available. Results: Overall, 97 (52.2%) patients were with low-normal BMI (&lt;25 kg/m2), 52 (28.0%) overweight (≥25-30 kg/m2) and 37 (19.9%) obese (≥30 kg/m2). Thyroid dysfunction (hyper or hypo, overt or subclinical) developed in 72/187 (38.7%) patients, of whom 29/97 (29.9%) had low-normal BMI, 22/52 (42.3%) were overweight and 21/37 (56.8%) obese (p=0.14). With every 1 kg/m2 increase in BMI, the likelihood of thyroid dysfunction increased by 8.8% (p=0.004). Overt hyperthyroidism occurred in 32/186 (9.1%) of the patients - in 4.1% of patients with low-normal BMI, 11.5% of overweight patients and 18.9% of obese (p=0.006). Overt hypothyroidism occurred in 32/186 (17.2%) of the patients and was not significantly associated with BMI. Hyperthyroidism followed by overt hypothyroidism, consistent with thyroiditis, occurred in 13/186 (7.0%) of patients and was significantly associated with increasing BMI category (p=0.03). Conclusions: Increased BMI was associated with increased thyroid irAEs in patients treated with PD-1/L1 inhibitors. Further exploration of the interaction between obesity and immunotherapy may provide insight into the role of inflammation in mediating immune response.
SUN-LB26 Radioligand Theranostics of Endocrine-Related Cancers; A New, Revolutionary Approach
Authors: Harris Alan G , O’Dorisio Sue M 
Published: May 2020

Abstract
The successful clinical development of octreotide targeting somatostatin receptors (SSRs) revolutionized treatment of Neuro Endocrine Tumors (NETs)and pituitary adenomas. Recently, clinical applications of peptide bioconjugates including octreotide have taken a giant leap forward into a new diagnostic and therapeutic arena of additional endocrine-related cancers including prostate, breast, and small cell lung cancers. Molecularly targeted radionuclide therapy (RT) opens new horizons for otherwise resistant or widely dispersed malignancies and has far-reaching implications as a personalized therapeutic approach. Cancer-type specific, radiolabeled diagnostic imaging agents have been developed to select patients who then receive precise radioligand therapy targeting the identified cancer cells. This RT using alpha or beta radiation is cytotoxic to targeted cancer cells, while nearby healthy cells are unharmed—minimizing side effects and improving patient quality of life. Thus, theranostics represent a groundbreaking approach to bring radionuclide endocrine cancer therapy to patients via a multidisciplinary team consisting of endocrinologists, surgeons, oncologists and nuclear medicine physicians. In recognition of this exploding new field, the US FDA approved 68Ga-DOTATOC and -DOTATATE for use in PET/CT and 177Lu-DOTATATE for the treatment of SSR-positive NETs. Clinical trials with new theranostic compounds are ongoing for prostate cancer (PSMA), breast cancer (bombesin receptor), and small cell lung cancer (cytokine receptor CXCR4). Exciting future developments will undoubtedly involve development of radionuclide agents targeting additional cell surface receptors, enzymatic pathways, and clonal variations as well as combinations of alpha- and beta-emitters. Health care facilities worldwideare in the process of adding RT to their armamentarium for cancer patients; this requires a multidisciplinary team approach to optimize access to and delivery of care. To advance the science and enable translation of theranostics worldwide, the Gordon Research Conferences (GRC) organization [www.grc.org] has selected the authors to organize a 5-day inaugural meeting on Radionuclide Theranostics for the Management of Cancer in June 2020 [https://www.grc.org/radionuclide-theranostics-for-the-management-of-cancer-conference/2020/]that brings together cancer biologists, radiation physicists, receptor pharmacologists, nuclear medicine physicians, and industry representatives to 1) Identify new molecular targets and targeting vectors for specific malignancies; 2) Explore development of novel radionuclides and molecularly targeted radiopharmaceuticals; and 3) Optimize therapeutic benefits based on an understanding of radionuclide risks to normal tissues. This presentation will review the key topics discussed during this GRC meeting
2496 characters (without spaces): limit 2500.
