bluuebunny/crossref_metadata_2025_split huggingface dataset:
12673 Epigenetic Subtyping Of Adrenocortical Carcinoma In Archival Material And Implications For Disease Evolution
Authors: Mohan D , Lerario A M , Almeida M Q , Mendonca B B , Latronico A , Fragoso M C , Hammer G D 
Published: October 2024

Abstract
Disclosure: D. Mohan: None. A.M. Lerario: None. M.Q. Almeida: None. B.B. Mendonca: None. A. Latronico: None. M.C. Fragoso: None. G.D. Hammer: None.
Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex, to date cured only by surgery. Pangenomic studies demonstrate that ACC is comprised of three molecular subtypes with distinct clinical outcomes. CIMP-high ACC, the most aggressive molecular subtype, is defined by abnormal epigenetic patterning including inappropriate DNA methylation. CIMP-high status of the primary tumor accounts for 30% of all ACC, but 70% of metastatic relapses. It remains unclear if ACC transitions molecular subtypes, e.g. acquires CIMP-high status, during metastatic dissemination. We and others have demonstrated that G0S2 methylation is a sensitive and specific single-locus biomarker capturing CIMP-high ACC. However, our prior studies utilized frozen tissues, often only available at specialized centers. Here, we measured G0S2 methylation in an expanded cohort of n=73 formalin-fixed paraffin-embedded (FFPE) primary, recurrent, and metastatic ACC samples. We show that G0S2 methylation status is stable in archival FFPE material, concordant with measurement in frozen specimen (Pearson r=0.94, n=28). We identify that, within individual patients, the G0S2 methylation status of the primary is often preserved in the metastasis or recurrence. These data suggest that ACC subtype switching is not required for metastatic evolution. In cases of advanced ACC with accessible lesions amenable to biopsy, epigenetic subtypes can be diagnosed prior to oncologic resection, enabling subtype-specific therapeutic interventions in the neoadjuvant setting.
Presentation: 6/1/2024
8474 SOX11 mutations cause hypogonadotropic hypogonadism through both hypothalamic and pituitary level deficits
Authors: Sun Bang , Stockman Sara , Stamou Maria , Plummer Lacey , Salnikov Kathryn , Kotan Damla , Topaloglu Kemal , Seminara Stephanie Beth , Balasubramanian Ravikumar 
Published: October 2024

Abstract
Disclosure: B. Sun: None. S. Stockman: None. M. Stamou: None. L. Plummer: None. K. Salnikov: None. D. Kotan: None. K. Topaloglu: None. S.B. Seminara: None. R. Balasubramanian: None.
AbstractPurpose: Human SOX11 mutations cause Coffin-Siris Syndrome (CSS) which is clinically characterized by aplasia or hypoplasia of the distal phalanx/nail of the fifth digit, developmental delay, cognitive impairment, and distinctive facial features. Recent studies show hypogonadotropic hypogonadism (HH) occurs in ∼20% of patients with SOX11 mutations. The genotypic-phenotypic spectrum of SOX11 mutations in patients presenting with Idiopathic Hypogonadotropic Hypogonadism (IHH) is unknown. Methods: Exome sequencing data from 1810 unrelated IHH probands (anosmic and normosmic forms) were reviewed for SOX11 rare sequence variants (RSVs) [minor allele frequency &lt;0.1%]. Rare variant association analysis (RVAS) and domain-based enrichment for SOX11 RSVs was performed between the IHH and gnomAD population cohort. RSVs predicted as pathogenic/likely pathogenic by ACMG criteria were deemed as pathogenic RSVs and detailed phenotypic analysis was undertaken for these variants. Results: A total of 4 pathogenic SOX11 RSVs were identified in 5 IHH cases. RVAS analysis showed that SOX11 inactivating RSVs (frameshift/non-sense) across the entire protein was enriched in the IHH cohort (2 RSVs in 3 IHH cases (p.S303X [de-novo]; p p.S345Afs*13); p&lt;0.0001) while SOX11 missense RSVs was enriched only within the SOX11-HMG domain (2 RSVs in 2 IHH cases (p.G84D [de-novo]; p.P114S; p=0.003). Phenotypic review of individuals with pathogenic SOX11-RSVs revealed a spectrum of endocrine defects including: anosmic and normosmic forms of IHH, growth-hormone (GH) deficiency, neuroimaging defects (pituitary microadenoma and hypothalamic mass), and hypothyroidism. Additionally, we also identified a pathogenic SOX11 HMG domain RSV in a patient with functional HH (p.R100Q). CSS-associated features were present in almost all individuals with pathogenic SOX11 RSVs. Conclusions: This study validates SOX11 mutations as causal for IHH and reiterates the critical importance of the SOX11-HMG domain in disease pathogenesis. The spectrum of endocrine abnormalities in SOX11-related human disorders includes IHH, functional HH, GH deficiency, pituitary lesions, and hypothyroidism. The association of congenital anosmic and normosmic forms of IHH, functional HH, and anatomic abnormalities of the pituitary gland suggest that the pathogenesis of HH in SOX11-disorder may stem from both hypothalamic and pituitary level deficits.
