bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRI215 Rifampin Induced Adrenal Insufficiency
Authors: Campbell Spencer Ramon , Tierney Ryan M , Lim Jonea 
Published: October 2023

Abstract
Disclosure: S.R. Campbell: None. R.M. Tierney: None. J. Lim: None.
Introduction: Rifampin is a main component of antimycobacterial therapy in active tuberculosis disease. Although adrenal insufficiency can be caused by infiltration of the pituitary or adrenal glands by Mycobacterium tuberculosis, rifampin has also been suggested as a potential causative agent. This case shows a rare example of rifampin-induced adrenal insufficiency in the setting of active tuberculosis disease. Case Presentation: A 42-year-old man with a history of gout and anemia presented with fevers, chills, unintentional weight loss, and productive cough for two weeks. He immigrated from Guatemala 20 years prior and was treated for tuberculosis disease as a child. Upon presentation, he was borderline hypertensive with chest CT showing bilateral nodular opacities in a pattern suggestive of atypical pneumonia. Acid fast bacilli stains were positive and cultures grew Mycobacterium tuberculosis. The patient was started on rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) therapy. Serum cortisol levels on day 4 of RIPE therapy were appropriate in the setting of acute illness (&gt;20 mcg/dl). On day 6 of RIPE therapy, the patient became hypotensive requiring vasopressor support. Labs at that time showed hyponatremia, hypokalemia, and inappropriately low cortisol levels (&lt;20 mcg/dl). ACTH stimulation testing was performed and was blunted with values of 14.50 mcg/dL at 30 minutes and 16.32 mcg/dl at 60 minutes. CT abdomen was also performed and showed no evidence of infiltration. He was started on IV hydrocortisone 50 mg every 6 hours with plans to taper after shock resolved. Following steroid taper, the patient again became hypotensive requiring vasopressors. IV hydrocortisone was resumed, and RIPE therapy was held. He was restarted on PO hydrocortisone 40 mg every 12 hours. Isoniazid, ethambutol, pyrazinamide, and rifampin were sequentially resumed. Pyrazinamide was replaced with moxifloxacin due to recurrent gout flares. The reintroduction of rifampin and rifabutin both resulted in fevers leading to the stoppage of rifamycin therapy. The patient was discharged with stable vital signs on isoniazid 300 mg daily, ethambutol 800 mg daily, moxifloxacin 400 mg daily, and hydrocortisone 30 mg every 12 hours with plans to follow-up with the State Department of Health, internal medicine, and endocrinology. Conclusion: Many drugs are known to cause adrenal insufficiency. There are a few examples in which rifampin has been suggested as a potential cause of adrenal insufficiency. Classically, adrenal insufficiency has been associated with infiltration of the adrenal glands or pituitary gland with Mycobacterium tuberculosis. This case, however, shows further clinical evidence of adrenal insufficiency caused by rifampin therapy and highlights the need for further research to be done to study this adverse effect.
Presentation: Friday, June 16, 2023
THU486 Identification Of Metabolic And Molecular Mechanisms Driving Estrogen Receptor Positive Breast Cancer Disparities Using A Machine-Learning Pipeline
Authors: Casiano Ashlie Santaliz , Mehta Dhruv , Patel Hariyali , Rauscher Garth , Kim Julie , Frasor Jonna M , Hoskins Kent , Erdogan Zeynep Madak 
Published: October 2023

Abstract
Disclosure: A. Santaliz Casiano: None. D. Mehta: None. H. Patel: None. G. Rauscher: None. J. Kim: None. J.M. Frasor: None. K. Hoskins: None.
Background: African American (AA) women in the United States have a 40% higher breast cancer mortality rate compared with Non-Hispanic White (NHW) women. The survival disparity is particularly striking among ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ positive breast cancer. Methods: We collected pretreatment plasma from AA and NHW ER+ breast cancer cases and cancer-free controls to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC-MS) to identify metabolites that may be altered in the different racial groups. Statistical methods combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from TCGA. Results: We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed changes in metabolites associated with amino acid metabolism, while fatty acid metabolism was significantly enriched in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant association with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene NELFE with histone methyltransferase activity was associated with poor survival exclusively for AA individuals. Conclusion: We employed a comprehensive and novel approach that integrates multiple machine learning methods and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women, and may ultimately lead to identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer, and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.
Presentation: Thursday, June 15, 2023
FRI217 False Negative Plasma Metanephrines In A Patient With A Bladder Paraganglioma
Authors: King Thomas F J , Sng Gerald , Puar Troy 
Published: October 2023

