bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRI374 Immunomodulatory Effects Of Progesterone And Glucocorticoids In Pregnancy Immunity
Authors: Yasuda Atsushi , Seki Toshiro , Kashiwagi Hirofumi , Kitajima Natsumi , Kametani Yoshie 
Published: October 2023

Abstract
Disclosure: A. Yasuda: None. T. Seki: None. H. Kashiwagi: None. N. Kitajima: None. Y. Kametani: None.
Immune tolerance to a semi-allogeneic fetus is crucial for a successful pregnancy. However, the mechanisms of tolerance to semi-allografts in the co-existence with normal defenses against cancer and pathogens is not clear. During pregnancy, levels of pregnancy-related proteins and hormones such as progesterone (P4), estrogen, testosterone, and glucocorticoids (GC) increase. We hypothesized that the most abundant pregnancy related hormone in the placenta, P4, might play an important role in the local tolerance in the placenta. Thus, we aimed to compare the effects of P4 and cortisol (COR) on human lymphocytes in vivo, to clarify their role in the systemic regulation of immunity during pregnancy. Healthy donor peripheral blood mononuclear cells (PBMCs) were treated with P4 or COR for 6 h. These PBMCs were washed and transplanted intravenously into 8- to 9-week-old NOG-hIL-4-Tg (formal name, NOD.Cg-PrkdcscidIl2rgtm1Sug/Tg(CMV-IL4)/Jic) mice. Human epidermal growth factor receptor-2 (HER2) peptide was emulsified in complete Freund's adjuvant and administered intraperitoneally to these PBMC-NOG-hIL-4-Tg mice at the same day. As a negative control, an equal volume of PBS was added to the culture and transplanted into NOG-hIL-4-Tg mice. Boosters were administered using incomplete Freund's adjuvant 2 weeks after the primary immunization. Peripheral blood was collected 4 weeks after transplantation and 2 weeks after booster administration. T and B cell profiles were analyzed using FCM 28 days later. The results revealed that significantly higher numbers of human CD45+ cells engrafted in the spleens of P4-treated mice compared to COR-treated mice 4 weeks post-transplantation. Transplanted human CD45+ cells included T and B cells, and CD8+ T cells were significantly higher in P4-treated mice compared to both control and COR-treated mice. Moreover, antigen-specific IgG production was maintained in the P4-treated mice, suggesting that the T cell/B cell function was maintained in the mice. Compared to control and P4-treated mice, COR-treated mice tended to engraft fewer human CD45+ cells. Moreover, B cell engraftment tended to be lower in COR-treated mice than in control mice. Antigen-specific IgG production was not maintained. There results suggest that lymphocytes which experienced a high P4 environment maintain engraftment and function of human lymphocytes in the NOG-hIL-4-Tg mice, while high COR environment rather dampens the engraftment and function of them. The high-P4 environment limited in the placenta may support pregnant immunity to protect the semi-allogeneic fetus from pathogen-induced infectious disease or cancer.
Presentation: Friday, June 16, 2023
FRI430 A Case Of Elevated Sex Hormone-binding Globulin Secondary To Variegate Porphyria In A Patient With Hypogonadotropic Hypogonadism
Authors: Law Jocelyn , Yip Churn-Ern 
Published: October 2023

Abstract
Disclosure: J. Law: None. C. Yip: Research Investigator; Self; Eli Lilly & Company.
Background: Acute porphyria is a group of disorders characterized by enzymatic defects in the heme biosynthetic pathway. The liver is the source of both acute intermittent porphyria (AIP) and variegate porphyria. AIP is known to cause an elevation in sex hormone-binding globulin (SHBG) levels, likely secondary to impaired hepatic function and hepatocyte abnormalities1.
We describe a case of elevated SHBG secondary to variegate porphyria, in a male with hypogonadotropic hypogonadism.
