bluuebunny/crossref_metadata_2025_split huggingface dataset:
12452 Unraveling An Intriguing Clinical Sequence: Thyrotoxicosis Antecedent To Stiff Person Syndrome
Authors: Jain Ashali , Natasha Rayan Melanie 
Published: October 2024

Abstract
Disclosure: A. Jain: None. M.N. Rayan: None.
Title: Unraveling an Intriguing Clinical Sequence: Thyrotoxicosis Antecedent to Stiff Person Syndrome Background: Stiff Person Syndrome (SPS) is an autoimmune phenomenon resulting in the progressive rigidity of limbs and trunk muscles. It is associated with GAD-positive antibodies in the CSF and serum and is linked to Type 1 Diabetes, Celiac disease, and other autoimmune diseases. Clinical Case: A 34-year-old female with no past medical history was brought into the ED by family for paranoia, suicidal ideations, and visual and auditory hallucinations. She was found to be tachycardic and altered in the ED. Endocrinology was initially consulted for concerns of hyperthyroid pathology due to lab work showing a TSH of &lt;0.008 uIU/mL and free T4 of 4 pg/mL. Thyroid ultrasound revealed heterogeneous, hypervascular thyroid tissue. Further investigation revealed TRAB 4.05 IU/L (n 0-0.9 IU/L) and TSI 3 IU/L (n &lt; 0.577 IU/L). A diagnosis of Graves’ disease was made, and she was started on methimazole 20mg daily and metoprolol 25mg daily. Due to a lack of response to methimazole, other organic causes were investigated including psychiatric and neurological etiology. The patient's symptoms continued to worsen, with new tremors of the upper and lower extremities. Thyroid labs showed improvement, and hence thyrotoxicosis was not thought to be the underlying etiology of her encephalopathy. Neurology was consulted, and EEG and MRI Brain were performed which were unrevealing. Lumbar puncture revealed elevated oligoclonal bands and GAD-65 antibodies, suggesting autoinflammatory encephalitis. High-dose steroids were started, with no improvement. Due to the failure of steroids to treat her symptoms, she was given 5 days of plasmapheresis and a dose of rituximab. Slowly, the patient began to improve and could follow commands and communicate with staff. A formal diagnosis of SPS was made at this time. Upon seeing her in follow-up 1 month after discharge, her TRAB and TSI antibodies were negative, and she was able to be titrated off of methimazole. Conclusion: SPS is strongly associated with autoimmune diseases, with up to 30-40% having T1DM. The association between hyperthyroidism and SPS, however, is exceedingly rare and the etiology remains unclear.
Presentation: 6/1/2024
7695 Impact Of Day Of Admission On Outcomes Of Adrenal Insufficiency- A National Inpatient Sample Study
Authors: Karki Sunita , Neupane Binita , Neupane Shila , Bhandari Abhishek , Farooq Umer , Rajamani Krishnakumar 
Published: October 2024

Abstract
Disclosure: S. Karki: None. B. Neupane: None. S. Neupane: None. A. Bhandari: None. U. Farooq: None. K. Rajamani: None.
Introduction: Admission day (weekend vs. weekday) significantly influences hospital outcomes and mortality in various diseases, with evidence suggesting higher mortality rates associated with weekend admissions. However, the “weekend effect” on adrenal insufficiency remains underexplored in national inpatient samples. Objective of the study:To assess the impact of admission day on mortality rates, hospital stays, costs, and overall outcomes in adrenal insufficiency patients. Methods: A retrospective cohort study encompassing adult patients (age&gt;18 years) was conducted using the National Inpatient Sample (NIS) data spanning from 2017 to 2020. The International Classification of Disease (ICD-10) was used to select codes for diseases and outcomes. STATA was employed for statistical analysis, using multivariate regression analysis to calculate adjusted odds ratios and account for potential confounding variables. Continuous variables were compared using the student t-test, while proportions were compared using the Fisher exact test. The primary outcome was mortality, with secondary outcomes encompassing length of stay (LOS), total hospitalization charges, acute coronary syndrome (ACS), septic shock, pulmonary edema, acute respiratory failure (ARF), mechanical ventilation, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and cerebrovascular accidents (CVA). Results: A total of 150,005 patients diagnosed with adrenal insufficiency were included in the analysis. Patients with adrenal insufficiency were categorized into two groups based on the day of admission: weekend and weekday. Weekend admissions constituted 23.5% of the total cases of adrenal insufficiency, with 35,330 patients. Significant differences in outcomes were observed in septic shock (aOR=1.16, 7.24 % vs. 6.30 %, p=0.007), ARF (aOR=1.23, 11.82% vs. 9.87%, p&lt;0.001), mechanical ventilation (aOR=1.35, 6.29% vs. 4.76%, p&lt;0.001), ARDS (aOR=1.83, 0.57% vs. 0.33%, p=0.003), and AKI (aOR=1.15, 24.74% vs. 22.58%, p&lt;0.001) in weekend vs weekday admissions. However, no significant differences were observed in mortality rates, mean length of hospital stay, total hospital costs, ACS, pulmonary edema, and CVA. Conclusion: Weekend admissions for adrenal insufficiency showed poorer outcomes which prompts further investigation into underlying factors. Insights gained might be helpful for strategic planning at state and national levels, aiding in outcome improvement.
Presentation: 6/1/2024
8072 Crosstalk Between E-Cadherin Loss And Estrogen Receptor Drives Tumorigenesis In Invasive Lobular Carcinoma
Authors: Ufondu Chinasa A , Musick Maggie , Joseph Sikora Matthew , Hanson Ostrander Julie 
Published: October 2024

