bluuebunny/crossref_metadata_2025_split huggingface dataset:
12209 Validation Of A Novel Placenta Explant Protocol For Studying Circadian Rhythms In The Mouse Placenta In Early, Mid And Late Pregnancy
Authors: Lee Jessica S , Yaw Alexandra M , Hoffmann Hanne Mette 
Published: October 2024

Abstract
Disclosure: J.S. Lee: None. A.M. Yaw: None. H.M. Hoffmann: None.
Introduction: The placenta serves as an interface facilitating the exchange of essential nutrients and oxygen between the mother and fetus. Preeclampsia, a complication of pregnancy driven by placental dysfunction, is one of the leading causes of maternal, fetal, and neonatal morbidity and mortality. While deregulation of the genes driving circadian rhythm has been associated with preeclampsia, the role of circadian rhythms in the placenta largely remains unknown. To address this gap of knowledge, our goal was to establish and validate an organotypic ex vivo preparation to study placenta circadian rhythms at gestation day (GD) 10, GD14, and GD18 in the mouse. Methods: To establish an organotypic placenta culture GD10, GD14, and GD18 placental explants, we sectioned the placenta into 350μm sections using a vibratome. The explants were prepared from the validated circadian Per2::Luciferase reporter mouse, allowing automated circadian rhythms recording of the explants in a LumiCycle. We compared explant success rate and rhythm quality in 2x2mm section vs whole slice explants at GD14. Using hematoxylin and eosin (H&E) staining we validated the explants to be decidua which is strictly of maternal origin, labyrinth which is strictly of fetal origin, and the junctional zone which consists of binucleated cells fused of maternal and fetal cells. Results: Through H&E staining, we confirmed the decidua is enriched with neutrophils, the junctional zone contains spongiotrophoblasts and glycogen trophoblasts, and the labyrinth has red blood cells. Both explant types were enriched with &gt;80% of cells from the targeted region. We next established a protocol to record Per2::Luciferase rhythms for &lt;6 days. The fragility of the GD10 placentas required the whole explant protocol, whereas the GD18 2x2mm sectioned explants produced strong rhythms with a high success rate. At GD14, the whole explants resulted in stronger rhythms with higher amplitude and higher goodness of fit compared to the 2x2mm explants. Conclusion: We found that depending on GD recording success differs. Specifically, the whole placental explant provides a more robust and reliable model for studying circadian rhythms in GD10 and GD14, whereas 2x2mm explants are successful at GD18. This novel placental preparation protocol will be valuable in studying disease- and drug-induced changes to circadian rhythms in a placenta layer-specific manner in the mouse.
Presentation: 6/1/2024
7542 Androgen Receptor Oligomerization State Allows Cells to Exhibit Non-Linear Dose Responses to Androgens Resulting in Distinct Biological Outputs
Authors: Safi R , Wardell S E , Watkinson P , Qin X , Lee M , Park S , Krebs T , Dolan E , Tsuji T , Nayak S , Khater M , Newlin M , Kirkland M , Xie Y , Long H , Fink E , Fanning S W , Runyon S , Brown M , Xu S , Owzar K , Norris J D , McDonnell D P 
Published: October 2024

Abstract
Disclosure: R. Safi: None. S.E. Wardell: None. P. Watkinson: None. X. Qin: None. M. Lee: None. S. Park: None. T. Krebs: None. E. Dolan: None. T. Tsuji: None. S. Nayak: None. M. Khater: None. M. Newlin: None. M. Kirkland: None. Y. Xie: None. H. Long: None. E. Fink: None. S.W. Fanning: None. S. Runyon: None. M. Brown: None. S. Xu: None. K. Owzar: None. J.D. Norris: None. D.P. McDonnell: None.
An unanswered fundamental question in androgen action is how cells recognize and respond in a non-linear fashion to different levels of androgens to elicit distinct biological outputs such as occurs in prostate cancer (PCa) cells. Indeed, most PCa express the androgen receptor (AR), and tumor growth and progression are facilitated by exceedingly low levels of systemic or intratumorally produced androgens. Paradoxically, high dose androgens have been used to treat patients with late-stage metastatic PCa. We have determined that androgen dose regulates the relative cellular abundance of AR monomers and dimers in cells and that the biological output of each oligomeric form of the receptor is different. Using in vitro systems that model exposure from castrate (low dose; LD) to eugonadal levels and above (high dose; HD) of androgens, we have determined that the global changes in gene expression are substantially different, with the changes induced by LD androgens (monomeric AR) being associated with cell proliferation, and HD androgens (dimeric AR) inducing a differentiated phenotype. A similar distinction in response to androgen levels was observed in vivo. Using a chemical biology strategy, we identified ligands which freeze AR in a monomeric form and demonstrate that these compounds faithfully recapitulate the LD biology exhibited by physiological AR agonists. Mechanistically, we determined that monomeric AR facilitates a non-genomic activation of the mTOR signaling pathway to drive proliferation, while the dimer suppresses c-MYC expression, inhibit proliferation, and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR-action in prostate cancer and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.
Presentation: 6/3/2024
6609 Central Serous Chorioretinopathy in the Eyes of the Beholder of Testosterone Depot Injection
Authors: Ni Huajing , Kankanamge Denuka , Jabbour James , Preda Veronica Angela 
Published: October 2024

