Medicine and Health Sciences Commons^™

The Scaffolding Function Of Lsd1 Controls Dna Methylation In Mouse Escs, Sandhya Malla, Kanchan Kumari, Carlos A García-Prieto, Jonatan Caroli, Anna Nordin, Trinh T T Phan, Devi Prasad Bhattarai, Carlos Martinez-Gamero, Eshagh Dorafshan, Stephanie Stransky, Damiana Álvarez-Errico, Paulina Avovome Saiki, Weiyi Lai, Cong Lyu, Ludvig Lizana, Jonathan D Gilthorpe, Hailin Wang, Simone Sidoli, Andre Mateus, Dung-Fang Lee, Claudio Cantù, Manel Esteller, Andrea Mattevi, Angel-Carlos Roman, Francesca Aguilo

Faculty, Staff and Student Publications

Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1MUT) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, increased H3K4me1 in Lsd1 knockout (KO) mouse ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but …

Targeting Igf2 To Reprogram The Tumor Microenvironment For Enhanced Viro-Immunotherapy, Min Hye Noh, Jin Muk Kang, Alexandra A Miller, Grace Nguyen, Minxin Huang, Ji Seon Shim, Alberto J Bueso-Perez, Sara A Murphy, Kimberly A Rivera-Caraballo, Yoshihiro Otani, Eunju Kim, Seung-Hee Yoo, Yuanqing Yan, Yeshavanth Banasavadi-Siddegowda, Hiroshi Nakashima, E Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo

Faculty, Staff and Student Publications

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

RESULTS: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. …

Neoadjuvant Parpi Or Chemotherapy In Ovarian Cancer Informs Targeting Effector Treg Cells For Homologous-Recombination-Deficient Tumors, Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Cocpo Consortium, Ding Ma, Yong Fang, Han Liang, Qinglei Gao

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD …

Single-Cell And Spatial Proteo-Transcriptomic Profiling Reveals Immune Infiltration Heterogeneity Associated With Neuroendocrine Features In Small Cell Lung Cancer, Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 …

Screening Of Anti-Prion Compounds Using The Protein Misfolding Cyclic Amplification Technology, Sandra Pritzkow, Isaac Schauer, Ananya Tupaki-Sreepurna, Rodrigo Morales, Claudio Soto

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Prion diseases are 100% fatal infectious neurodegenerative diseases affecting the brains of humans and other mammals. The disease is caused by the formation and replication of prions, composed exclusively of the misfolded prion protein (PrPSc). We invented and developed the protein misfolding cyclic amplification (PMCA) technology for in vitro prion replication, which allow us to replicate the infectious agent and it is commonly used for ultra-sensitive prion detection in biological fluids, tissues and environmental samples. In this article, we studied whether PMCA can be used to screen for chemical compounds that block prion replication. A small set of compounds previously …

Molecularly Imprinted Wearable Sensor With Paper Microfluidics For Real-Time Sweat Biomarker Analysis, Mayank Garg, Heng Guo, Ethan Maclam, Elizabeth Zhanov, Sathwika Samudrala, Anton Pavlov, Md Saifur Rahman, Myeong Namkoong, Jennette P Moreno, Limei Tian

Faculty, Staff and Student Publications

The urgent need for real-time and noninvasive monitoring of health-associated biochemical parameters has motivated the development of wearable sweat sensors. Existing electrochemical sensors show promise in real-time analysis of various chemical biomarkers. These sensors often rely on labels and redox probes to generate and amplify the signals for the detection and quantification of analytes with limited sensitivity. In this study, we introduce a molecularly imprinted polymer (MIP)-based biochemical sensor to quantify a molecular biomarker in sweat using electrochemical impedance spectroscopy, which eliminates the need for labels or redox probes. The molecularly imprinted biosensor can achieve sensitive and specific detection of …

G Protein Selectivity Profile Of Gpr56/Adgrg1 And Its Effect On Downstream Effectors, Raida Jallouli, Ana L Moreno-Salinas, Andréanne Laniel, Brian Holleran, Charlotte Avet, Joan Jacob, Trang Hoang, Christine Lavoie, Kendra S Carmon, Michel Bouvier, Richard Leduc

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GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13. Unlike constitutive activation and activation with 3-α-acetoxydihydrodeoxygedunin (3αDOG), stimulation with an antibody, 10C7, directed against GPR56's extracellular domain (ECD) led to an activation that favors G13 over G12. An autoproteolytically deficient mutant, GPR56-T383A, was also activated by 10C7 indicating that the tethered …