Case Report: A 44-year-old male presented with an elevated SHBG and symptoms of hypogonadism with low libido, weakness, and fatigue. Fasting morning bloodwork revealed an elevated SHBG at 89 nmol/l (13.5- 71.0), a normal total testosterone level at 12.95 nmol/l (8-32), and a low bioavailable testosterone at 0.82 nmol/l (2.5-10), with confirmatory repeat blood work.
His history was significant for longstanding variegate porphyria, manifesting as frequent attacks of abdominal pain. He was on opioids for greater then 10 years for his chronic pain, as well as metoclopramide.
On assessment of causes for his elevated SHBG, his TSH was normal at 1.49 mIU/L (0.35-4.30). He did not have cirrhosis, hepatitis, hereditary hemochromatosis, and was not on anticonvulsants. No other cause was found, and his elevated SHBG was deemed secondary to his variegate porphyria.
His normal total testosterone level was due to his elevated SHBG, but as mentioned, his bioavailable testosterone was low. His LH and FSH were both inappropriately normal, with his LH being 4.67 IU/L (0.6-12.0) and his FSH 4.7 IU/L (1.0-12.0), in keeping with hypogonadotropic hypogonadism. He went through normal pubertal development and had no anosmia. Workup revealed an elevated prolactin level of 73.8 ug/l (3.5-19.4). He had no galactorrhea or gynecomastia and an MRI sella revealed a normal pituitary gland. His elevated prolactin level was determined to be secondary to his opioid medication and/or metoclopramide use. His hypogonadotropic hypogonadism was deemed secondary to his opioid medications and/or hyperprolactinemia.
Conclusion: This case demonstrated variegate porphyria as a likely cause of elevated SHBG, similar to AIP. In patients with variegate porphyria and symptoms of hypogonadism, the SHBG should be measured and if it is elevated, the bioavailable or free testosterone levels should be used in assess instead of relying on the total testosterone levels. As has been previously shown, this case also illustrated the use of opioid medications as a cause of hypogonadotropic hypogonadism.
References: (1) Herrick AL, McColl KE, Wallace AM, Moore MR, Goldberg A. Elevation of hormone-binding globulins in acute intermittent porphyria. Clin Chim Acta. 1990 Feb 28;187(2):141-8. doi: 10.1016/0009-8981(90)90340-x. PMID: 2107988.
Presentation: Friday, June 16, 2023
SAT366 Expression of Amyloid-related Proteins Associated With Dementia in Polycystic Ovary Syndrome Compared to a Control Population
Authors: Butler Alexandra E , Moin Abu Saleh Md , Sathyapalan Thozhukat , Atkin Stephen Lawrence 
Published: October 2023

Abstract
Disclosure: A.E. Butler: None. A.S. Moin: None. T. Sathyapalan: None. S.L. Atkin: None.
Objective: Several risk factors in polycystic ovary syndrome (PCOS) are associated with increased risk for Alzheimer’s disease (AD). We hypothesized that circulatory levels of amyloid-related proteins would be elevated in PCOS but that these would potentially be mitigated by elevated levels of proteins associated with protection from AD. Methods: Somascan proteomic analysis of amyloid-related proteins was undertaken in a well validated PCOS database of 143 women with PCOS and 97 control women. Results: Amyloid-precursor protein (APP) (p&lt;0.05), amyloid P-component (APCS) (p&lt;0.001), apolipoprotein E (apoE) (p&lt;0.01) and apoE3 (p&lt;0.05) were elevated in PCOS, whilst alpha-synuclein (SNCA) (p&lt;0.05) was reduced in PCOS, all features associated with increased AD risk. Correlation analyses of the AD-related proteins with protective heat shock proteins (HSPs) showed that SNCA positively correlated with HSP90 (p&lt;0.01) and with HSP60 (p&lt;0.0001). Correlations with markers of inflammation showed APCS positively correlated with interleukin-6 (IL6) (p&lt;0.05) whilst ApoE and ApoE3 correlated positively with tumor necrosis factor-alpha (TNF-alpha) (p&lt;0.05). Conclusion: The AD-associated protein pattern found in PCOS, with basal elevated APP and reduced SNCA, parallels what has been reported in patients type 2 diabetes. This dysregulated AD-related protein expression in PCOS is likely exacerbated by obesity and insulin resistance-related inflammation and may be modulated by protective HSP mechanisms.
