bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP428 The Effects of Asprosin Pubertal Maturation in Female Rats
Authors: OZ Zeynep Dila , Ozdede Mehmet Ridvan , Kocoglu Samet Ramazan , Gok Gulendam , Ozgen Aslisah , Horoz Mert Ali , Yasar Abdullah , Kacar Emine , Serhatlioglu Ihsan , Yilmaz Bayram , Kelestimur Haluk 
Published: November 2022

Abstract
Adipokines play an important role in sexual maturation and reproduction in a variety of ways. The central Asprosin administration of asprosin, a new adipokine secreted by white adipose tissue, has been found to have the potential to stimulatory effects influence on the hypothalamus-pituitary-gonadal axis (HPG)pubertal maturation in male rats. However, there is no study on the effects of asprosin on the HPG axis. Interestingly, peri-ovarian adipose tissues, which surround the ovaries and perform both autocrine and paracrine functions, suggest that asprosin may have a role in ovarian function. Asprosin has been also shown to cross the blood-brain barrier. However, the effects of asprosin, a novel adipokine, are not fully defined on the hypothalamus-pituitary-gonadal axis at the peripheral levels. The aim of the research study aims is to see how asprosin affects pubertal maturation in female rats when it is given parentally. For the experimental studies, totally a total of 24 female Sprague-Dawley rats, 21 days old and 35 ± 2 g weight, were used and randomly divided into two groups as control and asprosin groups (n=12). Asprosin (500 ng/kg) was given intraperitoneally daily in the animals in the asprosin group from postnatal day 21 for about 8 weeks. Similarly, the control group received only saline. For determining the puberty onset, vaginal opening (complete canalization of the vagina, an external index of puberty onset) was monitored daily in rats. Vaginal smears were performed daily from the date of puberty onset to determine the day of the first estrus. The ELISA method is used to analyze hormones in blood samples. Asprosin administration did not affect the onset of puberty or pubertal weight compared to the control group (p&gt;0. 05). The first day of estrus in female rats administered with asprosin was shown to be significantly earlier than control rats (p&lt;0. 05). Asprosin administration significantly increased the levels of FSH, oxytocin, and estradiol in the blood(p&lt;0. 05). It significantly decreased inhibin B level (p&lt;0. 05). There was no significant difference in LH level (p&gt;0. 05). In conclusion, our findings suggest that asprosin may have stimulatory effects on pubertal maturation of the reproductive system in female rats. However, we believe that more research is needed to determine the mechanism by which asprosin affects the pubertal maturation of the reproductive system. This study was supported by TUBITAK (Project# 220S744).
Presentation: No date and time listed
ODP060 Treatment of Aldosterone-producing adenoma by CT-guided radiofrequency ablation in a high surgical risk patient: biochemical and clinical outcomes.
Authors: Lafranchi Andre , Filho Gilmar Tostes , Ravizzini Pedro Ivo , da Cunha Scalco Tirapelli Renata , Bueno Cristina Belotti Formiga , Scalissi Nilza Maria , Junior Jose Viana Lima 
Published: November 2022

Abstract

Background
Primary aldosteronism (PA) is a leading cause of secondary hypertension and harness a much higher cardiovascular risk than essential hypertension. About 30% of PA cases are due the existence of an aldosterone-producing adenoma (APA). Although the current guidelines recommend unilateral laparoscopic adrenalectomy as the standard treatment of APA, some patients might no be suited for the procedure.

Clinical Case
A 66-year man was referred to our institution following a 14-year history of resistant hypertension. His past history included a stage III chronic kidney disease, type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea (OSA), hypothyroidism, grade I obesity, and rheumatoid arthritis. Initial tests were consistent with PA: elevated serum aldosterone (26 ng/dL), suppressed plasma renin activity (PRA: 0. 07 ng/ml/H) and a high aldosterone/renin ratio (RAR: 65) with concomitant hypokalemia (3,4 mEq/L). Abdominal CT-scan demonstrated a 11×8 mm left adrenal nodule with an absolute washout of 60%. A diagnosis of an APA was confirmed by an adrenal vein sampling. Since the patient had multiple comorbidities and an unequivocal high surgical risk, laparoscopic adrenalectomy was contraindicated, and pharmacologic treatment was started with spironolactone. Despite the use of high doses of spironolactone, blood pressure (BP) control was not achieved. Moreover, severe side effects were experienced, notably sexual dysfunction and painful gynecomastia. In this setting, a decision for a CT-guided radiofrequency ablation was made. The procedure underwent under general anesthesia and had no adverse events. Three days after the ablation, biochemical analysis demonstrated a significant reduction of aldosterone (10 ng/dL) and RAR (10), whereas the PRA was notably higher (1,45 ng/mL/h). He transitioned from 6 different classes of anti-hypertensives drugs to only one and his blood pressure was well controlled in an appointment 30 days after the procedure. On the other hand, his glomerular filtration rate had decayed from 44 mL/min to 31 mL/h due to a rapid blood pressure control. Despite no changes in anthropometric measures and OSA related symptoms were observed, an expressive reduction in microalbuminuria (191 mg/dL to 28,6 mg/dL) was noticed.