Crizotinib Enhances Parp Inhibitor Efficacy In Ovarian Cancer Cells And Xenograft Models By Inducing Autophagy, Janice M Santiago-O'Farrill, Alicia Blessing Bollu, Hailing Yang, Vivian Orellana, Marc Pina, Xudong Zhang, Jinsong Liu, Robert C Bast, Zhen Lu

Faculty, Staff and Student Publications

Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and …

Racial And Ethnic Differences In Epithelial Ovarian Cancer Risk: An Analysis From The Ovarian Cancer Association Consortium, Nicola S Meagher, Kami K White, Lynne R Wilkens, Elisa V Bandera, Andrew Berchuck, Michael E Carney, Daniel W Cramer, Kara L Cushing-Haugen, Susan Jordan, Scott H Kaufmann, Nhu D Le, Malcolm C Pike, Marjorie Riggan, Bo Qin, Joseph H Rothstein, Linda Titus, Stacey J Winham, Hoda Anton-Culver, Jennifer A Doherty, Ellen L Goode, Celeste Leigh Pearce, Harvey A Risch, Penelope M Webb, Linda S Cook, Marc T Goodman, Holly R Harris, Loic Le Marchand, Valerie Mcguire, Paul D P Pharoah, Danja Sarink, Joellen M Schildkraut, Weiva Sieh, Kathryn L Terry, Pamela J Thompson, Alice S Whittemore, Anna H Wu, Lauren C Peres, Melissa A Merritt

Faculty, Staff and Student Publications

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations …

Pancreatic Epithelial Il17/Il17ra Signaling Drives B7-H4 Expression To Promote Tumorigenesis, Susana Castro-Pando, Rian M Howell, Le Li, Marilina Mascaro, Erika Y Faraoni, Olivereen Le Roux, David Romanin, Virginia Tahan, Erick Riquelme, Yu Zhang, Jay K Kolls, James P Allison, Guillermina Lozano, Seyed J Moghaddam, Florencia Mcallister

Faculty, Staff and Student Publications

IL17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. However, the cellular compartment and downstream molecular mediators of IL17-mediated pancreatic tumorigenesis have not been fully identified. This study examined the cellular compartment required by generating transgenic animals with IL17 receptor A (IL17RA), which was genetically deleted from either the pancreatic epithelial compartment or the hematopoietic compartment via generation of IL17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL17RA from the pancreatic epithelial compartment, but not from …

Tomivosertib Reduces Ectopic Activity In Dorsal Root Ganglion Neurons From Patients With Radiculopathy, Yan Li, Megan L Uhelski, Robert Y North, Juliet M Mwirigi, Claudio E Tatsui, Kathleen E Mcdonough, Juan P Cata, German Corrales, Greg Dussor, Theodore J Price, Patrick M Dougherty

Faculty, Staff and Student Publications

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors.

Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. …

Positive Airway Pressure, Mortality, And Cardiovascular Risk In Older Adults With Sleep Apnea, Diego R Mazzotti, Lemuel R Waitman, Jennifer Miller, Krishna M Sundar, Nancy H Stewart, David Gozal, Xing Song

Faculty, Staff and Student Publications

Importance: Positive airway pressure (PAP) is the first-line treatment for obstructive sleep apnea (OSA), but evidence on its beneficial effect on major adverse cardiovascular events (MACE) and mortality prevention is limited.

Objective: To determine whether PAP initiation and utilization are associated with lower mortality and incidence of MACE among older adults with OSA living in the central US.

Design, setting, and participants: This retrospective clinical cohort study included Medicare beneficiaries with 2 or more distinct OSA claims identified from multistate, statewide, multiyear (2011-2020) Medicare fee-for-service claims data. Individuals were followed up until death or censoring on December 31, 2020. Analyses …

Social Vulnerability And Sickle Cell Disease Mortality In The Us, Jia Yi Tan, Boon Jian San, Yong-Hao Yeo, Kok Hoe Chan, Hamid S Shaaban, Daniel E Ezekwudo, Modupe Idowu

Faculty, Staff and Student Publications

Importance: Social determinants of health (SDOH) influence health outcomes, including those of sickle cell disease (SCD), despite advancements in treatments like disease-modifying therapies.

Objective: To investigate the association of SDOH with SCD mortality rates from 2016 to 2020.

