bluuebunny/crossref_metadata_2025_split huggingface dataset:
PMON262 Systematic review and critical analysis on dietary supplements for male infertility: from a blend of ingredients to a rationale strategy
Authors: Grande Giuseppe , Petre Gabriel Cosmin , Pesenti Francesco Francini , Toni Luca D , Vitagliano Amerigo , Nisio Andrea D , Ferlin Alberto , Foresta Carlo , Garolla Andrea 
Published: November 2022

Abstract
The aim of this study was to evaluate the potential efficacy of each Dietary supplement (DS) proposed for male infertility and marketed in Italy, using an adapted version of the scoring system by the American Heart Association. In particular, the effect of any ingredients was evaluated according to semen alterations.
On the website of Italian ministry of health we found 23 supplements marketed for male infertility. We considered as eligible only randomized clinical trials (RCTs) evaluating substances included in DS marketed for male infertility. A formula allowed us to classify the expected efficacy of each DS, based on composition. Each DS was scored and included into three classes of expected efficacy: high, low and none.
Among 24 supplements,3 (12,5%) fall in high, 9 (37,5%) in lower and 12 (50,0%) in no expected efficacy class. DS composition showed 36 substances, 18 with no literature on male fertility and 18 showing positive effect on sperm parameters, thus considered potentially active ingredients (PAI). All DS were mixtures of ingredients, containing from 2 to 17 different substances. Fifteen supplements (65.2%) contained at least 1 ingredient without evidence of efficacy and 21 formulations had PAI dosed below mED. Some PAI were associated to the improvement of specific sperm parameters.
DS were usually blends of many substances, that are frequently employed at negligible dose or without any evidence of efficacy on male reproduction. Some ingredients have been demonstrated to be effective on specific sperm parameters by RCTs. We report a list of ingredients with potential efficacy on specific sperm parameters, aimed to allow a tailored use of DS.
In the light of our findings we rise three final considerations: i) the Italian market of DS for male infertility offers products with potential efficacy in the improvement of sperm parameters but also many with uncertain effect; ii) the actual literature is poor of well-designed studies on PAI investigating their mechanisms of action and effective dose in different pathological conditions; iii) based on current literature, our study can help in the choice of DS and PAI that are more likely to be effective on specific sperm alterations.
Our critical analysis suggests a rational strategy for a tailored use of DS in male infertility.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF02 | PMON309 Two Siblings with p.Arg92Trp Variant in NR5A1 Presenting with Testicular Disorder of Sexual Differentiation
Authors: Abisad Daniela Aguilar , Ballesteros Andrea Montano , Diaz Alejandro 
Published: November 2022

Abstract

Introduction
Disorders of sexual differentiation (DSD) are conditions of abnormal chromosomal development leading to atypical gonadal and anatomic sexual characteristics. We present the case of two siblings with 46, XX testicular DSD due to a mutation in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1). While there is extensive literature about pathogenic variants of this gene, this is the first variant that has been shown to cause DSD in XX individuals, rather than XY.

Case presentation
This is the case of a sibling pair with male phenotype and history of hypospadias and hypogonadism in the setting of 46, XX karyotype. Sibling A presented with hypospadias at birth and hypergonadotropic hypogonadism in childhood, initially managed with testosterone. Testicular biopsy revealed bilateral germ cell aplasia with degeneration of seminiferous tubules. Sibling B presented at age 8 with precocious puberty. He had a history of hypospadias and cryptorchidism at birth. Gonadotropins and testosterone levels were prepubertal. Testicular biopsy showed only Sertoli cells. Their adrenal gland and thyroid function was normal, their bone age was advanced. FISH was negative for the SRY gene in both cases, no ovaries or mullerian structures found in pelvic imaging. DSD genetic panels were sent, resulting positive for the R92W variant in NR5A1. Neither of them have intellectual disability; however, sibling B has attention deficit and hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Family history is remarkable for two uncles that have been unable to conceive. Their mother had oligomenorrhea and difficulty conceiving, typical presentation of a female carrier of this mutation.