Reference: Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE. Hypoglycaemia in type 2 diabetes exacerbates amyloid-related proteins associated with dementia. Diabetes Obes Metab. 2021 Feb;23(2):338-349. doi: 10.1111/dom.14220. Epub 2020 Oct 25. PMID: 33026133.
Presentation Date: Saturday, June 17, 2023
THU569 Steroid Receptor Coactivator 3 Is Required To Prevent Early Pregnancy Loss In The Mouse
Authors: Kumar Maurya Vineet , Hai Lan , Szwarc Maria M , San-Pin Wu , DeMayo Francesco J , Lydon John P 
Published: October 2023

Abstract
Disclosure: V. Maurya: None. L. Hai: None. M.M. Szwarc: None. W. San-Pin: None. F.J. DeMayo: None. J.P. Lydon: None.
Members of the Steroid Receptor Coactivator (SRC) family enact distinct transcriptional coregulator functions within a broad spectrum of physiologies and pathologies. We previously demonstrated that endometrial SRC-3 is critical for in vitro human endometrial stromal cell decidualization, a critical cellular process in the establishment of the maternofetal interface. To address SRC-3’s in vivo role in endometrial periimplantation biology, we recently generated a SRC-3 conditional knockout mouse model (SRC-3d/d) in which SRC-3 is selectively ablated in cells that express the progesterone receptor. A six-month breeding trial with wild type proven stud males demonstrated that the SRC-3d/d female fails to produce litters (n&gt;10 per genotype). Unlike the SRC-2d/d female, however, both embryo attachment and implantation into the stromal compartment of the SRC-3d/d endometrium are not impaired at gestation day (GD) 5 or 6. While endometrial stromal decidualization initiates with embryo invasion, pregnant SRC-3d/d mice exhibit early pregnancy loss (EPL) by GD-7.5 (before placentation). At GD-6, the SRC-3d/d decidua is significantly smaller than those of sibling controls. Histological analyses reveal extensive decidual cell death in the SRC-3d/d decidua by GD-7, which results in the sudden demise of the embryo. These histological findings are supported by recent genome-wide RNA profiling studies that show a pro-survival role for SRC-3 in this tissue. Based on these results, we conclude that endometrial SRC-3 is critical for maintaining the functionality and survival of the decidual stromal cell and embryo developmental progression to placentation. Therefore, endometrial SRC-3 (and its downstream signaling networks) are predicted to represent new molecular determinants of non-aneuploid EPL, a poorly understood pregnancy complication for which diagnostic and treatment options are limited.
Presentation Date: Thursday, June 15, 2023
THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia
Authors: You Tianming , Zhao Hong , Potluri Tanvi , Yin Ping , Ekrem Bulun Serdar 
Published: October 2023

Abstract
Disclosure: T. You: None. H. Zhao: None. T. Potluri: None. P. Yin: None. S.E. Bulun: None.