Abstract
Disclosure: C.A. Ufondu: None. M. Musick: None. M.J. Sikora: None. J.H. Ostrander: None.
Estrogen receptor (ER) expression and E-cadherin (CDH1) loss are the two major molecular hallmarks of invasive lobular carcinoma (ILC) of the breast; however, it is unclear how ER signaling and E-cadherin loss crosstalk during ILC tumor formation. Furthermore, the risk of ILC is increased by estrogen-only hormone replacement treatment, but not that of the more frequent invasive ductal carcinoma (IDC), suggesting that ER may have a unique role in the initiation and progression of ILC. We hypothesize that E-cadherin loss accelerates estrogen-driven tumorigenesis by reprogramming ER DNA binding through the dysregulation of pathways and transcription factors linked to E-cadherin. To test the effect of E-cadherin loss during estrogen driven tumorigenesis, we established a CRISPR/Cas9 approach for knocking out CDH1 in primary human mammary epithelial cells (HMECs). Since primary HMECs did not show robust ER expression, we also re-expressed ER using lentiviral transduction of ESR1 into HMECs. We performed RNAseq from two independent CDH1 targeting gRNAs vs non-targeting gRNA (NTG) control (-/+ ER). Importantly, when comparing the two independent CDH1 gRNAs to NTG there were 2882 shared genes (1436 upregulated only, 1407 downregulated only) that were differentially regulated. Analysis of these shared genes showed the enrichment of estrogen response, PI3K signaling and cell cycle pathways in the CDH1 knockout cells vs control. We also observed the repression of epithelial mesenchymal transition, hypoxia-related genes and p53 in the CDH1 knockout samples vs control. Overall, analysis of the RNAseq data suggests that the loss of E-cadherin in HMECS impacts proliferation and EMT, which will be explored in future studies. In addition, we hope to identify mediators that drive estrogen-induced tumorigenesis using the mouse mammary intraductal (MIND) model, which better recapitulates the progression of ILC and response to estrogen in vivo. We injected control and CDH1 knockout cells into the mammary glands of adult female NSG mice, with estrogen supplemented in their drinking water, and assessed for engraftment using bioluminescence imaging (BLI). BLI suggests enhanced engraftment of CDH1 knockout cells compared to CDH1 wild-type HMECs and a survival advantage for HMECs expressing ESR1. Importantly, analysis of mammary glands two-month post-MIND injections showed engraftment of human cells positive for cytokeratin-5 and lamin a/c. Ongoing studies aim to assess the estrogen response in the CDH1-knockout versus control HMECs in vitro and in vivo to determine whether loss of E-cadherin contributes to ILC-specific ER activity. Understanding the unique interactions between E-cadherin loss and ER in ILC could lead to novel therapeutic approaches for the prevention and treatment of ILC.
Presentation: 6/2/2024
9389 Defining The Effects Of PARP Inhibition On Androgen Receptor Function In Homologous Recombination-Proficient Prostate Cancer
Authors: Wheeler Esmé , Traphagen Nicole , Li Rong , Tewari Alok , Qiu Xintao , Brown Myles 
Published: October 2024