Abstract
Disclosure: H. Ni: None. D. Kankanamge: None. J. Jabbour: None. V.A. Preda: None.
Background: Central serous chorioretinopathy (CSC) is a characterised by subretinal fluid accumulation causing detachment of the neurosensory retina and visual disturbance[1]. It has been postulated that increased focal choriocapillaris permeability results in leakage of interstial fluid into the subretinal space[1]. CSC is a rare side effect of testosterone therapy, the exact mechanism is unclear. Case : We present a 32-year-old male gym manager who has been self-administering anabolic steroids with testsoterone ethanoate IM injections every 14 days for body building. He reported left blurred vision for 8 weeks. He was normotensive and reported taking doxycycline and azithromycin for mycoplasma genitalia. There was no history of glucocorticoid exposure, smoking, alcohol use, gastoesophageal reflux disease, hypertension, shift work, sleep apnoea, nor other established risk factors for CSC. The visual acuity was OD 6/6 and OS 6/9 with intraocular pressures of 12mmHg on the right and 15mmg on the left. Fundoscopy revealed a left serous macular elevation involving the left fovea. A macular OCT confirmed the left acute central serous chorioretinopathy and right retinal pigment epithelial changes. The latter were suggestive of right CSC in the past. Discussion: Androgens have been associated with CSC in the literature. It has been hypothesised that exogenous testosterone may cause increased choriodal blood flow and permeability, promote atheroscleorsis, cause sodium retention and potentially interact with retinal pigment epithelium (RPE) via androgen receptors4. Intramuscular testosterone therapy causes fluctuation in plasma testosterone concentration (which is thought to be more relevant than absolute value of testosterone). Most cases (60%) of CSC resolve spontaneously, and appear to coincide with cessation of testosterone therapy5. Conclusion: Clinicans need to be alert to the use of testosterone and other anabolic steroids, prescribed or self administered, particularly in their patients with CSC or who have other risk factors for CSC, such as corticosteroids, smoking and hypertension. References: 1.Kaye R, Chandra S, Sheth J, Boon CJF, Sivaprasad S, Lotery A. Central serous chorioretinopathy: an update on risk factors, pathophysiology and imaging modalities. Prog Re- tin Eye Res. 2020 Nov; 79:100865. 2.Kitzmann AS, Pulido JS, Diehl NN, et al. The incidence of central serous chorioretinopathy in Olmsted County, Minnesota, 1980–2002. Ophthalmology 2008; 115:169–173. doi: 10.1016/j.ophtha.2007.02.032. 3.Ahad MA, Chua CN, Evans NM. Central serous chorioretinopathy associated with testosterone therapy. Eye. 2006 Apr;20(4):503– 5.4.Nudleman E, Witmer MT, Kiss S, Williams GA, Wolfe JD. Central serous chorioretinopathy in patients receiving exogenous testosterone therapy. Retina. 2014;34(10):2128–32.
Presentation: 6/2/2024
8808 Characterization and pre-clinical study on a novel hormonal compound with potent analgesic and anti-inflammatory properties
Authors: Antakly T , Brox A , Menezes J , Zingg H H 
Published: October 2024