Discussion and conclusions
The majority of DSD in individuals with a 46, XX karyotype are due to congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, however, mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. NR5A1 is an essential transcription factor that regulates target genes crucial for normal reproductive physiology and endocrine function, controlling several steps of adrenal and gonadal development. While there is extensive literature about the phenotype caused by variants of NR5A1 in XY individuals, the recurrent heterozygous p.Arg92Trp NR5A1 variant R92W that our patients have, is the only one that has been shown to cause DSD in XX individuals, with variable degrees of testis development. It has previously been described, however, in women with primary ovarian insufficiency (POI). Morevariants of this gene will continue to arise, playing a pivotal role in reproductive endocrinology.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP144 Cushing Syndrome and Primary Hyperaldosteronism due to Synchronic Bilateral Adrenal Adenomas with Exclusive Production of Cortisol on the Right and Aldosterone on the Left
Authors: Rolim Marina Rocha , Mendonça Berenice Bilharinho , Ledesma Felipe , Charchar Helaine , Srougi Victor , Tanno Fabio , Chambo José Luis , Almeida Madson Queiroz , Latronico Ana Claudia , Fragoso Maria Candida Villares 
Published: November 2022

Abstract
Female patient, 37 years old, coming from China, with a history of resistant arterial hypertension since the age of 25 years old associated with spontaneous hypokalemia and classic ACTH-independent Cushing's syndrome. Radiological imaging exams showed bilateral adrenal nodules. Diagnosed primary hyperaldosteronism (Baseline aldosterone 103ng/dL (2.5-39.2), Renin 2.7uUI/mL (4.4 - 46.1), Aldo/renin ratio 38.1 and K 3.3) and confirmed laboratory hypercortisolism (Cortisol after 1mg of dexamethasone overnight 17.9mcg/Dl (&lt; 1.8), salivary cortisol at midnight 0.466mcg/dL (&lt;0.274), ACTH &lt;2pg/mL, basal serum cortisol 19.4 (3.7–19.4). Abdominal CT identified bilateral adrenal nodules, one on the right and two on the left, with &lt;10 HU, suggestive of adenomas. In the pandemic, we proposed the same surgical treatment for primary adrenocortical macronodular hyperplasia (total adrenalectomy of the largest gland and with greater uptake in PET-FDG and subtotal of the smallest and with less uptake). The patient was therefore submitted to total videolaparoscopic adrenalectomy on the left and subtotal on the right. The anatomopathological evaluation showed bilateral adenomas (Weiss 1) being the immunohistochemistry of the right adrenal nodule diffusely positive for CYP11B1 and negative for CYP11B2, inferring only cortisol production. In contrast, left adrenal nodules were positive only for CYP11B2, inferring exclusive aldosterone production. However, we also found bilateral subcapsular cell clusters with positivity for CYP11B2. This may infer a possibility of hyperaldosteronism recurrence. The patient developed secondary adrenal insufficiency postoperatively, requiring replacement with hydrocortisone, and cure of hyperaldosteronism with normalization of potassium and release of renin. Six months after the operation, there was no need for antihypertensive drugs. Currently, it is using only one class of antihypertensive, amlodipine 5mg a day, and it still needs to be replaced with hydrocortisone 20mg on waking up and 10mg at 2 pm with still undetectable serum cortisol concentrations, despite the ACTH being unblocked (17.3 pg /ml). Now we are working on genetic background of this case report.
Presentation: No date and time listed
RF34 | PMON254 Why Does Androgens Fail to Promote the Survival of the Wolffian Duct in the Absence of Wnt9b?
Authors: Crossen McKenna , Jia Shuai , Zhao Fei 
Published: November 2022