Abstract
Disclosure: T.F. King: None. G. Sng: None. T. Puar: None.
Introduction: Both plasma free metanephrines and urinary metanephrines have high (&gt;90%) sensitivity to detect phaeochromocytoma and paragangliomas (PPGL). False positive urine metanephrines are seen in many conditions including obstructive sleep apnoea (OSA), and plasma metanephrines have been proposed to be a useful diagnostic tool in this patient population. Clinical Case: A 53 year old female was recruited into a study evaluating the utility of plasma and urine metanephrines in the diagnosis of PPGL in patients with OSA. She had a 6 year history of hypertension that was well controlled with amlodipine 5mg daily. She had no headache, palpitations or paroxysmal symptoms. She had 3 previous uneventful pregnancies and there was no significant family history of note. She was overweight (BMI 28.3 Kg/m2) and blood pressure was 130/80 mmHg. Sleep studies revealed severe OSA. Screening plasma and 24 hour urine metanephrines were performed at baseline and again after 6 months (Table 1).
24 hr Urinary normetanephrine, mcg/day (Upper Reference interval 423): Baseline 437, Visit 2 (Six Months later) 535, Post-operative 235. Table 1. Serial measurements of urine and plasma metanephrines. In view of the persistently elevated urinary normetaneprine, a CT abdomen and pelvis was performed. This revealed normal adrenal glands, but an avidly enhancing 2cm focal nodular lesion was seen at the left lateral posterior wall of the urinary bladder. Transurethral biopsy revealed a tumour with immunohistochemistry positive for synaptophysin and GATA3, consistent with a paraganglioma. A CT/PET Ga68 dotatpeptide scan showed intense uptake in the same area with no evidence of lymphadenopathy or distant disease. Amlodipine was changed to terazosin pre-operatively and the patient went on to have an uneventful robot assisted excision and partial cystectomy. Histology was consistent with a bladder paraganglioma with clear tumour margins. Genetic analysis for hereditary PPGL was negative for mutations in SDHx, VHL, RET, NF1, but there was a variant of uncertain significance in the MUTYH gene, namely c.767C&gt;T (p.Thr245Ile). At two months post-operative review, the patient remained well and home blood pressure readings were all &gt;120/80mmHg on 5mg amlodipine. Repeat urine and plasma metanephrines were normal. Conclusions: Plasma metanephrines may not be sensitive enough to detect small asymptomatic bladder paragangliomas. Further studies are warranted to elucidate the optimal diagnostic tests in patients with sleep apnoea and suspected PPGL. Interval measurements of metanephrines may be useful in the diagnosis of small PPGL that may manifest with time.
Presentation: Friday, June 16, 2023
THU494 VHL Protein Deficiency Alters The Immune Microenvironment Of Pancreatic Neuroendocrine Neoplasms
Authors: Chmelnik Adiel , Telerman Alona , Tirosh Amit 
Published: October 2023

Abstract
Disclosure: A. Chmelnik: None. A. Telerman: None. A. Tirosh: None.
Introduction - Pancreatic neuroendocrine tumors (PanNENs) may develop sporadically or as part of an inherited disease, such as von Hippel-Lindau (VHL). VHL disease is caused by a germline pathogenic variant in the VHL gene encoding VHL protein (pVHL). Hypoxia inducible factor (HIF) is responsible for cellular oxygen supply. Its degradation is mediated by pVHL via ubiquitination in normoxic states. In pVHL-deficient state leads to HIF overexpression and pseudohypoxia. Several studies suggested immunomodulatory role for HIF in kidney cancer. Aims- To assess the impact of pseudohypoxia on PanNEN immune tumor microenvironment (iTME). Methods- A total of 16 vPanNEN and 23 sPanNEN were processed. Whole genome DNA methylation was performed by Illumine Infinium EPIC Array and analyzed using ChAMP on RStudio. Immune cells composition was compared using methylation-based deconvolution algorithms (MethylResolver, Robust Partial Correlations, Constrained Projection and Cibersort), and gene set enrichment analysis identified pathways affected in each group based on promoter methylation analysis. Results- Unsupervised hierarchical analysis of immune-related gene promoter methylation demonstrated separation of vPanNEN vs. sPanNEN. In GSEA analysis methylation was altered in immune memory-related genes in vPanNEN, and in T cells receptors-related genes in sPanNEN. Deconvolution algorithms revealed a lower fraction of CD4 and NK cells (p&lt;0.05) and a lower PD-L1 expression in vPanNENs (p=0.037). Conclusion- Pseudohypoxic vPanNEN have distinct iTME than sPanNEN, in immune cells composition and PD-L1 expression.
Presentation: Thursday, June 15, 2023
THU497 Elucidating The Role Of The IQGAP1-YAP Axis In ECM Stiffness-Mediated Hepatocellular Carcinoma Progression
Authors: Hobbs Steven E , Kimmel Hannah , Underhill Gregory , Anakk Sayeepriyadarshini 
Published: October 2023