Abstract
Disclosure: T. Antakly: Other; Self; Theriac Biomedical. A. Brox: Owner/Co-Owner; Self; Theriac Biomedical. J. Menezes: Advisory Board Member; Self; Theriac Biomedical. H.H. Zingg: None.
Hormones and naturally occurring compounds with therapeutic benefits have provided the basis of some of the most celebrated drugs e.g. Taxol (extracted from the Pacific Hew tree) and Premarin, a hormone replacement therapy (extracted from horse urine). Our team has discovered and chemically identified a bioactive compound (called “HIP-2”) found in folk medicinal admixtures. It has unique analgesic and anti-inflammatory properties. The chemical structure of HIP-2 consists of small fatty acid molecules which bind and activate the PPAR-gamma transcription factor, and furthermore they have HDAC inhibitory properties. A synthetic replica of the bioactive compounds was obtained and administered orally or by injection in a single dosage form. Using animal models for pain and inflammation, HIP-2 has demonstrated an outstanding efficacy and safety profile in animals (rats, mice) rendered experimentally inflamed (e.g. carrageenan injection) or osteoarthritic (surgery or iodoacetate injection). Pain and inflammation have decreased (by up to 50%) after HIP-2 administration. Inflammatory cytokines biomarkers were also reduced by about 50% as compared to baseline or to the positive controls (classical NSAID’s). HIP-2, with an outstanding safety and efficacy profile, offers an advantage over currently available analgesic and anti-inflammatory drugs, which have significant draw-backs due to limited efficacy and significant side effects such as gastrointestinal bleeding/ulcers/perforation and cardiac toxicity (Advil, Celebrex), osteoporosis and immunosuppression (corticosteroids), or addiction (opioids). As a potential solution to these problems, HIP-2 is likely to be superior both at the safety and efficacy levels. The HIP-2 IMP was cleared by FDA and is entering Phase 2 clinical trials.
Presentation: 6/3/2024
7005 Characterization of Clinical Candidate Miricorilant in Preclinical Models for NASH
Authors: Moll Tijmen J A , Viho Eva M G , Gentenaar Max , Hunt Hazel , Meijer Onno Cornelis , Kroon Jan 
Published: October 2024

Abstract
Disclosure: T.J. Moll: None. E.M. Viho: None. M. Gentenaar: None. H. Hunt: Employee; Self; Corcept Therapeutics. O.C. Meijer: Grant Recipient; Self; Corcept Therapeutics. J. Kroon: Research Investigator; Self; Corcept Therapeutics.
Background and aim: Miricorilant (CORT118335) is a selective glucocorticoid receptor (GR) modulator that is under clinical development for the treatment of non-alcohol steatohepatitis (NASH). It was previously shown that miricorilant treatment effectively lowers hepatic lipid content in mouse models of NASH. The aim of this study is to further characterize the effects of miricorilant in the mouse liver and in human liver tissue. Methods: In mouse liver tissue, we investigated the agonistic and antagonistic properties of miricorilant on GR activity. Eight-week-old male C57BL/6J mice were fed with a control diet or miricorilant-supplemented diet (resulting in an estimated dose of 60 mg/kg/day) for 6 days and 1.5 mg/kg corticosterone was injected to monitor the effects of miricorilant on GR-responsive gene expression. We next accessed the time-dependency of the lipid-lowering effects of miricorilant in the mouse liver. Mice were fed with a high-fat, high-fructose diet (HFHFD) for 3 weeks before treatment with 60 mg/kg/day miricorilant for one, three or six days by oral gavage, and triglyceride content in the liver was measured at endpoint. In human liver tissue, we investigated the effects of miricorilant on precision-cut liver slices (PCLS) obtained from two independent donors with pre-existing steatosis. PCLS were cultured for a total of 168 hours in the presence of 100 nM hydrocortisone, and with or without an exogenous lipid challenge. PCLS were treated with 200-600 nM miricorilant for 96 hours before triglyceride content was measured. RNA-sequencing was performed on PCLS after 24 hours of 200-400 nM miricorilant exposure. Results: In the mouse liver, miricorilant exhibited a unique combination of agonistic and antagonistic properties on GR-responsive gene expression. Miricorilant effectively lowered HFHFD-induced lipid accumulation in the mouse liver as soon as three days after treatment. In human PCLS, miricorilant treatment lowered triglyceride content in both donors. RNA-sequencing revealed respectively 40 and 128 differentially expressed genes after 200 and 400 nM miricorilant treatment. Pathway analysis revealed very-low-density lipoprotein (VLDL) particle remodeling as a significant enriched pathway, providing a possible explanation for the lowered triglyceride content upon miricorilant treatment. Conclusion: Miricorilant rapidly and effectively lowers hepatic lipid content in the mouse liver and in human PCLS, possibly via modulation of VLDL remodeling.
Presentation: 6/2/2024
8672 Disrupted Glucocorticoid Receptor Mediated Signalling Causes a Primary Cilia Defect in the Fetal Mouse Renal Tubule
Authors: Lao J , Short K L , Ng J , Cottle D L , Cole T J 
Published: October 2024