Inguinal hernias affect up to 27% of elderly men, with approximately 800,000 inguinal hernia repair surgeries performed annually. While these procedures are often effective, a significant subset of hernias are refractory to treatment, resulting in high mortality, high recurrence, and chronic pain. Until recently, little research has been done examining the molecular mechanisms that drive hernia-associated lower abdominal wall weakening. Our lab previously created a transgenic mouse model expressing the human aromatase gene (Aromhum) and showed that male Aromhum mice produced high levels of estrogen in the lower abdominal muscle (LAM) tissue, leading to extensive LAM fibrosis, muscle atrophy, and hernia formation. Single-cell analysis of fibrotic LAM tissue in these mice showed high expression of estrogen receptor alpha (ERα) in LAM fibroblasts as well as upregulation of Wnt signaling pathways in these ERα-positive fibroblasts. The canonical Wnt/β-catenin signaling pathway has been implicated in fibroblast activation and fibrosis in multiple organs, including the lung, heart, and skin. Thus, we hypothesized that canonical Wnt/β-catenin signaling acts as a downstream mediator of ERα to cause LAM fibroblast activation, tissue fibrosis, and hernia. To test our hypothesis, we cultured primary ERα-positive LAM fibroblasts from Aromhum mice in the presence of estrogen with or without siRNA knockdown (KD) of β-catenin. However, KD of β-catenin under these conditions did not alter fibroblast proliferation as measured by EdU assay, nor did it alter expression of genes involved in fibroblast activation or extracellular matrix formation. Furthermore, administration of LGK974, a Wnt signaling inhibitor, in male Aromhum mice did not prevent hernia development, decrease hernia size, or decrease the extent of LAM fibrosis and muscle atrophy. Thus, we concluded that the canonical Wnt/β-catenin signaling pathway does not serve as a downstream mediator of estrogen-induced skeletal muscle fibrosis in our Aromhum mouse model of inguinal hernia. Further studies are needed to evaluate the role of Wnt/β-catenin signaling in other inguinal hernia models or in humans.
Presentation Date: Thursday, June 15, 2023
SAT017 Investigating The Spatial Regulation Mediated By Constitutive Androstane Receptor
Authors: Asokakumar Anjana , Anakk Sayeepriyadarshini 
Published: October 2023

Abstract
Disclosure: A. Asokakumar: None. S. Anakk: None.
Xenobiotic nuclear receptor, Constitutive Androstane Receptor (CAR/NR1i3), is extensively studied in the liver for its detoxification functions. In addition, CAR is also involved in controlling metabolic processes, protein synthesis, immune functions, and cellular proliferation. We examined if CAR achieves these wide ranges of functions by the spatial distribution of labor within the liver. Although previous studies have shown that CAR transcriptionally regulates many genes involved in these pathways, their spatial control is yet to be examined. For instance, the liver is divided into three zones (pericentral, periportal and midzonal) and whether CAR is expressed equally in these zones remains unknown. However, CAR has not been studied at the protein levels due to the lack of reliable antibody. We generated a Flag-tagged CAR mouse model using CRISPR Cas that will enable us to investigate CAR protein expression, localization and its interactions with other proteins. The transgenic FLAG-CAR model will also allow us to monitor its transition between the cytoplasm and nucleus or between different liver zones upon activation. Further, we have generated single-cell RNA sequencing data from individual liver cells in both sexes of WT mice with and without CAR activation. We classified the hepatocytes, the major liver cell population, into different zones based on known biomarkers. Currently, we are investigating if these hepatocytes from different zone activate different CAR target genes. Our initial analysis revealed that CAR target genes are highly expressed in the central and midzonal regions. Next, we will examine the CAR target genes expression in different liver zones based on their functions. In the future, we aim to visualize the CAR protein and its target protein expression based on zonation. Overall, this study will help us to understand CAR localization and its target regulation both at transcriptional and translational levels.
Presentation: Saturday, June 17, 2023
SAT022 A Mechanism Of Resistance To Novel Inhibitors Of The N-Terminal Domain Of Androgen Receptor
Authors: Setiawan Josie , Mawji Nasrin R , Tien Amy H , Andersen Raymond J , Sadar Marianne D 
Published: October 2023

Abstract
Disclosure: J. Setiawan: None. N.R. Mawji: None. A.H. Tien: None. R.J. Andersen: Stock Owner; Self; ESSA Pharma. M.D. Sadar: Stock Owner; Self; ESSA Pharma.
