bluuebunny/crossref_metadata_2025_split huggingface dataset:
RF28 | PSUN301 Sex Differences in the Indolepropionic Acid Alterations in Response to Obesity Surgery
Authors: Silva Thaís R , Mara Spritzer Poli , Tuomainen Marjo , Sehgal Ratika , Pihlajamäki Jussi , de Mello Vanessa D 
Published: November 2022

Abstract

Introduction
Obesity surgeries improve type 2 diabetes (T2D) in most cases, with effects frequently evident before substantial weight reduction. Therefore, this study hypothesizes that the increase in indolepropionic acid (IPA), a gut-derived tryptophan metabolite considered to be a potential biomarker for the development of T2D, might contribute to the metabolic benefits occurring after obesity surgery. Since sex impacts the pathogenesis of numerous diseases, including T2D, our objective was to investigate sex-specific effects on the changes in IPA in response to obesity surgery.

Methods
One-hundred and twenty-one obese individuals (36 males and 85 females; age 48.4 ± 9.4 years; BMI 42.9 ± 5.3kg/m2) participants from the ongoing Kuopio OBesity Surgery (KOBS) Study, who were accepted for Roux-en-Y gastric bypass (RYGB) were included. Serum samples drawn after 12h fasting were available from both baseline and 1-year follow-up visits for measuring IPA by LC-QQQ-MS. Impaired fasting glucose (IFG) was defined as a fasting glucose level ≥5.6nmol/L.

Results
Male and female participants had similar ages, BMI and IPA [93.2 (44.3–137.8) vs 67.0 (44.6–113.8) ng/dL, P=0.444, males and females respectively) at baseline. Weight loss after 1 year of RYGB was lower in males in comparison with females (19.8 vs 23.5%, P=0.014). A significant interaction between time and sex on IPA changes was found during the first year of RYGB (P=0.028). We observed an increase in IPA in females but not in males, especially in the youngest female group (median age &lt;48.7 years). Fasting insulin interacted significantly with sex on the changes in IPA (P&lt;0.001), but not fasting glucose (P=0.962). In addition, females had lower prevalence of IFG at 1-year (25 vs 57%, P=0.042, female and male participants respectively), which was associated with changes in IPA independently of weight loss.

Conclusion
Our results suggest that changes in IPA concentrations may be associated with beneficial changes in glucose metabolism observed after obesity surgery in females. A comprehensive understanding of the sex-specific effects of the IPA could contribute to future non-surgical treatments for T2D.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.
PMON13 The Effects of Perfluorooctanesulfonic Acid (PFOS) on the Expression of Estrogen Receptor Alpha (ERα) and Tumor Suppressor Gene BRCA1 in Breast Cancer Cells
Authors: Hallman Erin , Farrar Katelyn , Whittaker Kaylin , Pfiffner Samantha , Zanib Aisha , Dinda Sumi 
Published: November 2022

Abstract
Perfluoroctanesulfonic Acid (PFOS) is a perfluorinated chemical (PFC) and endocrine-disrupting compound (EDC) found in fire-extinguishing foams, food packing, and commonly used household products such as nonstick cookware and cleaning products. PFOS is also an environmental toxicant that has polluted air, soil, and water in past years. Few studies have suggested PFOS may cause endocrine-disrupting effects, therefore it is critical to explore the effects of PFOS on breast cancer cells. This study examined the estrogenic-like effects of PFOS, alone and in combination with hormones and antihormones, on the expression of ERα and BRCA1 in T-47D and MCF-7 breast cancer cell lines by utilizing western blot analyses, cellular viability assays, confocal microscopy, apoptosis assay and RT-qPCR analyses. The cells were cultured with 5% charcoal-stripped fetal bovine serum (FBS) for six days to deplete endogenous steroids or growth factors. In the concentration-dependency study, cells were treated with various concentrations of PFOS (300µM-800µM) for 24 hours. Western blot analysis revealed alterations in the expression of ERα and BRCA1 related with these varying concentrations of PFOS (300 µM-800µM). In comparison to the control, a concentration-dependent decrease of ERα expression levels were seen in both cell lines. A concentration-dependent increase of BRCA1 was seen in both cells. Western blot analysis revealed the optimal concentration of PFOS to be 700 µM in cells, which exhibited the maximal estrogenic-like effect. To further examine the effects of PFOS on breast cancer cells, the optimal concentration (700 µM PFOS) was then used alone and in combination with hormones and anti-hormones in T-47D cells. Treatment with PFOS, E2and the combination of PFOS and E2 for 24 hours showed a significant down-regulation of ERα in T-47D cells when compared to the control. Treatment of PFOS with antiestrogen ICI revealed a significant down-regulation of ERα (approximately 50%) in T-47D cells. Image cytometric analysis with propidium iodide staining was utilized to examine the effects of PFOS on cellular viability in T-47D cells. PFOS alone and in combination with E2 revealed an increase in cellular proliferation compared to the control in T-47D cells and these effects were sensitive to the presence of antiestrogens. RT-qPCR studies revealed a transcriptional expression of ESR1 and BRCA-1 mRNA levels that correlate with the translational data obtained via western blot analyses. Cytolocalization experiments and effects of PFOS with hormones and antihormones on MCF-7 cells studies are in progress. Our studies provide exciting leads to clearly delineate the molecular mechanisms of PFOS as an EDC on the steroid receptors and tumor suppressor gene in breast cancer cells.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP610 Assessing ABO and Rh Blood Group as a COVID-19 Risk Factor
Authors: Heard Madeleine , Kim Luna , Comite Florence 
Published: November 2022