Abstract
Disclosure: J. Lao: None. K.L. Short: None. J. Ng: None. D.L. Cottle: None. T.J. Cole: None.
Primary cilia are microtubule-based organelles that protrude from cell membranes to mediate diverse developmental signalling pathways and senses extracellular stimuli to maintain tissue homeostasis. We show that glucocorticoid (GC) signalling via the glucocorticoid receptor (GR) is a regulator of normal primary cilia formation in kidney renal tubules. RNA sequencing of whole E18.5 fetal kidney from mice with global deletion of the GR (GR-null) compared to littermate wild-type controls identified significantly reduced mRNA levels of key ciliogenesis-related genes. Further analysis of whole fetal kidney RNA by real-time-qPCR confirmed reduced mRNA levels for the cilia-associated proteins Ccp110 (fold -2.18), Cep97 (fold -1.78), Cep290 (fold -2.91), Kif3a (fold -1.82) and Rpgr (fold -1.90). Confocal microscopy revealed abnormal, stunted primary cilia in renal proximal tubules, collecting ducts and podocytes in GR-null or in renal tubule conditional GR-deleted mice, created using the HoxB7 Cre-driver allele. Primary cilia length was significantly decreased in kidney proximal tubule cells in GR-null mice (5.01 ± 0.11μm) compared with wildtype controls (6.20 ± 0.15μm). Furthermore, scanning electron microscopy of E18.5 GR-null kidney further confirmed aberrant primary cilia morphology in the proximal renal tubules and the absence of an apical brush border. Activation of GR signalling with the synthetic GC dexamethasone in cultured mouse IMCD3 kidney tubule cells significantly increased primary cilia length (2.89 ± 0.04μm) compared to vehicle controls (2.46 ± 0.28μm), an effect blocked by the GR antagonist RU486 (vehicle + RU486: 2.06 ± 0.02μm, dexamethasone + RU486: 2.00 ± 0.02μm). Aurora kinase A (AURKA) is a known regulator of primary cilia formation via the AKT cell signalling pathway and distinct proteins at different stages of the mitotic cell cycle. AURKA protein levels were downregulated in GR-null kidney and in IMCD3 cells which suggest GR regulates AURKA to control the assembly and disassembly of primary cilia. Together, these results demonstrate that GC signalling via the GR is required for normal primary ciliogenesis in the developing renal tubule and suggests that synthetic GR agonists may provide a novel therapeutic option for human ciliopathies such as those observed in forms of polycystic kidney disease.
Presentation: 6/2/2024
7340 Elucidating the Role of Steroid Hormone Receptors in Anaplastic Thyroid Carcinoma and Pancreatic Ductal Carcinoma Models
Authors: Stockert O M , Lange C A 
Published: October 2024

Abstract
Disclosure: O.M. Stockert: None. C.A. Lange: None.
Steroid hormones play important roles in modulating transcription mechanisms in a variety of cancers, including breast cancer, prostate cancer, and ovarian cancer. These interactions are highly context-dependent and regulated by diverse ligands, cofactors, and dynamic post-translational modifications that occur in response to the activation of stress-sensing and oncogenic signaling pathways. Numerous other cancers are associated with elevated steroid hormones, steroid hormone receptors, or both, but have not been studied to explore the possibility of leveraging steroid or steroid receptor (SR)-modulated transcriptional regulation to combat cancerous growth. Two of these cancers are pancreatic ductal adenocarcinoma (PDAC) and anaplastic thyroid carcinoma (ATC). PDAC is an aggressive cancer with a very poor 5-year survival of 8-11%. It is also rapidly growing in incidence and has been shown to be associated with other increasing health conditions, including diabetes and obesity. PDAC is associated with metabolic reprogramming and elevated Progesterone Receptor (PR), Glucocorticoid Receptor (GR), and Mineralocorticoid Receptor (MR) expression. ATC is another aggressive cancer with less than 10% 6-month survival from diagnosis. Like PDAC, ATC has a rapidly increasing incidence and is associated with obesity and high-fat diets. ATC is also associated with elevated cholesterol biosynthesis and elevated GR expression. Herein, we probed public data sets and screened a panel of PDAC and ATC models to demonstrate the expression of mixed SRs. In this study, we take an initial exploration of the hypothesis that related SRs (such as PR, GR, and/or MR) contribute to PDAC and ATC progression and that post-translational modifications, ligand binding, and/or selected cofactors modulate SR actions in the context of activated signaling pathways associated with these aggressive cancers. This study gives us a preliminary understanding of the potential role of steroid hormones and their receptors in the aggressive biology of two deadly and increasingly prevalent endocrine cancers in aging and obese populations.
Presentation: 6/3/2024
6891 Exclusive Normetanephrine Secreting Pheochromocytoma In A Young Male
Authors: Askar Esraa , Moran Heberth , Yuksel Simge , Bleich David 
Published: October 2024