Presentation: 6/1/2024
7895 The accumulation of p63 in oocyte of primordial follicle is essential for triggering apoptosis following cisplatin treatment
Authors: Abazarikia A , So W , Kim S Y 
Published: October 2024

Abstract
Disclosure: A. Abazarikia: None. W. So: None. S. Kim: None.
Background: Women are born with a finite supply of primary oocytes housed in the ovaries, commonly known as the ovarian reserve, which represents their reproductive lifespan. The ovary serves as a crucial organ for production of oocytes and endocrine hormones, including 17β-estradiol and progesterone. However, chemotherapy inevitably leads to the depletion of the ovarian reserve, resulting in primary ovarian insufficiency (POI), which manifests as endocrine dysfunction and infertility. Within the oocytes of primordial follicles, the p63 protein is highly expressed as an inactive, dimeric form, playing a pivotal role in responding to DNA damage, thereby determining the fate of the oocytes. It is well-established that p63 undergoes activation through hyperphosphorylation and a conformational shift to a tetrameric structure. This activation subsequently triggers apoptosis by inducing the expression of proapoptotic genes. Hypothesis: Different chemotherapeutic agents may exhibit distinct mechanisms in the theregulation of p63 in oocytes. Methods: Postnatal day 5 CD-1 mice were utilized in the experimental groups, comprising control (Ctr), CDDP (cisplatin), CHX (cycloheximide), and PYR-41 (a Ubiquitin-Activating Enzyme E1 Inhibitor). We assessed the number of ovarian primordial follicles, the expression of p63, DNA double-strand breaks (DSBs), and apoptosis through immunoblotting and immunofluorescence assays. Additionally, p63 conformation was examined using Native PAGE Gel. Statistical differences were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's post-hoc test, with significance defined as a p-value less than 0.05. Results: Treatment with CDDP significantly increased p63 levels in oocytes (p&lt;0.05). The combined administration of PYR-41 with CDDP induced a further substantial increase in p63 levels (p&lt;0.001) compared to CDDP treatment alone. Conversely, p63 expression was significantly decreased (p&lt;0.01) with CHX treatment, falling below the levels observed in the CDDP group. Notably, CHX appeared to protect ovarian follicles from the adverse effects of CDDP, as evidenced by the decreased levels of ɣH2AX, cleaved PARP, and PUMA, which is a known target gene of p63 in oocytes. Conclusion: Therefore, our findings strongly indicate that the accumulation of p63 represents the initial step in oocytes preceding CDDP-induced oocyte death, which is subsequently followed by hyperphosphorylation, tetramerization, and degradation of p63. Significance: Comprehending the mechanism behind cisplatin-induced oocyte death will contribute to the development of effective adjuvant therapies aimed at preserving ovarian reserve in young female cancer survivors undergoing CDDP treatment.
Presentation: 6/2/2024
8610 The Role of Adenylyl Cyclase 2 Gene-Dosage Changes in Congenital Male Genitourinary Anomalies
Authors: Lamb D J , O’Neill M A 
Published: October 2024

Abstract
Disclosure: D.J. Lamb: Advisory Board Member; Self; Ro Health, Inc. Stock Owner; Self; Fellow Health, Inc. M.A. O'Neill: None.