Abstract

Objective
Precision medicine harnesses the N-of-1 approach to detect, predict, reverse, and stop progression of disorders of aging through longitudinal observation of biomarkers with respect to genetic makeup. ABO and Rh blood group are two genetic markers that inform risk for dysglycemia, hypercortisolemia, and hypothyroidism, among others. Early in the pandemic, scientists sought to understand whether ABO and Rh blood group was also a risk factor for COVID-19 susceptibility. If proven true, the presence of mutual disease mechanisms between COVID-19 and diseases of the endocrine system may also exist. In the present study, ABO and Rh blood group was examined as a risk factor for COVID-19 susceptibility.

Methods
Inclusion criteria for this retrospective observational study were an active patient status in December 2019 and a record of ABO and Rh blood group on Quest Laboratory's online portal. ABO and Rh blood groups were compiled and analyzed using chi-square test, odds ratio (OR), and 95% confidence interval (CI) for association to COVID-19 susceptibility.

Results
136 adult patients met inclusion criteria for this study, 44 of whom tested positive for COVID-19. The cohort was 30% female, ranging in age from 20-78 years (mean=54 years). In the COVID-19 patients, the respective frequencies of A, B, O, and AB phenotypes were 27.27%, 25. 00%, 38.64%, and 9. 09%. Of these patients, 88.64% were Rh positive. Blood group A (OR = 0.70; CI, 0.32-1.5; p &gt; . 05), group B (OR = 1.58; CI, 0.66-3.78; p &gt; . 05), group O (OR = 0.78; CI, 0.38-1.63, p &gt; . 05), and group AB (OR = 2.97; CI, 0.63-13.9; p &gt; . 05) were not significantly associated with COVID-19 susceptibility. Rh factor was also found to be an insignificant variable (OR = 2. 03; CI, 0.70-5.85; p &gt; . 05).

Discussion
These findings support the growing body of literature dissociating ABO and Rh blood group from COVID-19 susceptibility. As such, it could be advised that ABO and Rh blood group is not factored into risk stratification for COVID-19 susceptibility in contrast to particular endocrine disorders. A significant limitation of this analysis is that ABO genotypes were unknown. A recent genome-wide association study confirmed a potential involvement of ABO blood group in COVID-19 clinical presentation1. Therefore, deeper analysis may also reveal the mechanistic influence of ABO genotypes on COVID-19 susceptibility, such as the type and quantity of ABO-antibodies in circulation. Further investigation is warranted to determine whether biomarkers known to inform risk of endocrine disorders also influence COVID-19 susceptibility. Understanding what governs this relationship would allow endocrinologists to develop targeted interventions to optimize an individual's health trajectory. References: 1. The Severe Covid-19 GWAS Group. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. NEJM 2020;383: 1522-1534.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
OR08-2 Functional Association of the Stem Cell Protein Musashi With LSM14B in Control of mRNA Translation
Authors: Banik Jewel , Bronson Katherine , Childs Gwen , Hardy Linda , Lim Juchan , MacNicol Melanie , MacNicol Angus 
Published: November 2022