Conclusion
The CT-guided radiofrequency ablation is a suitable minimally invasive treatment for PA in high surgical risk patients. For patients with high surgical risk and intolerance to clinical treatment, radiofrequency should be offered as an option for treatment in a specialized center.
Presentation: No date and time listed
ODP600 Is this a case of surreptitious hormonal supplements?
Authors: Rimal Priya , Musurakis Clio , Gilden Janice 
Published: November 2022

Abstract

Background
Hypogonadism in males results when there is either a failure of the testes to produce testosterone, hypothalamic or pituitary dysfunction. Although testosterone supplementation is used for documented hypogonadism, it has become widely abused, with a variety of false claims for promoting energy, virility, and muscular development, as well as enhanced athletic performance. We present a case of surreptitious abuse.

Clinical Case
A 63-year-old male with coronary artery disease, was initially consulted to endocrinology for evaluation of Graves’ disease with ophthalmopathy. He was treated with methimazole 5 mg daily. However, on subsequent visits, he requested measurement of testosterone levels. Laboratory tests showed FSH&lt;0.2 mIU/ml (0.7-10.8); LH&lt;0.2 mIU/ml; free testosterone 3050 pg/ml (35-155); total testosterone 7377 ng/DL (250-1100); prolactin 9.6 ng/ml; Hgb 14.7 g/dL (13. -17); HCT 45.5% (40-51); TSH 1.94 uIU/ml (0.358-3,74); Free T4 0.74 ng/dL (0.76-1.46); Free T3 2.60 pg/ml (2.82-3.98). When confronted with these values, he admitted that due to interest in building muscle mass and energy, for lifting weights, he was taking hormone and protein supplements ordered from an internet program. These therapies were claimed to enhance muscle mass and energy, increase testosterone and lower estrogen. He did not have blood tests for over 6 months, and it was not clear who monitored this plan. He was taking testosterone 400 mg injections of testosterone cypionate and proprionate twice weekly, as well as another form of oral testosterone, which amounted to more than double the total dose required to treat hypogonadism in 1 week. He was counseled about the risks of taking excess testosterone, for which he had no prior knowledge (including CAD, cardiomyopathy, erythrocytosis, coagulation abnormalities, major mood disorder, gynecomastia, increased risk for prostate cancer), and also that it is unclear whether he even had hypogonadism. He agreed to stop taking these supplements. Four months later, he reported slightly less energy, but he was not exercising due to back pain, and no other changes. Laboratory tests: Total testosterone 572 ng/dL, Free Testosterone 74.6, LH 3. 0 mIU/ml; FSH =3.4 mIu/ml (8-10.8).

Discussion and Conclusion
Although hyperthyroidism can cause an increase in total testosterone via an increase in hepatic synthesis of SHBG, the free level is normal. Abnormally high testosterone levels in men are most commonly due to anabolic steroids taken to increase muscle mass and enhance athletic performance. It is also important to evaluate for other causes, such as adrenal or testicular tumors. This case is an example of a patient innocently taking unregulated and hazardous hormonal supplements for false claims, which may result in abnormal hormonal laboratory results, and lead to unnecessary and expensive evaluations. Therefore, it is important to take a good medication history, and to query abnormal lab results at each outpatient visit.
Presentation: No date and time listed
RF10 | PMON216 Aromatase Inhibition Fails to Exaggerate Weight Gain and Induce Bone Loss in Ovariectomized Female Marmosets
Authors: Willging Molly , Kraynak Marissa , Kuehlmann Alex , Kapoor Amita , Flowers Matthew , Colman Ricki , Levine Jon , Abbott David 
Published: November 2022