SUN-LB15 A Case of Familial Male-Limited Precocious Puberty With a Novel Mutation
Authors: Owens Lindsey L , Carakushansky Mauri , Gurnurkar Shilpa 
Published: May 2020

Abstract
Introduction:
Familial Male-Limited Precocious Puberty (FMPP), also known as testotoxicosis, is a rare cause of precocious puberty in males. It is caused by a mutation in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene, resulting in the receptor to be constitutively activated. This results in precocious puberty in males with rapid skeletal maturation and compromised final adult height if not treated. A combination on anti-androgens and aromatase inhibitors are the mainstay of treatment.
Case:
A 16-month-old male presented to our clinic due to concerns of precocious puberty. Pubic hair was noted at 6 months of age along with rapid growth acceleration. There was no known exposure to testosterone and no family history of early puberty or subnormal adult height. Upon presentation, his height was over the 99th percentile while his target height is at the 50th percentile. Physical examination revealed prepubertal testes with pubic hair at Tanner stage II. A bone age was reported as 12-18 months at a chronologic age of 12 months. Initial lab evaluation revealed normal serum levels of 17 OHP, androstenedione and DHEA-S with a slightly elevated serum LH (0.7mIU/ml), and very elevated serum testosterone level (289ng/dl). Leuprolide and ACTH stimulation tests as well as MRI of the abdomen and pelvis were normal. Serum levels of AFP, β-hCG and IGF-1 were also normal. Bone age advanced to 6 years at a chronological age of 21 months and to 8 years by 26 months of age. At 26 months of age, his stretched penile length measured 11cm. LH receptor testing was obtained, which revealed a novel heterozygous missense mutation in the LHCGR gene (c.1733A&gt;C; p.Asp.578Ala). The mutation was reported to be a variant of unknown significance though likely in the pathological end of the spectrum by variant analysis with SIFT and PolyPhen. He was started on treatment with anastrozole 1 mg daily and bicalutamide 25 mg daily at 2 and 9/12 years of age. Pubertal progression, linear growth and skeletal maturation slowed down with treatment. His bone age remained stable at 13 years from the age of 2 and 10/12 years to 4 years old. Pubertal stage and stretched penile length have also remained stable on treatment. He is tolerating treatment well.
Conclusion:
We report a novel mutation in the LHCGR gene causing FMPP in a 6-month-old male who is responding very well to a combination of bicalutamide and anastrazole with marked decrease in growth velocity, pubertal progression and skeletal advancement.
SUN-LB91 The Arg16/Gln27 Polymorphism of the Beta2-Adrenergic Receptor Impacts Blood Pressure Levels in a Transgenic Mouse Model via Sex-Specific Mechanisms
Authors: Treesaranuwattana Thitinan , Williams Gordon H , Pojoga Luminita 
Published: May 2020

Abstract
Background : The β2-adrenergic receptor (β2-AR) has been implicated in blood pressure (BP) homeostasis via its effects on the sympathetic nervous system, cardiac function, peripheral vascular resistance, and renin release. We also have documented that a β2-AR diplotype (Arg16/Gln27), carried by 15% of hypertensives, have salt sensitive hypertension (SSBP) and increased aldosterone (ALDO).
Gap in knowledge: it has been reported that hypertensive men and women respond differently to beta blockers. However, information regarding sex differences in carriers of the β2-AR risk diplotype is limited.
Hypothesis : In mice, the phenotype in female carriers of the mutant β2-AR risk diplotype will differ from male carriers.
Methods: The CRISPR/Cas9 approach was used to generate transgenic mice carrying 0, 1 or 2 Arg16/Gln27 variant alleles (i.e. wild-type (WT), heterozygous (Het) or mutant (Mut)). The experimental design included twelve weeks old mice divided into 6 genotype/gender groups (male and female; WT, Het and Mut) maintained on low (0.03% Na+, LS) and high sodium diets (1.6% Na+, HS) for a week each.
Results: 1) Both male and female mice displayed significantly increased BP on LS and HS with increasing number of mutated alleles.
2) Only Mut females displayed SSBP (P&lt;0.05).