Abstract
Disclosure: E. Wheeler: None. N. Traphagen: None. R. Li: None. A. Tewari: None. X. Qiu: None. M. Brown: None.
Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors as a potential treatment for advanced prostate cancer. Despite promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. As such, combination AR pathway inhibition and PARP inhibition has been approved by the US FDA only in the HR-deficient setting. To elucidate this discrepancy between preclinical and clinical results, we aimed to comprehensively profile the effects of PARP inhibition on AR function in HR-proficient prostate cancer models. In pursuit of this goal, we conducted experiments using HR-proficient prostate cancer cell lines, including LNCaP, 22RV1, VCaP, LN95, and LNCaP-abl, and assessed the effects of the PARP1/2 inhibitors olaparib, rucaparib, talazoparib, and the PARP1-selective inhibitor AZD-5305. Our findings reveal impacts of PARP inhibitor treatment on AR function. RNA-sequencing analysis demonstrates inhibition of AR transcriptional function in PARP inhibitor-treated cells. Treatment with PARP inhibitors inhibited androgen-induced expression of a subset of genes, with analysis revealing enrichment for Hallmark MYC targets in this gene set. Conversely, treatment with PARP inhibitors also inhibited androgen-induced repression of a subset of genes. However, despite these PARP inhibitor-mediated effects on AR function, our testing of the combination of PARP inhibitors and enzalutamide showed no evidence of synergy or enhanced growth-inhibitory effects at physiologically relevant doses of these inhibitors. Additionally, contrary to previously published data, we observed no evidence that androgen deprivation inhibits the expression of DNA damage response gene sets. This is concordant with the lack of synergy between PARP inhibitors and AR inhibition found in these HR-proficient models. Finally, our analysis comparing PARP1/2 with PARP1-selective inhibitors suggests that these drugs exhibit similar biological effects, both in terms of their growth-inhibitory effects and in modulating AR activity. Collectively, our results indicate that while PARP inhibitors influence AR transcriptional function, they do not synergize with androgen deprivation or AR inhibition in HR-proficient prostate cancer cells.
Presentation: 6/2/2024
12406 Epidemiology Of Multiple Endocrine Neoplasia Type 1 In South Korea: A Nationwide Cohort Study
Authors: Jin Kim Kyoung , Hwang Yoon-a , Heui Yu Min , Moon Shinje , Hong Namki , Rhee Yumie 
Published: October 2024

Abstract
Disclosure: K. Kim: None. Y. Hwang: None. M. Yu: None. S. Moon: None. N. Hong: None. Y. Rhee: None.
Multiple Endocrine Neoplasia Type 1 (MEN1) is one of the rarest endocrine disorders, with a scarcity of comprehensive epidemiological data globally. This deficiency in data is even more pronounced in Asian populations, where MEN1 remains an under-researched area. Therefore, our aim is to identity the prevalence, demographic characteristics, and patterns of comorbidities associated with MEN1.This nationwide cohort study assessed likely MEN1 cases from the Korean National Health Insurance Service database (2003-2020), selected via two operational definitions: one requiring an ICD-10 code for MEN1 (D44.8) and the other mandating at least two related procedures for MEN1-associated conditions (Primary Hyperparathyroidism, Pituitary Adenomas, and Duodenopancreatic Neuroendocrine Tumors). Cases were 1:10 matched by age, sex, and index year with controls who did not have any MEN-1 associated tumors. Our study evaluated 412 patients with likely MEN1 (mean age 43.6 ± 15.8 years; 35.4% male) against an age-sex matched control group of 4,120. Baseline characteristics showed a higher prevalence of comorbidities in MEN1 patients, including diabetes mellitus (22.6% vs 4.8%), hypertension (38.1% vs 16.4%), and dyslipidemia (20.6% vs 11.2%), all with p&lt;0.001. Cancer prevalence was markedly elevated in MEN1 patients across most types, compared to controls. Adrenal involvements were observed in 34.7% of MEN1 patients, with adrenal adenoma being the most common (31.6%). Parathyroid, pituitary, and duodenopancreatic involvements were identified in 58.6%, 22.3%, and 19.9% of MEN1 patients, respectively. Mortality analysis revealed MEN1 patients had a higher mortality rate (16.0 per 1000 person-years) and a younger mean age at death (60.1 years) compared to controls (68.0 years), with an adjusted mortality hazard ratio of 3.1. Additionally, mortality risk varied with organ involvement; parathyroid involvement showed an adjusted HR of 2.7, pituitary involvement 4.7, and duodenopancreas involvement 4.0. The risk increased significantly with multi-organ involvement, where patients affected in more than two organs had HRs from 2.8 to 7.3. Our findings indicate that MEN1 significantly impacts patient morbidity and mortality, necessitating improved surveillance and tailored management to enhance early detection and optimize care for this vulnerable patient group. These insights underscore the pressing need for further research into MEN1 and other rare diseases to advance patient care and outcomes.
Presentation: 6/2/2024
12234 Gα13 Promotes Clonogenic Growth By Increasing Tolerance To Oxidative Metabolic Stress In Prostate Cancer Cells
Authors: Wu Di , Kiang Lim Wei , Chai Xiaoran , Seshachalam Veerabrahma P , Rasheed Suhail A K , Ghosh Sujoy , Casey Patrick J 
Published: October 2024