Abstract
Disclosure: S.E. Hobbs: None. H. Kimmel: None. G. Underhill: None. S. Anakk: None.
Hepatocellular Carcinoma (HCC), the primary form of liver cancer, is the second leading cause of cancer associated-associated deaths worldwide. Complex signaling mechanisms and several cellular processes are coordinated using scaffolding proteins. IQ motif-containing GTPase Activating Protein 1 (IQGAP1) is a scaffolding protein that is overexpressed in multiple epithelial cancers, including ovarian, breast, and liver. Previous work has shown that overexpression of IQGAP1 activates Yes-associated Protein (YAP) to promote HCC in mice. Extracellular matrix (ECM) stiffness, due to liver fibrosis in HCC, can activate YAP to promote tumor progression. Remarkably, our preliminary data show that IQGAP1 has increased localization at the plasma membrane when HepG2 cells (an HCC cell line) are seeded onto a stiff ECM (25 kPa). YAP is modulated by actin dynamics, which can be altered by changes in the plasma membrane. Therefore, IQGAP1’s movement to the plasma membrane can potentially activate YAP by modulating actin dynamics. We also found that the anti-HCC drug sorafenib, can induce the expression IQGAP1 and activate YAP in HepG2 cells grown on plastic. These sorafenib-mediated changes are counterproductive and can contribute to drug resistance of HCC. Finally, we found that inhibition of YAP in HepG2 cells significantly decreases IQGAP1 expression, indicating that there is bidirectional crosstalk between the two proteins. Future directions will elucidate if loss of IQGAP1 decreases ECM stiffness-induced YAP activation, proliferation, and migration in HCC cells. In addition, we will determine if ECM stiffness alters sorafenib-mediated IQGAP1 upregulation, as ECM stiffness has been linked to drug resistance in HCC. Overall, this work will shed light on the potential role of the IQGAP1-YAP axis in ECM stiffness-mediated HCC progression.
Presentation: Thursday, June 15, 2023
THU499 The Mesenchymal Stem Cells Induce Immunosuppressive Microenvironment In Pituitary Tumors
Authors: Marrero-Rodríguez Daniel , Cortes-Morales Victor A , Taniguchi-Ponciano Keiko , Valenzuela-Perez Alejandra , Vela-Patiño Sandra , Cano-Zaragoza Amayrani , Martinez-Mendoza Florencia , Kerbel Jacobo , Andonegui-Elguera Sergio , Montesinos Juan Jose , Mercado Moises 
Published: October 2023