Collectively, congenital genitourinary (GU) birth defects are the most common birth defects in males, yet relatively little is known about their cause. In part, this reflects the current clinical perspective that, because most of these birth defects can be surgically repaired, there is nothing to be gained by understanding the cause. Yet our studies show that seemingly simple birth defects like hypospadias or cryptorchidism, may be associated with other more significant underappreciated defects, such as those affecting the kidney, heart, eyes or behavior. We tested the hypothesis that chromosome microdeletions and microduplications (called copy number variations, CNVs) result in gene-dosage changes that are important regulators of GU development and when haploinsufficient or duplicated normal genitourinary development is impacted causing birth defects of the upper and/or lower genitourinary tract. We successfully used this strategy to identify 15 different previously unrecognized genes that when microduplicated or microdeleted result in conditions such as cryptorchidism, hypospadias, disorders of sexual differentiation (DSD) and other anomalies. Remarkably, gene-dosage changes affected major signaling pathways and post-translational modifications in novel, previously unrecognized ways. Herein, we focused on defining the role of a candidate gene commonly microdeleted or microduplicated in patients with cryptorchidism, hypospadias and/or micropenis. Locus mapping allowed identification of adenylate cyclase 2 (ADCY2) as a candidate gene at the 5p15.31 Cri-du-Chat region in patients with male genital tract anomalies. ADCY2 CNVs were more common in non-syndromic patients with micropenis, cryptorchidism, and/or hypospadias (1.6%) than the general population (0.07%; p&lt; 0.001). Whole exome sequence studies revealed a range of phenotypic anomalies in patients with damaging and potentially damaging ADCY2 variants in addition to the male GU anomalies, including congenital anomalies of the kidney and urinary tract. It is our hypothesis that ADCY2 duplications result in a de-sensitization of the LH receptor diminishing testosterone biosynthesis in the testis, whereas deletions diminish LH receptor signaling. ADCY2 CNVs were assessed in 100 men with spermatogenic failure who were born with cryptorchidism. The ADCY2 CNV frequency was the same as in our cohort of boys with GU anomalies, but as adults they also have hypergonadotropic hypogonadism, which we predicted if ADCY2 over-expression was impacting adult Leydig cell steroidogenesis through partial desensitization of the LH receptor. These studies identified an unrecognized cause of GU anomalies. In the future, such knowledge may lead to improved diagnosis and therapeutic approaches to ameliorate these common birth defects.
Presentation: 6/2/2024
8622 The Severity of Vasomotor Symptoms Is Associated With Metabolic Dysfunction Associated Liver Disease (Masld) in Peri- AndPostmenopausal Women
Authors: Armeni E , Augoulea A , Karagkouni I , Avgousti I , Charamanta M , Stergiotis S , Lambrinoudaki I 
Published: October 2024

Abstract
Disclosure: E. Armeni: None. A. Augoulea: None. I. Karagkouni: None. I. Avgousti: None. M. Charamanta: None. S. Stergiotis: None. I. Lambrinoudaki: None.
Introduction: Reproductive aging and ovarian senescence are associated with accelerated accumulation of cardiometabolic risk factors, but also progressively increasing risk for cardiovascular disease (CVD). Metabolic-dysfunction-associated steatotic liver disease (MASLD) is linked with a higher risk for CVD. The prevalence of MASLD with regards to reproductive aging, and the possible link with vasomotor symptoms has not been evaluated yet Methods: For the purpose of this cross-sectional study, we evaluated 106 peri- and postmenopausal women, retrieved from the outpatient Menopause clinic of the Second Department of Obstetrics and Gynecology, University of Athens, Aretaieio Hospital, Athens, Greece. The extent of steatotic liver disease (SLD) was estimated as values of the fatty liver index; using the known cut-off ≥ 60 for higher risk for SLD. MASLD was defined as the presence of ≥1 of the following risk factors in a woman with hepatic steatosis: 1) body mass index (BMI) ≥25 kg/m2 or waist circumference ≥85 cm; 2) fasting glucose ≥100 mg/dL or type 2 diabetes or hypoglycemic treatment; 3) blood pressure ≥130/85 mmHg or antihypertensive treatment; 4) triglycerides ≥150 mg/ dL or related treatment; and 5) high-density lipoprotein cholesterol ≤40 mg/dL or lipid-lowering treatment. The severity of vasomotor symptoms (VMS) was assessed using the Greene Climacteric Scale. Results: Moderate-to-severe VMS were evident in 42 women of our sample while 64 women had no-to-mild severity of VMS. Logistic regression analysis showed that moderate-to-severe VSM, as opposed to no-to-mild symptoms, were associated with MASLD (MASLD rates, moderate-to-severe VSM vs no-to-mild: 26.2% vs 12.5%, p-value=0.072; OR = 3.022, p-value =.041). This association became even stronger when we restricted the sample to early postmenopausal women (up to 5 years after the final menstrual period, N=57, VMS no-to-mild vs moderate-to-severe, 3.6% vs 24.1%, p-value = 0.025; OR=9.333, p-value=0.045). The models were adjusted for age, physical exercise, alcohol intake, current smoking, history of menstrual irregularity, and HRT use. Conclusion: The results of this study indicate that the severity of vasomotor symptoms is associated with the diagnosis of MASLD in midlife women, irrespective of the use of HRT. These observations underscore the importance of cardiovascular risk assessment in women with bothersome vasomotor symptoms.