3) As compared to WT, urine and plasma ALDO levels were lower in male (but not female) carriers of the mutated allele (P&lt;0.05).
4) As anticipated, urine K+ excretion was significantly lower in the Mut male (but not female) mice (P&lt;0.05).
5) Doppler ultrasound measurements of renovascular function shows that the resistive index was significantly lower in Mut vs WT males (P&lt;0.05), consistent with an appropriate increase in renal blood flow (RBF) in the face of an elevated BP. However, in the Mut females the RBF was inappropriately decreased compared to the WT (P&lt;0.05).
6) β2-AR expression was significantly lower in female vs. male WT mice; however, this difference was lost in the carriers of the mutated allele, as B2-AR expression levels were significantly higher in female carriers of the mutated allele, as compared to WT (P&lt;0.05). Interestingly, the B2-AR genotype had no effect on the receptor expression levels in males.
Conclusion: Both male and female Mut animals have increased BP compared to WT mice, but the mechanisms underlying their increased BP differ by sex. Female Mut mice have SSBP, inappropriately non-suppressed ALDO and decreased RBF. Male Mut mice do not have SSBP and have appropriate ALDO and RBF response to the salt load.
SAT-LB99 Inflammation May Mediate Coronary Artery Disease in Women With Hypothalamic Hypoestrogenemia: Findings From the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE)
Authors: Torbati Tina , Suppogu Nissi , Cook-Wiens Galen , Berga Sarah , Braunstein Glenn , Johnson Delia , Stanczyk Frank , Noel Bairey Merz C , Shufelt Chrisandra L 
Published: May 2020

Abstract
Background: Among premenopausal women presenting with ischemia, hypothalamic hypoestrogenemia (HHE) has been associated with angiographic coronary artery disease (CAD). Further, serum amyloid-alpha (SAA), a marker of systemic inflammation strongly predicts future adverse cardiovascular events. We sought to relate inflammatory markers to HHE and understand if inflammation mediates relations between HHE and CAD.
Methods: We assessed premenopausal women not on exogenous hormones undergoing coronary angiography for suspected ischemia. HHE was defined as estradiol&lt;50 pg/ml, luteinizing hormone&lt;10 IU/l and follicle stimulating hormone&lt;10 IU/l. Serum inflammatory markers, reproductive hormones, and angiographic CAD were measured.
Results: Overall, 40 (31%) of the 127 women had HHE with similar age and body mass index compared to no HHE (p=0.48 and p=0.77, respectively). Women with HHE had lower estradiol compared to no HHE (30.4+11.7 vs 112.5+62.4 pg/ml, p&lt;0.0001). There were no significant differences between high sensitivity C-reactive protein (hsCRP) (0.86 ± 1.45 vs 0.65 ± 1.17, p=0.5211) and interleukin 6 (IL-6) (4.95 ± 6.06 vs 3.90 ± 3.90, p=0.2358). However, HHE women had significantly higher SAA compared to no HHE (4.44+13.5 vs 0.94+2.37, p=0.0495).
Conclusion: Among premenopausal women undergoing coronary angiography for suspected myocardial ischemia, SAA levels were significantly elevated in women with HHE, suggesting that inflammation may serve as a mediator between HHE and CAD. Further investigation relative to inflammation as a treatment target in this cohort may be warranted.
SAT-LB302 From Urolithiasis to Genetic Testing: An Unusual Presentation of MEN-4 Syndrome
Authors: Alamri Bader Nasser , Palma Laura , Andonian Sero , Foulkes William D , Rivera Juan Andres 
Published: May 2020

Abstract
Background:Germline mutations in the CDKN1B gene are responsible for Multiple Endocrine Neoplasia Type 4 (MEN 4) syndrome (Alrezk et al. 2017). Around 20 cases have been reported to date. Here, we report on a new MEN4 family which possibly extends the phenotypic spectrum attributable to germline mutations in CDKN1B.