Abstract
Disclosure: D. Marrero-Rodríguez: None. V. Cortes-Morales: None. K. Taniguchi-Ponciano: None. A. Valenzuela-Perez: None. S. Vela-Patiño: None. A. Cano-Zaragoza: None. F. Martinez-Mendoza: None. J. Kerbel: None. S. Andonegui-Elguera: None. J. Montesinos: None. M. Mercado: None.
The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells. MSC are a subset of heterogeneous cell populations characterized by the expression of CD105, CD73, and CD90 that can differentiate into chondrocytes, osteoblasts, and adipocytes in vitro. They are known to have immunomodulatory capabilities. Our aim was to isolate and characterize the immunomodulatory capabilities of MSC from pituitary tumors (PT) and non-tumoral gland as well as to describe the immune TME. We isolated and cultivated MSC from LH/FSH-PT and ACTH-PT, as well as non-tumoral pituitary glands. The MSC obtained from PT and non-tumoral gland were co-cultured in the presence of monocytes from healthy donors and their ability to transform into M0, M1 or M2 macrophages was assessed by flow cytometry. The results showed that pituitary tumors derived MSC induce an immunosuppressive M2 macrophage state, by increasing the expression of CD14 and CD206 markers, and decreasing HLA-DR. Upon co-culturing them with naïve T cells, PT MSC were capable inducing a Treg phenotype. To identify PT TME, we performed tumor whole transcriptome characterization and cellular deconvolution using CIBERSORT. Our analysis was indicative of a strong presence of M2 macrophages, TCD4+ and TCD8+ cells, which was confirmed by immunofluorescence, suggesting an immunosuppressive TME. Thus, the MSC immunosuppressive induction correlates directly with immune TME. ACTH-PT derived MSC showed a stronger anti-inflammatory activity than LH/FSH-PT. We also characterized the transcriptomic differences between non-tumoral and PT derived MSC by means of RNAseq. We found differences between the non-tumoral MSC and pituitary tumor derived MSC, but mainly between ACTH- and LH/FSH-PT derived MSC. In conclusion our data suggest that the presence of MSC influence an immunosuppressive tumor microenvironment alongside with tumor cells.
Presentation: Thursday, June 15, 2023
THU500 Geospatial Analysis To Quantify Spatial Heterogeneity Of Tumor Microenvironment
Authors: Yoo Jin Young , Mitra Chancharik , Yue Yang , Soliman Aiman , Erdogan Zeynep Madak 
Published: October 2023

Abstract
Disclosure: J. Yoo: None. C. Mitra: None. Y. Yue: None. A. Soliman: None. Z. Madak Erdogan: None.
Metabolic heterogeneity, a concept describing distinct differences in nutrient metabolism within the cells of a healthy or diseased tissue, is a common challenge in development and cancer research. Current methods, such as histology and Magnetic Resonance Imaging (MRI), cannot visualize nutrient uptake into single cells, making it difficult to understand the heterogeneity that affects cellular growth and metabolism. Visium Spatial Transcriptomics, a method that shows regional gene expression, is emerging as a powerful spatial analysis tool, and we aim to integrate this transcriptomic method with other biologically relevant datasets to highlight the importance of cell-microenvironment interactions. We propose to leverage geostatistical tools to model the multivariate covariance structure of genes expression profiles to allow: 1) understanding of their spatial characteristics and covariance changes under certain conditions (e.g. drug treatment or damage), 2) using these covariance structures to simulate synthetic samples at a scale sufficient to train the state of art neural network architectures, and 3) incorporating spatial awareness directly in the machine learning/deep learning models by enriching the spatial transcriptomics data using distance proximity functions. We will quantify the tumor microenvironment spatial heterogeneity using different approaches. First, we will analyze the degree of spatial auto-correlation to estimate the ranges of spatial heterogeneity within a tumor. We also plan to quantify the degree of anisotropy to identify if the tumor heterogeneity is happening along specific axis. Different local clustering indicators will be also calculated, such as the Getis-Ord (Gi*) statistic and Local Moran's I to identify the prevalence of hot and cold spots in the tumor. These hot and cold spots will be used to segment the tumor area into sub-regions and further quantify the local heterogeneity with a single tumor. We hypothesize that transcriptional heterogeneity reflects phenotypic differences in different regions of healthy or diseased tissue, rendering cells in certain regions to display a differential response to external stimuli (e.g. diet or drugs). Integration of multiple information (e.g. retrospective patient data) with different spatial heterogeneity indicators identified from the geospatial analyses could aid in identification of patients who are resistant to cancer therapies and further advance personalized therapy.
Presentation: Thursday, June 15, 2023
THU501 Examining The Link Between Exposure To Neighborhood Violence And PRMT6 And Glucocorticoid Receptor Binding To Chromatin In Lung Tumors
Authors: Heath Hannah , Kim Sage , Erdogan Zeynep Madak 
Published: October 2023