Abstract
Disclosure: D. Wu: None. W. Lim: None. X. Chai: None. V.P. Seshachalam: None. S.A. Rasheed: None. S. Ghosh: None. P.J. Casey: None.
Gα13 and Gα12 are members of the G12 family of Gα proteins that, along with their associated Gβγ subunits, mediate signaling from specific G protein-coupled receptors. Analyses of tumor specimens indicate that Gα13 expression correlates with patient survival in several solid cancers. We previously reported a role for Gα13 in cell migration and invasion in prostate cancer cell lines. Interestingly, patient data supports the notion that mitochondrial superoxide dismutase 2 (SOD2) correlates with prostate cancer risk and prognostic Gleason scores. Gα13 lower-expressing LNCaP cells also have lower SOD2 protein levels compared to the Gα13 higher-expressing PC3 cells. Hence, we explored the role of Gα13 in prostate tumorigenesis, and its effect on cellular processes such as cell survival and mitochondrial metabolism, in human prostate cancer cell lines PC3 and LNCaP. We stably knocked-down GNA13 expression in PC3 cells and overexpressed GNA13 in LNCaP cells. We found that Gα13 promoted anchorage-independent cell growth in PC3 and LNCaP cell lines, as assessed by soft agar colony formation, spheroid formation, and xenograft tumor growth. Whole-genome transcriptome analyses suggested that Gα13-regulated genes are functionally enriched in the mitochondria compartment and that GNA13 expression positively correlated to SOD2 transcript levels in PC3 cells. We found that silencing GNA13 sensitized PC3 cells to long-term oxidative metabolic stress when cultured in media containing non-glycolytic metabolites, namely galactose, glutamate plus malate, and succinate. Furthermore, Gα13 levels impacted the abundance of SOD2 protein in the mitochondria, as well as SOD2 promoter activity and mRNA expression. In addition, silencing GNA13 increased mitochondrial superoxide levels in PC3 cells when cultured in galactose medium, as assessed by MitoSOX staining and flow cytometry. Moreover, overexpression of SOD2 could rescue the effect of Gα13 loss on suppression of anchorage-independent cell growth in PC3 cells. Importantly, anchorage-independent cell growth was not rescued when a catalytically-inactive SOD2(Q167A) mutant was expressed. Likewise, stable knockdown of SOD2 suppressed the effect of overexpression of Gα13 on anchorage-independent cell growth in LNCaP cells. We propose a novel biological route of Gα13-mediated anchorage-independent growth and response to oxidative metabolic stress through regulation of SOD2 expression in prostate cancer cells. Given that SOD2 protein levels correlate with prostate cancer Gleason grade, identifying the upregulated GPCRs that signal through Gα13 in prostate cancer could lead to novel preventive or therapeutic strategies.
Presentation: 6/1/2024
8553 GDF-15 Levels In Patients With Prostate Cancer On Androgen Deprivation Therapy
Authors: Jaramillo-Quiroz Sofia del Carmen , Caeiro Lucas , Jayne Anderson Lindsey , Manuel Garcia Jose 
Published: October 2024