Clinical Case: A 56-year-old female presented with urolithiasis & was found to have hypercalcemia (serum calcium of 2.76 mmol/l ref. 2.12-2.62 mmol/l). Workup was in keeping with primary hyperparathyroidism (PHPT) (PTH 28.7 pmol/l ref. 1.50-9.30 pmol/l; phosphorus 0.89 mmol/l ref. 0.80-1.45 mmol/l). Sestamibi & US of the neck revealed no clear parathyroid adenoma. Two incidental thyroid nodules were benign on FNA cytology.
The patient underwent neck exploration & a single enlarged parathyroid gland was removed. Pathology showed an enlarged hypercellular gland. Her calcium & PTH normalized after surgery but recurrence was documented a year later. Her family history was significant for PHPT in two brothers & a history of kidney stones in a third brother. Multi-gene panel testing (CASR, CDC73, CDKN1B, MEN1, RET, Invitae Corp.) revealed a pathogenic variant (PV) in CDKN1B (c.215delG). The patient underwent a 2 ½ parathyroidectomy with subsequent normalization of her calcium & PTH. Further work-up showed a 4.5mm non-secreting pituitary adenoma. Plasma metanephrines & NE were intermittently elevated. Serum gastrin was also mildly elevated 83 pmol/l (&lt;53 pmol/l). A Ga68-DOTATATE PET scan was negative. Her 23-year-old daughter tested positive for the familial PV. She is asymptomatic & has normal calcium & PTH; pituitary function is normal except for an elevated IGF-1 at 63.9 nmol/l (ref 13.3- 42.6 nmol/l) with borderline growth hormone during OGTT (0.40 ug/l). Her pituitary MRI was normal. One brother with history of prostate cancer, PHPT & partial parathyroidectomy has tested positive for the familial CDKN1B variant. A second brother was also found to carry the familial variant & was clinically asymptomatic.Endocrinological workup has revealed he has PHPT, elevated chromogranin A at 196.2 ng/ml (ref &lt;=82), calcitonin at 25 ng/l (normal &lt;=9 ng/l), IFG1 (35.3 nmol/L ref. 13-21) but normal plasma metanephrines. An MRI of the sella shows an 8mm hypoenhancing lesion. On CT, a retroperitoneal hyperenhancing 4cm mass adjacent to the left ilio-psoas was seen, in keeping with a paraganglioma; additionally, he has a congenital left atrophic kidney & ureter. Two additional brothers; one with history of non-Hodgkin’s lymphoma, PHPT & partial parathyroidectomy & a second brother, also with prostate cancer & recurrent renal stones, have yet to be tested.
Conclusions: A new MEN4 family is described here which expands the spectrum of clinical manifestations of this syndrome. Of great interest in our cases is the presence of paraganglioma, urological malformation, & pre-clinical GH/IGF1 elevation.
MON-LB102 Metformin-Induced Weight Loss in Patients With or Without Type 2 Diabetes/Prediabetes
Authors: Chukir Tariq , Mandel Lindsay , Al-Mulla Nada , Kumar Rekha Babu , Igel Leon I , Waitman Jonathan , Aronne Louis J , Shukla Alpana P 
Published: May 2020

Abstract
Background: Metformin is the first-line pharmacologic treatment for type 2 diabetes (T2DM). Its use has been associated with significant weight loss in patients with obesity with or without T2DM. However, it is unknown whether weight loss outcomes differ with metformin monotherapy in patients with excess weight and euglycemia compared to patients with T2DM/prediabetes (PreDM).
Methods: This is a retrospective study of new patients with overweight/obesity seen at an academic weight management center between 4/1/14-4/1/16. Patients who received metformin as a sole pharmacotherapy were identified, and data pertaining to demographics, medications, comorbidities, and weight changes during 1-year follow-up were obtained from their electronic medical records. Mean and categorical weight losses were compared between patients with and without T2DM/PreDM. We also assessed the rate of metformin discontinuation due to side effects, lack of efficacy or other reasons in the entire cohort.