Abstract
Disclosure: H. Heath: None. S. Kim: None. Z. Madak Erdogan: None.
Despite smoking less, Black men experience a higher incidence of lung cancer than white men. This health disparity is even more prevalent in Black men from Chicago, suggesting local neighborhood factors impacting tumorigenesis. Preliminary data found that Black men compared to white men exhibit overexpression of the epigenetic regulator known as PRMT6, have elevated levels of hair cortisol, and live in neighborhoods with disproportionately high levels of violence. This research aims to investigate the receptor for cortisol called glucocorticoid receptor (GR), and PRMT6 recruitment to chromatin and to correlate this recruitment with tumor cortisol levels and exposure to neighborhood violence. Using a version of ChIP-sequencing known as CUT & RUN, the gene binding sites of PRMT6 and GR will be identified using 16 lung tumor samples from patients living in Chicago. Cortisol levels present in lung tumors will be detected using LC-MS. These cortisol levels will be correlated with GR and PRMT6 recruitment to chromatin and neighborhood homicide data obtained using patients’ zip codes. We hypothesize that PRMT6 and GR will be recruited to regulatory regions of genes related to increased lung tumor aggressiveness. We also anticipate that cortisol levels will correlate with neighborhood violence levels and elevated PRMT6 and GR colocalization, indicating chronic exposure to stress as a regulator of lung tumor formation.
Presentation: Thursday, June 15, 2023
THU510 The Frequency Of Mutations In Advanced Thyroid Cancer In Japan: A Real Clinical Setting
Authors: Toda Soji , Takahashi Akari , Masudo Katsuhiko , Iwasaki Hiroyuki 
Published: October 2023

Abstract
Disclosure: S. Toda: None. A. Takahashi: None. K. Masudo: None. H. Iwasaki: None.
Background: Thyroid cancer has a high incidence of actionable genetic alterations, but the frequency of mutations in advanced thyroid cancer that requires drug therapy is unknown. Therefore, we examined the outcomes of genetic testing performed in a real clinical setting for the purpose of pharmacotherapy. Methods: In Japan, Oncomine Dx is approved for thyroid cancer that requires drug therapy, and comprehensive genomic profiling is approved for anaplastic thyroid carcinoma and other thyroid carcinomas after the induction of tyrosine kinase inhibitors. We retrospectively reviewed the cases of those who had their tests performed between 2020 and 2022. Results: The study included 65 patients, and the testing methods used were Oncomine Dx in 36 cases, FoundationOne in 25 cases, and FoundationOne Liquid in 4 cases. With a median age of 74 years (range 17–86), 42 were female and 23 were male. Moreover, 13 cases had anaplastic thyroid carcinoma (ATC), 4 follicular thyroid carcinoma (FTC), 42 papillary thyroid carcinoma (PTC), and 6 poorly differentiated thyroid carcinoma (PDTC). Of the PTC examined by Oncomine Dx, 96.8% (30/31) were RAI-refractory; all comprehensive genomic profiling testing cases except ATC had previously been treated with tyrosine kinase inhibitors. In the following cases, actionable mutations were observed. Among 13 ATC cases, 46.2% (6) had BRAF mutation and 7.7% (1) had RET fusion. Of 42 PTC cases, 85.7% (36) had BRAF mutation and 7.1% (3) had RET fusion. Of 6 PDTC cases, 33.3% (2) had BRAF mutation and 16.7% (1) had RET fusion. No actionable mutations were observed in FTC (0/4). We found one case each of ATC and PTC with tumor mutation burden of 10 or higher, both with BRAF mutation. NTRK fusion was not observed in any of the 65 patients studied. There were four PTC cases (9.5%) with iodine accumulation in metastases, two with BRAF mutations, one with RET fusion, and one without detectable mutations. Comparing mutations in ATC and non-ATC, TERT promoter mutations were found in 84.6% of ATC (11/13) vs. 56.2% of non-ATC (9/16), whereas TP53 mutations were found in 76.9% of ATC (10/13) vs. 12.5% of non-ATC (2/16). ATC has a significantly higher prevalence of TP53 mutations. Conclusion: Advanced thyroid cancer is more likely to have actionable mutations. BRAF mutations in advanced PTC may be more common than those previously reported in standard PTC. Moreover, ATC has a higher rate of TP53 mutation than other thyroid carcinomas.
Presentation: Thursday, June 15, 2023