Presentation: 6/3/2024
12465 Unraveling The Enigma: A Multifaceted Presentation Of Hormonal Dysregulation In A 37-year-old Woman
Authors: Rizvi Syeda Yumna , Jones Krister J , Ahmad Nazish 
Published: October 2024

Abstract
Disclosure: S.Y. Rizvi: None. N. Ahmad: None.
Title: Unraveling the Enigma: A Multifaceted Presentation of Hormonal Dysregulation in a 37-Year-Old Woman Background: Leydig cell tumors (LCTs) are rare gonadal tumors, arising from the interstitial cells of the testis or, less commonly, the ovary, 0.1%. These tumors are known for their potential to produce androgens, leading to virilization symptoms such as hirsutism. While LCTs are typically benign, they can occasionally exhibit malignant features. Accurate diagnosis and appropriate management are crucial to prevent complications and ensure favorable outcomes. Clinical Case: A 37-year-old, G3P3A0 woman, presented to our endocrinology clinic for a follow-up visit following the removal of a malignant thyroid nodule. During the visit, her endocrinologist noted elevated testosterone levels and worsening hirsutism. She reported mild abdominal pressure but denied other symptoms. She also complained of pain in the lower abdomen, although physical examination findings were limited due to type II obesity. Diagnostic investigations revealed a history of imaging studies, including CT scans and pelvic ultrasounds, demonstrating various findings such as a fibroid uterus, ovarian abnormalities, and a heterogeneous mass in the left adnexa. Laboratory evaluations over time showed fluctuations in androgen levels, with notable values including DHEA-sulfate (137.5 ug/dL), total testosterone (309.6 NG/dL), and free testosterone (12.85 NG/dL). Tumor markers, including CA 19-9= 16 U/mL, CA 125= 23.3 U/mL, CEA = 1.7 NG/mL, and HCG, were unremarkable. Gynae/Oncology was consulted, and she underwent surgical exploration with laparoscopic left oophorectomy. It revealed a Leydig cell tumor without overt malignant features, as confirmed by histopathological examination and immunohistochemical analysis. Her testosterone improved since oophorectomy. Patient undergoes frequent post-op follow up of her testosterone, free+total lc/MS to monitor for hyperandrogenism. Conclusion: This case highlights the importance of considering Leydig cell tumors in the differential diagnosis of hirsutism, particularly in the presence of elevated androgen levels. Multidisciplinary collaboration involving endocrinologists, gynecologists, oncologists, radiologists, and pathologists is essential for accurate diagnosis and optimal management. Surgical resection remains the cornerstone of treatment for Leydig cell tumors, with careful histopathological evaluation necessary to assess for potential malignancy. Long-term follow-up is warranted to monitor for recurrence or metastasis, although the prognosis for benign Leydig cell tumors is generally favorable. Patients with large body habitus may present challenges in physical examination, necessitating reliance on imaging and laboratory studies for diagnostic evaluation. Keywords: hirsutism, testosterone, ovary
Presentation: 6/2/2024
12604 Use Of A Novel Program "WordMiner" To Identify Cellular Proliferation Related Genes Induced In FSTL3 KO Mouse Testis
Authors: Mukherjee Neelkantha , Ballesteros Randy , Mukherjee Abir 
Published: October 2024

Abstract
Disclosure: N. Mukherjee: None. R. Ballesteros: None. A. Mukherjee: None.