Abstract
Declining serum estradiol (E2) levels during the menopausal transition are associated with increased central adiposity and heightened risk for metabolic disease. Ovarian estradiol, E2, supports female metabolic function. While ovariectomy (OVX) in rodents enables obesity, OVX in nonhuman primates (NHPs) inconsistently alters weight gain. We therefore hypothesized that in female NHPs, extra-ovarian E2 provides key support for metabolic homeostasis. To test this, we employed aromatase inhibition to eliminate extra-ovarian E2 biosynthesis together with diet-induced obesity (DIO) to enhance weight gain. Thirteen adult female marmoset monkeys were OVX and received: (1) E2-containing capsules and daily oral treatments of vehicle (E2; n=5); empty capsules and daily oral treatments of either vehicle (VEH, 1ml vehicle/kg, n=4), or (3) letrozole (LET, 1 mg/kg in 1ml vehicle/kg, n=4). After 6-7 months, VEH and LET compared to E2 females demonstrated increased % body weight gain (p=0.01) and increased caloric intake VEH (p&lt;0.001) and LET (p&lt;0.001) corrected for fat-free mass. Dual energy x-ray absorptiometry (DXA)-determined body composition at 6 months showed no between female group differences in total fat mass or fat mass in validated body regions of interest. Total body (p=0.014), abdominal region (p=0.002) and upper leg region (p=0.025) DXA-determined fat free mass, however, increased ∼5-10% in all female groups. In addition, lumbar spine and total body DXA-determined bone mineral density (BMD) and bone mineral content (BMC) were comparable across all female groups. Relative circulating E2 levels were E2&gt;&gt;&gt;VEH&gt;LET, while those in hypothalamus ranked E2=VEH&gt;LET, confirming aromatase inhibition of local hypothalamic E2 in LET females. Our findings demonstrate ovarian E2 and extra-ovarian E2 depletion induce comparable increases in DIO weight gain without bone loss in female marmoset monkeys and highlight E2 as a key regulator of female metabolic homeostasis in NHPs.
Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP438 Canonical and Non-canonical Function of EZH2 in Progesterone Receptor Target Genes in Breast Cancer
Authors: Elizalde Patricia , Belmonte Martina , Cenciarini Mauro , Deamicis Agustina Roldan , Madera Santiago , Mercogliano Florencia , Mauro Florencia , Bruni Sofia , Russo Rosalía Cordo , Schillaci Roxana , Proietti Cecilia 
Published: November 2022

Abstract
Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase which catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3), an epigenetic mark associated with chromatin compaction and transcriptional repression of target genes. This constitutes its canonical mechanism of action. Several studies have shown that EZH2 is able to activate gene transcription by forming transcriptional complexes through mechanisms that do not involve histone methylation. Indeed, EZH2 can also act in a non-canonical function by regulating transcription independently of its enzymatic activity. We have previously described that progestins induce the interaction between Progesterone Receptor (PR) and EZH2 in breast cancer (BC) cells, which results in the downregulation of tumor suppressor GATA3 and in the increase in cell proliferation. Since EZH2 has been implicated in the progression of several types of cancer, including those of the breast, and our own previous results indicate that EZH2 is required for progestin-induced breast cancer growth, we hypothesized that EZH2 could function as a mediator in the pro-tumorigenic effects of progestins, targeting specific tumor suppressor and differentiating genes to allow ER/PR-positive BC growth. In the present work we found that progestin treatment of T47D cells induced EZH2 mRNA and protein expression, which was abolished by the use of the progestin antagonist RU486 and when PR expression was blocked by siRNAs. We also studied the participation of EZH2 in the regulation of PR-regulated genes TNFalpha (TNFα), cyclin D1 and TIMP2. By ELISA assays, we observed that progestin treatment of T47D cells for 24 h induced TNFα secretion. This effect was abolished when EZH2 expression was inhibited in the presence of EZH2 siRNAs and when EZH2 enzymatic activity was blocked by the use of GSK126. Regarding TIMP2, we observed that EZH2 canonical activity participates in TIMP2 downregulation exerted by progestin treatment. We showed that EZH2 non-canonical function is also involved in progestin modulation of TIMP2 given that blockage of EZH2 activity did not completely revert progestin effect. Finally, we demonstrated that progestin upregulation of cyclin D1 did not require EZH2 activity. Our results prove that EZH2 engagement in PR target genes may involve its canonical or non-canonical function and therefore support further studies on other progestin-regulated cancer genes implicated in tumor growth.
Presentation: No date and time listed
ODP651 Abnormal Primary Ciliogenesis in the Developing Mouse Kidney of Glucocorticoid Receptor-Deficient Mice
Authors: Cole Timothy , Lao Jianshen , Ng Judy , Short Kelly 
Published: November 2022