Abstract
Disclosure: S.D. Jaramillo-Quiroz: Other; Self; VAPSHCS: Director Fund Research Fellowship/UW Abrass Family Fellowship Fund. CDMRP (PC170059).. L. Caeiro: None. L.J. Anderson: None. J.M. Garcia: None.
Growth Differentiation Factor 15 (GDF-15) is a stress-induced cytokine known to induce anorexia and cachexia and a biomarker of biological aging, mitochondrial dysfunction, and worse hand grip strength and poor survival in different settings. Also, GDF-15 has pleiotropic functions at all stages of tumorigenicity and is suggested as a marker to differentiate BPH from PCa. Androgen Deprivation Therapy (ADT) is the standard treatment for advanced prostate cancer (PCa), but it also decreases muscle mass and function and Quality of life (QOL). The role and effects of GDF-15 in prostate cancer patients undergoing ADT are not well characterized and was explored in this longitudinal, 6-month, observational study that recruited men with (PCa) starting ADT (n=60, mean age 69). Body composition [dual energy X-ray absorptiometry (DEXA), body weight history], physical performance [handgrip strength (HGS), 6-minute walk test (6MWT), energy expenditure (indirect calorimetry and actigraphy)], were assessed before, at 3 and 6 months after starting ADT. QoL was assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). GDF-15 was measured by ELISA. Mean differences performed with standard error of the mean, repeated measures ANOVA and Tukey’s Post Hoc test. Correlations were assessed by Spearman’s. After 6 months of ADT, fat mass was increased (mean difference: 1.14 ±0.38, p=0.0029), and lean muscle mass (mean difference: -1.214 ± 0.38, p=0.005), appendicular lean mass (ALM, mean difference: -0.879 ± 0.19, p=&lt;0.0001). HGS (mean difference: -2.927 ± 0.59, p=&lt;0.0001), and VO2 max decreased (mean difference -3.31 ± 0.83, p=0.0007). Baseline GDF-15 (mean 1456.59 ± 1022.80) was correlated with the changes in weight (r: -0.38, p=0.01), BMI (r: -0.33, p=0.01), ALM (r: -0.29, p=0.04), and fatigue (r: -0.38, p=0.004). As shown, baseline GDF-15 was inversely correlated with changes in weight, appendicular lean mass, and fatigue in subjects undergoing ADT, highlighting the possibility of its role as a biomarker and therapeutic target of body composition and patient-reported outcomes in this setting.
Presentation: 6/1/2024
9308 GPNMB Promotes Tumor Growth And Is A Biomarker For Lymphangioleiomyomatosis (LAM)
Authors: Gibbons Erin , Taya Manisha , Wu Huixing , Lopa Samia , Moss Joel , Henske Elizabeth P , McCormack Francis X , Hammes Stephen R 
Published: October 2024

Abstract
Disclosure: E. Gibbons: None. M. Taya: None. H. Wu: None. S. Lopa: None. J. Moss: None. E.P. Henske: None. F.X. McCormack: None. S.R. Hammes: None.
Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB regulates TSC2-null tumor cell invasion as well as TSC2-null xenograft tumor growth, and that GPNMB expression is dependent on mTORC1 signaling. Further, we show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by ADAM10 and 17 proteases, and we identify the protease target sequence on GPNMB. In fact, mutating this cleavage sequence so that the GPNMB ectodomain can no longer be shed results in cessation of TSC2-null tumor growth. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.
Presentation: 6/3/2024
9218 Highly Multiplexed Mapping Of The Ductal Carcinoma In Situ Ecosystem To Predict Disease Outcome
Authors: Wilson Gemma M , Doan Tram B , Guild Barbara J , Pathmanathan Nirmala , Graham J Dinny 
Published: October 2024

Abstract
Disclosure: G.M. Wilson: None. T.B. Doan: None. B.J. Guild: None. N. Pathmanathan: None. J.D. Graham: None.
Mammographic screening programs have resulted in remarkable improvements in breast cancer survival due to early-stage detection. However, this has resulted in a dramatic increase in the detection of non-invasive ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive ductal carcinoma (IDC), which is confined to the ducts and surrounded by a normal myoepithelial cell layer. Many DCIS cases will not progress to IDC within the lifetime of the patient. However, there are limited tools to accurately predict progression, thus virtually all DCIS is surgically removed, and most patients receive adjuvant radiotherapy as it halves recurrence rates. This likely represents overtreatment for a majority of patients. Emerging evidence has revealed that the adjacent microenvironment becomes progressively altered in DCIS and IDC compared to normal tissue, and this is correlated with disease outcome. The objective of this study was to investigate changes to the DCIS microenvironment during disease progression and identify disease states that predict patient outcome. We used immunohistochemistry and imaging mass cytometry with a well-annotated cohort of DCIS, with or without adjacent IDC, to measure a panel of 40 phenotypic and functional markers that allowed us to distinguish the diverse cell populations present in the tissues. We observed striking changes to almost all cell types within the DCIS tissue when comparing pure DCIS cases to DCIS adjacent to IDC. In particular, there were considerable changes to tissue-resident immune populations, with differences observed in the type, location and population size of a variety of immune cell subsets, in IDC-associated DCIS compared with DCIS-only cases. Computational mapping of cell type communities in pure and IDC-adjacent DCIS tissues revealed specific differences that could be used to predict the emergence of invasive disease, informing clinical management of this good prognosis malignancy and potentially avoiding over-treatment.
Presentation: 6/3/2024