Abstract
The Musashi RNA-binding protein functions as a gatekeeper of cell maturation and maintains stem cell plasticity by regulating the translation of target mRNAs. The adult anterior pituitary tissue expresses a high level of Musashi and also demonstatres a high level of cell plasticity, indicating a Musashi-dependent function in maintaining endocrine homeostasis in the anterior pituitary. Towards understanding the mechanism(s) by which Musashi functions to control cell plasticity, we have identified co-associated proteins necessary for Musashi function. The two Musashi isoforms (Musashi1 and Musashi2) are conserved across species and are structurally characterized by two N-terminal RNA-recognition motifs (RRMs, that associate with specific sequences in the 3' untranslated region of mRNAs targets) and a disordered C-terminus. Musashi uses these domains to selectively repress, or to activate, mRNA translation in a manner specific to target mRNA and cell context. Both Musashi isoforms contain two C-terminal regulatory serine residues that require phosphorylation to enable mRNA translational activation. However, the Musashi proteins do not have inherent mRNA translation function and utilize co-associated protein complexes to mediate mRNA translation. We have previously identified Musashi1 binding protein partners through mass spectrometry. Here, we have identified the protein interactions that are required for Musashi1-dependent translational activation. Knockdown of target protein levels in Xenopus laevis oocytes indicated that the PABP4, CELF2, LSM14A/B, ELAVL1, ELAVL2, ELAVL4, and PUM1 proteins are required for Musashi target mRNA translational activation. We further determined that the effect of LSM14A/B dual knockdown was in fact specific to LSM14B alone. LSM14B is an RNA-binding protein that is required for RNA granule formation, RNA transcript metabolism, and mRNA translation. Studies in mouse oocytes have shown that LSM14B is required to maintain transcript levels of the Musashi1 target Cyclin B1 (Ccnb1) mRNA prior to mRNA translation. In the adult murine pituitary, LSM14B is ubiquitously expressed in both hormone-producing cells and in stem cells as indicated through single cell RNA sequencing. These findings indicate that LSM14B and Musashi1 may function cooperatively to regulate pituitary hormone production and cell differentiation in response to changes in physiological demand.
Presentation: Saturday, June 11, 2022 11:45 a.m. - 12:00 p.m.
OR08-3 Untargeted Nuclear Receptor-Wide Screening reveals Novel Ligands From the Brain and Gut.
Authors: Campbell Jhenielle , Cummins Carolyn , Krause Henry , Liu Jiabao , Main Sridhar , Malekoltojari Ainaz , Navarre William , Peng Hui , Sahin Cigdem , Krause Henry 
Published: November 2022

Abstract
The 48-member family of human nuclear receptors (NRs) plays major roles in metabolic homeostasis, immunity, and inflammatory responses, largely under the control of small lipophilic molecule interactions. A critical barrier precluding major breakthroughs in the discovery of new metabolic ligands is a lack of new methods that allow comprehensive mining of the natural metabolome, most of which remains uncharacterized in terms of identity and function. To address this challenge, our group has developed and optimized an NR pulldown and untargeted metabolomics pipeline that can identify novel NR ligands from various complex mixtures, including tissues, fecal samples, microbiotic cultures, environmental waste and compound libraries. In a first proof of concept screen using brain extracts, a novel omega-3 fatty acid ligand was identified using PPARα as bait. 7(S)-HDHA was selectively isolated despite the presence of other more abundant previously published PPARα ligands. Mass spectrometric detection of 7(S)-HDHA in mouse and rat brain, time-resolved FRET analyses, and thermal shift assay results collectively show that 7(S)-HDHA is the strongest activator and highest affinity natural PPARα ligand identified to date. We also show that 7(S)-HDHA activation of PPARα in cortical neurons effectively stimulates neuronal growth and arborization, key measurements of synaptic capacity in neurons. Since many NRs are expressed in or near the gut, and the interplay between NRs and gut-derived metabolites is largely unaddressed, we have since focused the majority of our efforts on intestinal and microbiome extracts. Dozens of new ligands for xenobiotic-sensing receptors have been identified, including fatty acid, phytoestrogen, peptide, and secondary bile acid, with identities soon to be made available in a public database. A subset will be pursued in-house or with collaborators to identify bacterial sources and receptor-based outcomes. Examples of new PPARα, CAR, PXR, and/or RORα ligand-NR interactions and outcomes will be presented. These discoveries will facilitate new directions for drug development, nutritional supplements and probiotic therapies for the prevention and treatment of a wide spectrum of diseases.
Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.
OR22-1 Temporal And Spatial Cellular Heterogeneity Of Hepatocyte Metabolism
Authors: Landgraf Austin , Okada Junichi 
Published: November 2022