Background: Androgen receptor (AR) is a steroid hormone receptor and a major therapeutic target in prostate cancer. Antiandrogen therapies directed at the AR C-terminal ligand-binding domain (LBD) provide initial benefit to patients with advanced prostate cancer, but they eventually progress to lethal metastatic castration-resistant prostate cancer (CRPC). AR N-terminal domain (NTD) inhibitors are a novel class of antagonists that were developed to overcome resistance mechanisms related to the AR-LBD, including splice variants lacking the LBD (AR-V7). While mutations in the AR-LBD have been well-characterized, the impact of NTD mutations on AR transcriptional activity and drug efficacy remains unclear. The mutation W435L was discovered from clinical samples of prostate cancer from patients treated with antiandrogens. This mutation stabilizes interaction between the AR’s NTD and LBD (N/C interaction) to increase AR transcriptional activity. Tryptophan residues W435 and W397 in AR NTD are essential in the binding site for the AR-NTD inhibitor EPI-7386 that is currently in clinical trials. We hypothesize that tryptophan mutations within the EPI-7386 binding site of AR are a potential mechanism of resistance. Methods: Site-directed mutagenesis was used to create expression vectors with W435 and W397 point mutations in AR. Plasmids were transfected into AR-negative CV-1 cells to compare the transcriptional activity of wild-type (WT) versus mutant ARs. IC50s for each inhibitor were generated for androgen-induced reporter gene constructs. A mammalian two-hybrid system assay was used to assess the impact of inhibitors and AR mutations on N/C interaction. Results: The AR-W435L mutation led to higher IC50s to inhibit androgen-induced MMTV-luciferase activity by NTD inhibitors and antiandrogens. Differences in N/C interaction were observed between WT and mutant ARs treated with EPI-7386. Importantly, the ability of another EPI analog, EPI-7170, to decrease AR-N/C interaction was not significantly impacted by W435L. These data support that loss of efficacy with EPI-7386 is not across the entire class of EPI analogs and may be specific to EPI-7386. Conclusion: Tryptophan mutations in the EPI-7386 binding site are predictive of resistance to this specific antagonist and do not broadly apply to the entire class of EPI analogs. Key differences were revealed between AR-LBD and AR-NTD inhibitors that support the recruitment of different tau regions in the NTD.
Presentation: Saturday, June 17, 2023
FRI182 Cardiometabolic Risk And Outcomes In Patient With Adrenal Adenomas
Authors: Lam Han , Han Hye Jeong , Athimulam Shobana 
Published: October 2023

Abstract
Disclosure: H. Lam: None. H. Han: None. S. Athimulam: None.
Background: Approximately 5% of adults undergoing cross-sectional imaging are reported to have an adrenal adenoma. Although most adenomas are considered non-functioning (NFAT), up to 48% can present with mild autonomous cortisol secretion (MACS). Published studies have reported an increased prevalence of cardiometabolic risk factors, cardiac and cerebrovascular events in MACS patients. Objective: To determine the prevalence of cardiometabolic disease and outcomes in a population-based cohort of patients with adrenal adenomas. Design: Retrospective cross-sectional study of patients with adrenal adenomas over a 10-year period (Jan 2012 – Dec 2021). Setting: Academic primary and tertiary care setting. Main outcomes measured: Prevalence of cardiometabolic disease, cardiovascular events requiring procedure (percutaneous coronary intervention, PCI or coronary artery bypass graft, CABG) and cerebrovascular events. MACS was diagnosed based on cortisol level ≥ 1.8cmg/dL after overnight 1mg dexamethasone suppression testing (DST) and NFAT if cortisol &lt; 1.8mcg/dL. Patients who did not undergo 1mg DST were categorized as unknown cortisol status (UCS). Results: Preliminary results include 198 patients with adrenal adenomas [(135 women (67%) with a median age of 67y, 106 Black (54%), 83 White (42%) and 9 other races (4%)]. 