Results:
Of 1056 patients who were prescribed metformin for weight loss over the 2-year study period and had at least 2 office visits, 99 (9.38%) discontinued the medication due to the following reasons: side effects 59 (60%), lack of efficacy 15(15%) or other reasons 25(25%). A total of 254 patients received metformin as a sole pharmacotherapy for weight loss and had 6 and/or 12-month follow-up visits. In this cohort, the mean age was 53 ± 14 years, 66% were women. The mean BMI was 35 ± 7 kg/m2. The average percent weight loss at 6 and 12 months were similar in patients with euglycemia compared to patients with T2DM/PreDM (6.12% ± 5.68 vs 6.36% ± 6.52 p=0.73 at 6 months; 7.13% ± 6.42 vs 7.23% ± 7.74 p=0.93 at 12 months). The proportion of patients who experienced ≥5% weight loss was similar in both groups at 6-month (54.04 vs 54.55%, p=0.94) and 12-month follow-up visits (63.95 vs 55.42%, p=0.26). The proportion of patients who experienced ≥10% weight loss was also similar in both groups at 6-month (25.81 vs 27.72%, p=0.81) and 12-month follow-up visits (33.72 vs 30.12%, p=0.62).
Discussion: Among patients with obesity, metformin as a sole pharmacotherapy for weight loss achieved significant and comparable weight reduction in patients with or without T2DM/PreDM. Further studies are needed to evaluate the long-term weight loss in patients with euglycemia.
SUN-LB5 GnRHR ECL-2 Epitopes Targeted by Activating Autoantibodies in Polycystic Ovary Syndrome
Authors: Guo Yankai , Deng Jielin , Gege Zhang , Li Hongliang , Weeden Elizabeth A , Aston Christopher E , Burks Heather R , Craig Tasha B , Yu Xichun , Kem David C 
Published: May 2020

Abstract
Background: Activating autoantibodies (AAb) are directed to the gonadotropin releasing hormone receptor second extracellular loop (GnRHR-ECL2) and are pathogenic when induced in rats. We previously reported GnRHR-ECL2-AAb were elevated in sera from patients with PCOS (Rotterdam criteria) compared to ovulatory infertile controls (OIC). Methods:Human studies: ELISA detection of GnRHR Abs used a synthetic h-GnRHR-ECL2 28 mer peptide (LifeTein) as the target antigen. We assayed AAb activity in GnRHR transfected cells using a GeneBLAzer FRET assay (Invitrogen). ELISA AAb epitope locations on the ECL2 were identified on a minipin plate (pins 1-11 containing sequential 2 aa offsetting octapeptides, Mimotope, Inc) using sera from 30 PCOS subjects, 33 OIC and 18 normal controls (NC). Results:Human sera: An ELISA assay for GnRHR-ECL2-AAbs in the PCOS group was markedly higher than the NC group (P&lt;0.0001) and the OIC subjects (P&lt;0.003). The minipin data demonstrated one or more positive OD peaks on pins 4 (20%), 5 (47%) and 8 (47%) which shared L-aa sequences FSQC or CSFSQ. OIC had only 5 subjects with peaks at minipins 4 or 5 and NC had only 3 lower peaks and one with higher OD values over all minipins. GnRHR-AAb Specific Activity (SA) was estimated by measuring serum activity before and after suppression of AAb sensitive activity by addition of retro inverso D-aa (RID) peptides. These were specifically designed to mimic and decoy the AAb L-aa epitope sequences of pins 5 and 8). SA was measured in 10 selected PCOS and 10 OIC subjects who had positive ELISA values. The baseline activity in the PCOS group was significantly higher than OIC (P &lt; 0.01) and dropped 50% with preincubation with peak 5 RID and 25% with peak 8 RID. The addition of both peak 5 and peak 8 RID suppressed the PCOS group activity to OIC levels (P &gt; 0.2). There was no significant change in activity in the OIC subjects by the addition of peaks 5 + 8 RID peptides. Conclusion: These PCOS GnRHR-AAb data confirm the presence of significant activation of the GnRHR by AAb targeted to specific epitope(s) proximate to the disulfide GnRHR-ECL2 linkage to the nearby ECL1. These data are compatible with a pathophysiological role for GnRHR-AAb in PCOS and may provide both diagnostic and therapeutic opportunities.