Abstract
Gene expression plays a pivotal role in the long-term regulation of gluconeogenesis and lipogenesis in the liver. Although most of the previous studies were analyzed as a whole liver, it is known that hepatocytes across the liver display specific aspects of liver function in a zonation dependent manner. Using a combination of single-cell RNA sequencing (scRNA-seq) and single molecule Fluorescence In Situ Hybridization (smFISH) technologies, we examined several novel molecular and cellular aspects of the normal regulation of hepatocyte metabolic gene expression during the transitions from the fed to fasted, and subsequent starvation states in male C57BL/6J mice. Targeted scRNA-seq was used to quantitively analyze the temporal and spatial differences of gluconeogenic and lipogenic genes following a post-prandial time course. Initially, in the fed state lipogenic genes (such as Fasn) were highly expressed in both the periportal (PP) and pericentral (PC) hepatocytes that were rapidly turned off as the mouse entered the fasted state. In contrast, gluconeogenic genes (such as Pck1) were expressed in a subset of PP hepatocytes in the fully fed state. As the mouse entered the fasted state gluconeogenic genes became activated primarily in the PP hepatocytes. However, as the mouse enters a starvation state the PC hepatocytes also increase their expression of gluconeogenic genes. Analyses by smFISH not only confirmed the scRNA-seq data but is also applicable to determine the spatial context in the native liver tissue as well as analyzing the transcriptional regulation of gluconeogenic and lipogenic genes at the single molecule resolution. In the fed state, few PP hepatocytes expressed gluconeogenic transcription sites (TS), and during a fasted time-course, over time the TS expanded outwards to the PC hepatocytes. On the other hand, lipogenic TS were expressed in both PC and PP hepatocytes in the fed state, but during a fasted time-course, TS were not detected. In summary, these data suggest that hepatocyte zonation of gluconeogenic genes is dynamic and can vary substantially depending upon the fasted and fed states. Understanding the regulation of the liver hepatocyte normal physiology will provide the molecular basis for which we can more precisely determine the dysregulation that occurs in states of insulin resistance.
Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.
OR22-6 Ovarian Cancer Cell Glucocorticoid Receptor Activity Is Associated With Cytokine Secretion Promoting Infiltration of Immunosuppressive Cells Into the Tumor Microenvironment
Authors: Taya Manisha 
Published: November 2022

Abstract
Immunosuppressive cells abundantly infiltrate tumors during cancer progression. Notably, immunosuppressive myeloid-derived suppressor cells (MDSCs) have recently been identified as a heterogeneous cell population that expand during tumor-associated inflammation and are significantly increased in the tumor, peripheral blood, as well as ascites of ovarian cancer patients. MDSCs contribute to tumor immune tolerance via inhibition of T-cell proliferation and activation. Signals from the tumor microenvironment in the form of soluble cytokines are proposed to lead to MDSC infiltration. It is also known that high tumor cell glucocorticoid receptor (GR) expression is associated with a relatively poor prognosis in ovarian cancer patients. We hypothesized that ovarian cancer cell GR expression and activity may modulate tumor cell cytokine secretion thereby leading to increased MDSC generation and recruitment to the tumor, thereby creating an immunosuppressive environment. Our preliminary data confirm that GR activation in two high-grade ovarian cancer cell lines (HeyA8 and SKOV3) modulates the cytokine secretome. Our results demonstrate GR-mediated secretion of several pro-tumorigenic and immunosuppressive proteins including G-CSF, M-CSF, TGF-b, and MCP-1 in those ovarian cancer models. We also observed downregulation of potent cytotoxic T-cell activating cytokines required for anti-tumor T-cell function including IL-2, IFN-g and MIP1 upon GR activation. Importantly, treatment of cells with a selective GR modulator (SGRM) reverses this immunosuppressive secretome effect. Furthermore, upon culturing healthy peripheral blood mononuclear cells (PBMCs) with tumor conditioned media from GR activated ovarian cancer cells, we show that secreted immunomodulatory factors have the capacity to promote differentiation of human MDSCs from progenitor myeloid cells. The resulting MDSC population was characterized via expression of activation markers including Arginase-1, iNOS, VEGF and TGF-b. Most importantly, the suppressive function of these MDSCs is being evaluated by determining their inhibitory potential on cytotoxic T-cell proliferation and/or activation. Based on the insight provided by these data, we propose to determine whether ovarian tumor cell-intrinsic GR activation and resulting MDSC generation contributes to earlier relapse of GR-positive ovarian cancers, and eventually whether this mechanism may be targeted to improve patient outcomes in this subset of ovarian cancers.
Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.
LBODP079 A Case of Silent Invasive Corticotroph Adenoma
Authors: Bendaram Snigdha Reddy , Kantorovich Vitaly 
Published: November 2022