Abstract
The male reproductive tract development has been predominantly dependent upon androgen action, which is mainly mediated by the androgen receptor (AR). Under the influence of androgen actions, the primitive male reproductive tract, also known as the Wolffian duct, is first stabilized then differentiates into the epididymis, vas deference and seminal vesicle. Impairment of androgen signaling during fetal programming causes a spectrum of male reproductive disorders that manifest in adulthood. Despite the dominant roles of androgen action in the male reproductive tract development, it has been noticed that androgen's capability in promoting Wolffian duct survival and development is completely lost in the absence of Wnt9b. Wnt9b belongs to the WNT family of secreted proteins. It is specifically expressed in the Wolffian duct epithelium to regulate the surrounding mesenchyme. This project aims to investigate why the androgen action fails to maintain the male reproductive tract in the absence of Wnt9b. We first examined the expression pattern of Wnt9b during the window of sexual differentiation, which was not investigated in the previous publication. We found that during sexual differentiation, Wnt9b is still specifically expressed in the Wolffian duct epithelium in both XX and XY embryos. Androgen action exists in XY but not in the XX embryos during sexual differentiation. These observations indicate that Wnt9b does not lie downstream of the androgen signaling. We are in process of collecting Wnt9b+/+ and Wnt9b-/- male embryos to examine whether expression of AR and AR downstream genes is altered in the absence of Wnt9b. In addition, WNT9B can activate two intracellular pathways under the context of target cells: β-catenin dependent and independent pathways. Since Wolffian duct mesenchyme is the major target of epithelium-derived WNT9B, we next determined which pathways WNT9B acts through in the mesenchyme by specific deletion of β-catenin in the Wolffian duct mesenchyme. Interestingly, the loss of β-catenin in the mesenchyme led to the partial degeneration of Wolffian ducts at the caudal region and cystic formations at the cranial region, the similar phenotypes observed in mesenchymal AR knockout male embryos. Taken together, our study demonstrates that the local WNT9B/β-catenin pathway provides the permissive signaling for androgen actions in Wolffian duct development.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.
RF34 | PMON276 The Effect of Gender Affirming Hormone Therapy (GAHT) on Non-Conventional Cardiovascular Risk Markers in Transgender Men: A Systematic Review
Authors: Moreira Allgayer Roberta Martins Costa , Gustavo da Silva Borba , Ramos Ramon Bossardi , Filho Ruy Silveira Moraes , Mara Spritzer Poli 
Published: November 2022

Abstract
The process of gender transitioning includes the employment of gender-affirming hormone therapy (GAHT) to attenuate gender dysphoria. Although considered relatively safe, there is still debate whether GAHT may increase the risk of cardiovascular disease (CVD) in transgender men (TM). Non-conventional subclinical cardiovascular (CV) risk markers, such as inflammation or coagulation markers, endothelial activity-related substances, and the use of ultrasound-assisted vascular function evaluation, may improve CV risk prediction in specific populations. Therefore, we conducted a systematic review to summarize the available findings regarding GAHT and its effects on these non-conventional cardiovascular risk markers in TM. Medline, LILACS, SCOPUS, and Embase databases were searched for cross-sectional, case-control, cohort, or randomized clinical trial studies published until July 2020. The selection criteria for the studies were as follows: ≥ 18 years old transgender male, no established CVD, using GAHT (androgens) for at least 2 months and compared with cis women or untreated transmen or before and during/after treatment for cohort studies. From 152 studies initially identified, 7 studies (3 cohorts and 4 case-control) were included in the systematic review. Some of these studies assessed different CV risk markers in the same group of participants. No changes were found in t-PA PAI-1, ICAMs, and PCR-us after 4 and 12 months of GAHT. Fibrinogen did not differ either in TM with or with no GAHT. Three studies evaluated flow-mediated-vasodilation (FMD) of the brachial artery. The only cohort study found no changes in FMD after 12 months of GAHT. One case-control study observed significant impaired FMD, and another one showed impaired FMD- after-nitroglycerin in transmen compared with cis women. One study reported increased homocysteine and higher carotid intima-media thickness (C-MIT) after 12 months of hormone use. Further, one study observed testosterone did not affect distensibility (DC) or compliance (CC) coefficient after 12 months, but the changes in fasting insulin levels were negatively associated with changes in the CC and DC. One study assessed the vascular function using brachial-ankle pulse wave velocity (baPWV) and observed a higher risk in TM with GAHT versus the untreated group. The results of the present systematic review suggest that GAHT may be associated with worse subclinical cardiovascular markers in TM. Further studies assessing long-term clinical follow-up of transgender men using GAHT could positively impact the prevention of CVD and management strategies for this population.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:00 p.m. - 1:05 p.m.
ODP444 The Effect of Glucocorticoid Therapy on Cardio-Metabolic Risk in Patients with Multiple Sclerosis
Authors: Brovkina Snezhana , Dzherieva Irina , Volkova Natalya , Davidenko Ilya , Reshetnikov Igor , Komurdzhyants Maria , Tishchenko Yulia 
Published: November 2022

Abstract

Multiple sclerosis (MS) often requires usage of glucocorticoids (GC). Excess of GC may affect muscles, which increases mortality. This study evaluates the effect of GC therapy on muscles and cardiovascular disease (CVD) risk factors in patients with MS.