74 (37%) were diagnosed with NFAT, 42 (21%) with MACS, and 82 (41%) with UCS. Hypertension (n=163,83%; MACS vs NFAT vs UCS: 23% vs 34% vs 43%) is the most prevalent cardiometabolic risk factor, followed by hyperlipidemia (n=146, 75%; MACS vs NFAT vs UCS: 21% vs 38% vs 41%), prediabetes (n=94, 50%; MACS vs NFAT vs UCS: 18% vs 43% vs 39%) and type 2 diabetes mellitus (n=82,43%; MACS vs NFAT vs UCS: 22% vs 35% vs 43%), respectively. 14% of patients with adrenal adenomas underwent procedures (PCI or CABG) for cardiovascular events (MACS vs NFAT vs UCS: 33% vs 26% vs 41%) and 11% were diagnosed with cerebrovascular events (MACS vs NFAT vs UCS: 29% vs 19% vs 52%). Conclusions: Patients with adrenal adenomas and mild autonomous cortisol secretion (MACS) are at increased risk of cardiovascular events requiring intervention and cerebrovascular events, compared to non-functioning adrenal tumors. 41% (n=82, 61% Blacks, 30% White, 2% Others) of patient population was classified as unknown cortisol status indicating further need to educate health care professionals on evaluation of adrenal adenomas to improve health care outcomes and disparities in management.
Presentation: Friday, June 16, 2023
THU669 Time To Achieve Euthyroidism In Graves Disease Using Methimazole In An Urban Population
Authors: Sultana Habbsa Samima , Yunasan Elvina , Krishnan Adityanarayan , M Kashif 
Published: October 2023

Abstract
Disclosure: S.S. Habbsa: None. E. Yunasan: None. A. Krishnan: None. K.M. Munir: None.
Context: Previous studies of treatment response in Graves disease have shown that that the mean time to reach euthyroidism with methimazole (MMI) was several weeks to months. In 1987 Okamura et al. concluded that the average period was 6-7 weeks with MMI 30mg daily. Nakamura et al. showed similar data in 2007 (5.8 +/- 4 weeks). These studies were performed in Japanese hospitals over 15 years ago. Limited data exists regarding treatment response times with different doses in a diverse urban population, which may vary with regards to typical dietary patterns, thyroid hormone metabolism and thionamide pharmacokinetics. Objective: The objective of this retrospective chart review was to determine the mean time to achieve euthyroidism with MMI in patients with newly diagnosed Graves disease in Baltimore City. Methods: Patients with Graves hyperthyroidism newly diagnosed in the last 5 years were identified from outpatient endocrine and primary care clinics within the University of Maryland Medical Center healthcare system. Time to achieve euthyroidism (from the start of thionamide therapy to date of euthyroid labs, defined as normal free T4 level) was assessed. Results: 128 patients with recently diagnosed Graves hyperthyroidism were identified (126 patients treated with MMI only and 2 with PTU only). 78% of subjects were female and the mean age at diagnosis was 47 years. The average daily dose of MMI ranged from 2.5mg to 60mg. On average, Free T4 decreased by 0.47 ng/dL per week. The mean time to achieve euthyroidism was 10.1 weeks (8.6, 11.6) overall, similar in males and females. On sub analysis, time to achieve euthyroidism was lower in younger males (age &lt; 40 years) [6.6 weeks (3.9, 9.3)] and older females (age &gt; 40 years) [8.3 (6.9, 9.7)]. Conclusion: The above data may inform expectations for treatment response for newly diagnosed Graves disease, specifically in an urban population on a Westernized diet. Patient forums have shown increasing interest in therapeutic alternatives to thionamides, including specialized diets. This data may help to determine whether other proposed therapies for initial treatment of Graves hyperthyroidism are more or less efficacious.
Presentation: Thursday, June 15, 2023