Abstract
ACTH-secreting pituitary adenomas account for about two-thirds of cases of endogenous Cushing's syndrome and are considered the most common cause of endogenous hypercortisolemia. Silent corticotroph adenomas (SCAs) are pituitary tumors that stain positive for adrenocorticotropic hormone (ACTH) but do not produce biochemical levels of excess ACTH or cortisol. These tumors account for approximately 20% of all corticotroph adenomas and 5.5% of nonfunctioning pituitary adenomas. New immunohistochemical (IHC) techniques continue to be the gold standard in diagnosis, while having prognostic implications.
Presentation: No date and time listed
HES1 promoter activation dynamics reveal the plasticity, stemness and heterogeneity in neuroblastoma cancer stem cells
Authors: Riya Paul Ann , Basu Budhaditya , Surya Suresh , Parvathy Surendran , Lalitha Soundararajan , Jyothi Nair Pradeep , Meera Vadakkath , Jaikumar Vishnu Sunil , Sunitha Padmanabhan , Shahina Afzal , Sukumaran Rashmi , Nair Achuthsankar Sukumaran , Dhanesh Sivadasan Bindu , Jiffy John , Nelson-Sati Shijulal , Maliekal Tessy Thomas , Das Ani Venmanad , James Jackson 
Published: November 2022

ABSTRACT
Notch signaling and its downstream gene target HES1 play a critical role in regulating and maintaining cancer stem cells (CSCs), similar to as they do during embryonic development. Here, we report a unique subclass of Notch-independent Hes-1 (NIHes-1)-expressing CSCs in neuroblastoma. These CSCs maintain sustained HES1 expression by activation of HES1 promoter region upstream of classical CBF-1 binding sites, thereby completely bypassing Notch receptor-mediated activation. These stem cells have self-renewal ability and potential to generate tumors. Interestingly, we observed that NIHes-1 CSCs could transition to Notch-dependent Hes-1-expressing (NDHes-1) CSCs where HES1 is expressed by Notch receptor-mediated promoter activation. We observed that NDHes-1-expressing CSCs also had the potential to transition to NIHes-1 CSCs and during this coordinated bidirectional transition, both CSCs gave rise to the majority of the bulk cancer cells, which had an inactive HES1 promoter (PIHes-1). A few of these PIHes-1 cells were capable of reverting into a CSC state. These findings explain the existence of a heterogenic mode of HES1 promoter activation within the IMR-32 neuroblastoma cell line and the potential to switch between them.
This article has an associated First Person interview with the first authors of the paper.
Analysis by metagenomic next-generation sequencing of the lung virome during mechanical ventilation
Authors: Do Vale Julien , Roux Damien , Bridier Nahmias Antoine , Salmona Maud , Mercier-Delarue Séverine , Ranger Noémie , Ricard Jean-Damien , Le Goff Jérôme , Fromentin Mélanie 
Published: November 2022

Background: The lung microbiome is composed of bacteria, viruses and fungi that interplay with each other and participate in mucosal defense protecting the lungs from colonization and infection by pathogenic microorganisms. In intensive care, a change in the composition of the lung microbiome, called dysbiosis, could be associated to the occurrence of ventilator-associated pneumonia. The objective of the study was to test a method to assess the lung virome. Methods: We applied a protocol including the same nucleic acid extraction methods as used for bacterial lung microbiome and a metagenomic next-generation sequencing (mNGS) to detect eukaryotic RNA, DNA viruses and bacteriophages. Results: Our method was able to detect all viruses identified with multiplex polymerase chain reaction (PCR), other eukaryotic viruses not included in the multiplex PCR panel, and bacteriophages. Notably persistent viruses, mainly Herpesviridae, associated with opportunistic infections and those showing immunodepression such as Anellovirus have been identified. Conclusions: A better description of the global composition and evolution of the lung microbiome, including viruses, could help to better understand ventilator-associated pneumonia occurrence and outcomes.