Methods
45 patients (55.5% women), 37.8 (20-45) years, were examined. 51% of patients received GC (methylprednisolone 3000-5000 mg, 3-5 days). MS duration was 5.9±1.2 years, the assessment by EDSS - 3.3±1.2. Muscle tissue was assessed by bioimpedance analysis, a chair-rising test, dynamometry. Glucose and lipid metabolism, blood pressure (BP), body mass index (BMI), waist circumference (WC),physical activity were evaluated. Statistical analysis was carried out using "Statistica 10. 0". Normal distribution was tested by the Shapiro–Wilks test, p&gt;0. 05. А Mann-Whitney U-test, a t-test,χ2 test were used,p&lt;0. 05.

Results
Patients with GC had significantly higher BMI (28.56±5. 02 vs 22.87±3.49 kg/m2), WC (98 (66-123) vs 79.9±5.27cm), lower muscle mass (36.4 (35-38) vs 40.75±2. 02 kg). A negative correlation between GC dose and a grip strength of the dominant hand among men was noted (r=-0.88, p&lt;0. 0001). A normal WС was identified in 52% of patients. Comparing with others received GC, they had a lower level of low-density lipoproteins (1.35±0.39 vs 1.39(1-3,32) mmol/l), systolic BP (132.3±15.7 vs 141 (100-165)) and better handgrip strength (40 (25-47) vs 27±7.3 daN).

Conclusions
The negative effect of GC on cardiometabolic parameters in all patients with MS and muscle strength in men was confirmed. Metabolic healthier patients probably have a resistance to GC side effects, which may be determined genetically. It is promising for finding protective factors against GC.
Presentation: No date and time listed
OR07-2 Endocrine Response And Resistance Is Driven By Novel Transcriptional Co-Regulator Activity In Invasive Lobular Carcinoma Of The Breast
Authors: Costello James , Danis Etienne , Goodspeed Andrew , Mohammed Hisham , Sottnik Joseph , Sikora Matthew 
Published: November 2022

Abstract
Invasive lobular carcinoma of the breast (ILC) affects ∼40,000 US women annually and is a top ten most diagnosed cancer in women. ∼95% of ILC express estrogen receptor alpha (ER), but ILC is associated with poor long-term outcomes and anti-estrogen resistance, suggesting ER function is distinct in ILC cells. We reported that MDC1 (mediator of DNA damage checkpoint 1) is an ILC-specific ER co-regulator required for ER-driven proliferation, and that MDC1 knockdown dysregulates the ER transcriptome in ILC. Mechanisms of MDC1 co-regulator activity are unknown, but must be defined to understand endocrine response and resistance in ILC.
To understand MDC1 co-regulator functions, we profiled ER/MDC1 genomic binding (ie. "cistrome") using CUT&RUN in ER+ ILC cell line MDA MB 134VI (MM134). We identified ∼2500 binding sites each for ER and MDC1, but only ∼8% of sites were bound by both factors. However, using BETA to integrate cistrome and transcriptome data predicted that both ER and MDC1 activate estrogen-regulated genes with over half of direct ER target genes also direct MDC1 targets (p=9.8×10-375). Among shared ER: MDC1 direct target genes (n=760), 58% had MDC1 binding in the promoter region with ER bound at nearby enhancers, while only 15% were linked to shared ER: MDC1 binding sites, suggesting MDC1 primarily facilitates promoter access for ER-bound enhancers. Further, MDC1 knockdown reduced ER binding at enhancer sites at ER: MDC1 target genes, implicating MDC1 in regulating chromatin access.
Importantly, MDC1 does not have known enzymatic activity to directly regulate chromatin structure. We profiled MDC1-interacting proteins in ILC cells by RIME (Rapid immunoprecipitation mass spectrometry of endogenous proteins), and determined whether knockdown of putative ER: MDC1 partners disrupted ER function. This identified the SWI/SNF complex protein BRG1 (SMARCA4) as a critical ER: MDC1 partner. BRG1 was required for ILC cell growth, and BRG1 knockdown specifically suppressed ER regulation of MDC1-dependent ER target genes.
Taken together, our data suggest that in ILC cells, MDC1 facilitates ER access to and activity at target gene promoters. The BRG1 SWI/SNF complex is a putative ER: MDC1 partner and mediator of MDC1 co-regulator functions. Ongoing research is focused on understanding how MDC1 regulates ILC-specific ER activity by licensing access to ILC-specific target genes, and the role of the SWI/SNF complex in mediating genomic ER: MDC1 activity.
Presentation: Saturday, June 11, 2022 11:45 a.m. - 12:00 p.m.
OR26-2 mTOR Interacts with the Mineralocorticoid Receptor to Regulate its Activation by Ligand
Authors: Gomez-Sanchez Celso E , Gomez-Sanchez Elise P , Ali Yusuf 
Published: November 2022

Abstract

Background
Phosphorylation of the mineralocorticoid receptor (MR) at serine 843 inhibits its activity. mTOR phosphorylation of ULK1 prevents this MR phosphorylation.