TGFβ family ligands play crucial roles in promoting cellular proliferation. Moreover, activin and TGFβ are linked with cancer. Deletion of FSTL3, an inhibitor of a subset of TGFβ ligands, in mice leads to increased proliferation in all tissues investigated including the testis. We also find increased SMAD2/3 activation in FSTL3 knockout (KO) compared to wildtype (WT) in these tissues. Therefore, the FSTL3 KO mouse is a model of increased activity of endogenous TGFβ ligands that are inhibited by FSTL3, such as activin. It is likely that increased signalling by these ligands leads to the observed increased cellular proliferation in FSTL3 KO mice. To discover genes that might be involved in activin-dependent mitosis, we studied gene expression datasets linked to cellular proliferation. We hypothesised that genes important in cellular proliferation will be downregulated in senescent cells and upregulated in models of increased cellular proliferation and activin action such as the FSTL3 KO mice. We queried GEO datasets to identify studies related to senescence and selected Hutchinson-Gilford progeria syndrome (HGPS): fibroblast (HG-U133A), GSE3860. We found 4048 transcripts showing significantly (p&lt;0.05) altered expression in HGPS fibroblasts compared to WT. We developed a Python-based program, “WordMiner”, that inputs a keyword and a list of terms (e.g. genes) and then searches a specified database sequentially for publications including the keyword and each term. The output is a table of search result frequencies and hyperlinks to the search result pages, compiled in an auxiliary file, produced with greater speed and efficiency than manual search methods. The greater the search result frequency, the stronger the known link between the keyword and the term. We used WordMiner to query the association of the search term “mitosis” with the 4048 genes above using PubMed as the database and identified 1235 transcripts. We refined this list further using the keyword “activin” to identify 420 transcripts linked to activin and mitosis. Importantly, by comparing against our RNAseq data, we find 20 of these genes upregulated in the FSTL3 KO postnatal day 3 transcriptome. This finding supports our hypothesis, and also demonstrates WordMiner as an efficient and versatile cross-referencing query tool. Among the 20 genes identified are transcripts known to be important in proliferation, such as Akap9 and Wnt2b. These and the remainder in the list of genes highlighted are therefore likely to be involved in pathways induced by activin, promoting cellular proliferation in FSTL3 KO testis. Currently, siRNA transfection experiments are underway to address whether knockdown of these genes in a Sertoli cell line (TM4) limits proliferation. This will help in the elucidation of the molecular pathways involved in postnatal Sertoli cell proliferation.
Presentation: 6/3/2024
7963 Analysis of the inhibition of adrenal synthesis and peripheral metabolism of corticosteroids by oteseconazole and two preclinical tetrazole antifungals
Authors: Jäger Marie-Christin , González-Ruiz Víctor , Joos Friedrich L , Winter Denise V , Boccard Julien , Degenhardt Thorsten , Brand Steve , Rudaz Serge , Thompson George R , Odermatt Alex 
Published: October 2024

Abstract
Disclosure: M. Jäger: None. V. González-Ruiz: None. F.L. Joos: None. D.V. Winter: None. J. Boccard: None. T. Degenhardt: Employee; Self; Mycovia Inc. S. Brand: Employee; Self; Mycovia Inc.. S. Rudaz: None. G.R. Thompson: None. A. Odermatt: None.
The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia by blocking adrenal cortisol synthesis and its peripheral inactivation [1]. Mechanisms of pseudohyperaldosteronism include inhibition of adrenal cytochrome P450 enzymes CYP11B1 and CYP17A1, as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazole compounds have been developed [2]. Here, we used adrenal H295R cells and enzyme activity assays to assess the inhibition of steroidogenesis by the tetrazoles oteseconazole, VT-1129 and VT-1598. In addition, the three tetrazoles were tested for inhibition of 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted LC-HRMS with steroid annotation indicated common features of the oteseconazole and VT-1129 patterns with that of the triazole itraconazole, and similarities between VT-1598 and the triazole isavuconazole. Targeted quantification of nine adrenal steroids by UHPLC-MS/MS in supernatants of treated H295R cells showed an overall inhibition of steroidogenesis by the tetrazoles and the triazoles itraconazole and isavuconazole. Experiments using recombinant human enzymes suggested that this effect is not caused by direct inhibition of steroidogenic enzymes because no or very weak inhibition could be observed. Furthermore, oteseconazole, VT-1129 and VT-1598 did not inhibit 11β-HSD2, suggesting that they unlikely cause pseudohyperaldosteronism. Further research needs to uncover the exact mechanism for the observed overall inhibition of steroidogenesis by the tetrazoles as well as itraconazole and isavuconazole, and whether concentrations reached in patients are high enough to cause adrenal insufficiency and hyperplasia. References: [1] Beck K. R. and Odermatt A. 2021, Mol. Cell. Endocrinol., 524, 111168. [2] Gintjee T. J., Donnelley M. A. and Thompson G. R. III 2020, J. Fungi, 6.
Presentation: 6/2/2024