Abstract
Disclosure: E. Askar: None. H. Moran: None.
IntroductionPheochromocytomas and paragangliomas arise from chromaffin cells and produce excessive catecholamines. Hypertension is their primary clinical symptom. they differ in their catecholamine secretory phenotype; paragangliomas typically secrete norepinephrine, while pheochromocytomas typically secrete epinephrine. Here, we present a case 21-year-old male with pheochromocytoma with elevated norepinephrine but normal epinephrine levels.Case presentationA 21 -year-old male with no past medical history presented with episodes of palpitations, sweating, and elevated blood pressure. He also reported abdominal pain. On admission, his blood pressure was 143/92 mmHg, pulse was 71/min, respiration was 16/min, and oxygen saturation was 100% in room air. The rest of physical exam was not significant. His electrolyte panel was normal. Computed tomography (CT) abdomen and pelvis with contrast was performed and showed a right adrenal mass measuring 4.9 x 4.0 x 6.5 cm which is predominantly hypoattenuating (approximately 30 Hounsfield units) with thick nodular rim of enhancement. Hormonal workup showed normal serum testosterone, DHEA-S, AM cortisol, ACTH, aldosterone, plasma metanephrine, and urine metanephrine, but profoundly high plasma normetanephrine 3641.6 (0.0-210.1) pg/mL. His 24-hour urinary normetanephrine was elevated at 14874 (80-440) ug/24hr, confirming a pheochromocytoma. The high norepinephrine level in the setting of normal epinephrine raised suspicion for Von Hippel Lindau (VHL). He was started on alpha and beta blockage and had laparoscopic removal of the right adrenal gland. The pathology report confirmed the diagnosis of pheochromocytoma confined to right adrenal. The patient was then referred for genetic testing. Conclusion: Pheochromocytoma can be a part of familial disorders, although being sporadic in nature most of the time. As demonstrated in our case, the hallmark of pheochromocytoma associated with VHL is nearly exclusive normetanephrine secretion and a high ratio of normetanephrine to metanephrine. Confirmation and testing of genes aid in proper monitoring and follow-up. The preferred course of treatment is radical resection.
Presentation: 6/2/2024
8236 Hepatocyte Vitamin D Receptor (VDR) Regulates Liver Regeneration
Authors: Gunton J E 
Published: October 2024

Abstract
Disclosure: J.E. Gunton: None.
Harendran Elangovan [1], Rebecca A. Stokes [1], Jeremy Keane [1], Sarinder Chahal [1], Caroline Samer [1], Miguel Agoncillo [1], Josephine Yu [1], Jennifer Chen [1], Michael Downes 2, Ronald M. Evans 2, Christopher Liddle [1],2, Jenny E. Gunton [1] [1]Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia 2 Salk Institute for Biological Studies, La Jolla, CA. USA Background: Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes, however, is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Methods: In these studies, hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. Mice underwent 2/3 partial hepatectomy and liver regeneration and function were studied. Results: hVDR mice had impaired liver regeneration with impaired hepatocyte proliferation. This was associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. CDCA (chenodeoxycholate) is an FXR ligand, which was increased after surgery in controls but not in hVDR mice. FXR signaling is important for hepatocyte proliferation. Real-time PCR of hVDR and control livers showed significant changes in expression of cell cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia / hyperproliferation and liver necrosis / cell death. Conclusions: Together these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, these studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.
Presentation: 6/2/2024