Purpose
To study the relationship between mTOR and MR and its role in the modulation of aldosterone signaling.

Methods
Mouse cortical collecting duct M1 cells stably expressing the rat wild type MR or mutated MR (mu/S843A) and a Gaussia luciferase gene reporter under a hormone response promoter tyrosine aminotransferase (TAT) were incubated with mTOR activator and inhibitors in the presence and absence of aldosterone or corticosterone. Co-immunoprecipitation was performed to study protein interactions with the MR, and a phospho-serine antibody was used to demonstrate MR and ULK1 phosphorylation. Effects of mTOR knockdown in M1 cells by lentiviral transduction with CRISPR/gRNA for Raptor and Rictor were also studied.

Results
mTOR and the adaptor proteins of mTOR complex 1 and 2, Raptor and Rictor, respectively, co-precipitated with the MR of M1-rMR cells. Expression levels of these proteins were not changed by aldosterone. mTOR inhibitors significantly reduced ligand-induced MR reporter gene transactivation, however the mTOR activator MHY1485 had no effect. CRISPR/gRNA gene knockdown of Raptor or Rictor also inhibited MR activation stimulated by ligands, supporting a role of mTOR in maintaining the active MR. The mTOR inhibitor AZD8055 attenuated ligand-mediated MR gene transcription assessed by the reporter gene product and measurement of products of the endogenous MR target genes ACSBG1, LCN2 and Psca. AZD8055 also decreased phospho-ULK1 levels in a dose-dependent manner. We thus assumed that mTOR decreases ULK1 activity and prevents ULK1 phosphorylation of the MR at Serine (S843). Indeed, phosphorylation of the MR was increased in M1-rMR cells treated with AZD8055. However, AZD8055 still inhibited ligand-induced MR activity in cells carrying the mutated MR in which the Serine at 843 was replaced with an Alanine. These results suggest that mTOR has an additional role in MR activity unrelated to the specific phosphorylation at S843 by ULK1. This merits further investigation.
Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.
OR26-4 Glucocorticoid Receptor Expression and Signaling During Critical Illness, in Relation to the Duration of Illness and the Systemic Glucocorticoid Availability: A Prospective, Observational, Cross-Sectional Human and a Translational Mouse Study
Authors: Téblick Arno , Van Dyck Lisa , Van Aerde Nathalie , Vander Perre Sarah , Pauwels Lies , Derese Inge , Debaveye Yves , Wouters Pieter J , Vanhorebeek Ilse , Langouche Lies , Van den Berghe Greet 
Published: November 2022

Abstract
Critically ill patients are thought to develop maladaptive glucocorticoid-resistance which convinces many clinicians to administer stress doses of glucocorticoids to overcome this state of glucocorticoid-resistance. However, supportive data arises mainly from whole blood cells. It is currently not known if the observed changes in regulators and markers of glucocorticoid signaling and activity are also present in other cell and tissue types with a role in critical illness. We quantified regulators and markers of glucocorticoid signaling and activity in several cell and tissue types in critically ill humans and animals and in healthy controls. We found that throughout critical illness, glucocorticoid activity appeared suppressed in neutrophils, but upregulated in monocytes and skeletal muscle. Also in vital tissues GRα-signaling was altered in a tissue-specific, largely time-independent manner. Increasing systemic glucocorticoid availability increased glucocorticoid activity in adipose tissue, diaphragm and lung, whereas in immune cells and other tissues regulatory pathways counteracted. These data argue against glucocorticoid-treatable generalized glucocorticoid resistance and rather point towards an adaptive response in each specific cell or tissue type to optimally guide the beneficial actions of glucocorticoids to the tissues that need it while protecting collateral undesirable effects in tissue that are harmed by elevated systemic glucocorticoid availability.
Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.