Abstract
Glucocorticoid (GC) hormones have well characterised regulatory roles for the development and maturation of several fetal organs, however, specific developmental roles of GCs in the fetal kidney have not been described (1). We have explored both the expression and localisation of the glucocorticoid receptor (GR) within the developing fetal mouse kidney during organogenesis and the effect on the transcriptome of eliminating GR expression in gene-targeted GR-deficient mice. Staining for the GR by immunohistochemistry at E14.5, E16.5 and E18.5 demonstrated widespread expression of the GR in the renal tubule and the interstitial renal mesenchyme, with strong staining in collecting ducts and increasing expression in mesenchyme up to E18.5. Loss of GR expression in GR-null mice had a profound effect on the renal transcriptome with altered expression (at an FDR of 0.5 and fold change &gt;2. 0) for 454 genes in the GR-null mouse kidney at E18.5, with a greater number of genes showing significantly reduced mRNA levels (305) than increased mRNA levels (99) relative to wild-type controls. Interestingly these deregulated genes included key primary cilia-associated genes, such as centrosomal protein 290 (Cep290), with the largest fold change of -3.6, Cep97, Ccp110, and the primary cilia-associated kinesin Kif3A. In addition, two renal tubule markers, Kidney androgen regulated protein (Kap) (proximal tubule marker) and S100 calcium binding protein G (S100g) (distal tubule marker) were also strongly downregulated with fold changes of -8.61 and -2.5 respectively. Analysis of primary cilia in sections of E18.5 kidney using multicolour confocal microscopy demonstrated that primary cilium length was significantly decreased and abnormally projected from kidney proximal tubule cells in E18.5 GR-null mice (5.23 + 0.12, µm + SEM) compared with wild type controls (6.27+ 0.15, µm + SEM). Finally, in cultured IMCD3 mouse collecting duct cells dexamethasone treatment was shown to increase the length of primary cilia compared to vehicle-treated control cells (vehicle 2.49 + 0. 03, µm + SEM vs dexamethasone 3.17 + 0. 05 µm + SEM), an effect that could be blocked by pre-treatment with the GR antagonist RU486. Taken together these results indicate that GC signalling mediated via the GR contributes either directly or indirectly to the normal formation of primary cilia in the proximal tubule and is therefore required for normal kidney development. This also suggests that abnormalities in GR-regulation of ciliogenesis may underpin or contribute to causes of human ciliopathy conditions. 1. Cole TJ, Short KL, Hooper SB (2019) The Science of Steroids. Sem. Fetal and Neonatal Med. 24: 170-175.
Presentation: No date and time listed
OR07-4 Regulation of Mineralocorticoid Receptor Transactivation By Circadian Protein Timeless
Authors: Young Morag 
Published: November 2022

Abstract
The mineralocorticoid receptor (MR) is a ligand activated transcription factor that plays an important role in cardiovascular physiology and disease. MR transactivation is regulated by ligand-dependent conformational change in the MR and recruitment of coregulator binding partners to form a unique DNA-binding complex at the hormone response element in target gene promoters. Differences in the recruitment of coregulatory proteins can promote tissue-, ligand- or gene-specific transcriptional outputs. The goal of this study was to evaluate a candidate MR coregulator, the circadian gene timeless for ligand and cell-selective regulation of MR transactivation. While timeless is not essential for mammalian clock function and does not bind DNA, timeless RNA and protein levels oscillate over 24hr. Co-expression of timeless dose-dependently down-regulated MR transactivation of an MR-responsive reporter in HEK293 cells, yet enhanced transactivation mediated by other steroid receptors. Timeless also inhibited MR transactivation of synthetic and native gene promoters, and expression of endogenous MR target genes, in H9c2 cardiac myoblasts. Immunofluorescence staining of timeless, and MR showed colocalization to the nucleus in the presence of aldosterone and co-immunoprecipitation which suggested an interaction, although a direct interaction was not confirmed. Taken together, these data suggest timeless is a novel MR coregulatory protein that may contribute to time-of-day-dependent MR transcriptional outputs and suggest new opportunities for the development of MR antagonists with selective actions.
Presentation: Saturday, June 11, 2022 12:15 p.m. - 12:30 p.m.
RF03 | PMON289 KLF4 drives estrogen driven tumor heterogeneity in breast cancer
Authors: Mohammed Hisham , Wen Yahong 
Published: November 2022

Abstract
Whilst hormonal therapies have proved effective in targeting ER positive breast cancer, intrinsic and acquired resistance to therapy has meant that the disease remains deadly. To identify potential drivers of transcriptional and epigenetic heterogeneity in breast cancer, we performed detailed single-cell multi-ome experiments +/- estrogen stimulation. Our results identified that the transcription factor KLF4 is highly associated with heterogeneity in our experimental models. KLF4 is one of four Yamanaka pluripotency factors that can reprogram cells to a stem like state and is also a pioneer factor, that possesses the ability to bind to condensed chromatin. Silencing of KLF4 significantly reduced transcriptional heterogeneity in multiple models. Importantly, we also found that KLF4 acts as a pioneer factor for ER. ER binding, transcriptional activity and chromatin accessibility at ER binding sites were lost upon KLF4 silencing. Using proteomics based interactome profiling, we find multiple other signaling pathway rely on KLF4. Together, our results suggest that KLF4 maintains plasticity in ER+ breast cancer cells and also functions as a pivotal factor for ER to function.
Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF15 | PMON294 Disrupting a Key H-bond Network Drives Glucocorticoid Receptor Gene Suppression Without Off-target Gene Activation for Duchenne Muscular Dystrophy Treatment
Authors: Liu Xu , Hoffman Eric , Ortlund Eric 
Published: November 2022

Abstract
Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Anti-inflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.
Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.