Design, setting, and participants: This cross-sectional study combined county-level data from the Centers for Disease Control and Prevention and Agency for Toxic Substances and Disease Registry Social Vulnerability Index (SVI) with SCD mortality data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from January 1, 2016, to December 31, 2020. US counties were divided into …

Angiotensin-(1-9) Retro-Enantiomer Peptide With Cardioprotective Activity, Yvo Flores, Gerald Zapata-Torres, Agustín Nuñez, Douglas J Matthies, Larissa Alemán, Carolina Hernández-Fuentes, Gina Sánchez, Eyleen Araya, Fanny Guzman, Zully Pedrozo, Salvador Guardiola, Mónica Varese, Ernest Giralt, Ivan Maslov, Mark Del Borgo, Robert E Widdop, Silvana Valdebenito, Eliseo A Eugenin, Mario Chiong, Joseph A Hill, María Paz Ocaranza, Marcelo J Kogan, Sergio Lavandero

Faculty, Staff and Student Publications

No abstract provided.

Prognostic Impact Of Notch1 Intracellular Domain, P63, And C-Myc In Lacrimal Gland Adenoid Cystic Carcinoma, Jiawei Zhao, Michelle D Williams, Mike Hernandez, Grace Kuang, Hila Goldberg, Janet Fan, Jing Ning, Renata Ferrarotto, Bita Esmaeli

Faculty, Staff and Student Publications

PURPOSE: We assessed whether NICD1 expression, c-MYC expression, and P63 expression by immunohistochemistry (IHC) correlate with prognosis and high-risk clinicopathological features in lacrimal gland adenoid cystic carcinoma (ACC).

METHODS: Records of patients with lacrimal gland ACC who underwent surgery between 1998 to 2018 were reviewed. Clinicopathologic and treatment data were collected. Tumor tissues were subjected to light microscopy and IHC.

RESULTS: Of 43 patients treated during the study period, 21 had archived tumor tissue available and were included. The median age at diagnosis was 47 years, and 13 patients (62%) were male. Thirteen patients (62%) had T2 disease, and none …

Rad21 Promotes Oncogenesis And Lethal Progression Of Prostate Cancer, Xiaofeng A Su, Konrad H Stopsack, Daniel R Schmidt, Duanduan Ma, Zhe Li, Paul A Scheet, Kathryn L Penney, Tamara L Lotan, Wassim Abida, Elise G Dearment, Kate Lu, Thomas Janas, Sofia Hu, Matthew G Vander Heiden, Massimo Loda, Monica Boselli, Angelika Amon, Lorelei A Mucci

Faculty, Staff and Student Publications

Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene,

The Cancer-Associated Secretory Phenotype: A New Frontier In Targeted Therapeutics, Xiaochao Tan, Guan-Yu Xiao, Priyam Banerjee, Shike Wang, Jonathan M Kurie

Faculty, Staff and Student Publications

No abstract provided.

Skin Tone Discrimination And Birth Control Avoidance Among Women In Harris County, Texas: A Cross-Sectional Study, Kimberly Baker, Susan Tortolero Emery, Evelyn Spike, Jazmyne Sutton, Eran Ben-Porath

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INTRODUCTION: Structural racism plays a major role in reproductive health inequities. Colorism, discrimination based on skin color, may profoundly impact reproductive health access and service delivery. However, quantitative research in this area is limited.

METHODS: We administered an online survey of women (n = 1,299) aged 18-44 from Harris County, Texas to assess the relationship between skin color discrimination and reproductive health service avoidance. The survey included questions on demographics, self-reported skin tone, and dichotomous measures of previous discrimination experiences and avoidance of care because of perceived discrimination. Binary logistic regression was used to examine whether race/ethnicity, skin tone, and …

Risk Of Anxiety Disorders In Men With Prostate Cancer: A National Cohort Study, Casey Crump, Pär Stattin, James D Brooks, Jan Sundquist, Kristina Sundquist, Weiva Sieh

Faculty, Staff and Student Publications

BACKGROUND: Men with prostate cancer (PC) may experience significant psychosocial distress from physical symptoms, treatment side effects, or fear of recurrence. However, little is known about the long-term risk of anxiety disorders in men with PC.

METHODS: A national cohort study was conducted of 180 189 men diagnosed with PC during 1998-2017 and 1 801 890 age-matched population-based control men in Sweden. Anxiety disorders were ascertained from nationwide outpatient and inpatient records through 2018. Cox regression was used to estimate hazard ratios (HRs) while adjusting for sociodemographic factors and prior psychiatric disorders. Subanalyses explored differences by PC treatment during 2005-2017. …

Glycemic Control In Diabetic Patients Improved Overall Lung Cancer Survival Across Diverse Populations, Wayne Y Wu, Brian Luke, Xiao-Cheng Wu, J Jack Lee, Yong Yi, Samuel C Okpechi, Barry Gause, Paras Mehta, Steven I Sherman, Augusto Ochoa, Ethan Dmitrovsky, Xi Liu

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Background: The consequence of diabetes on lung cancer overall survival (OS) is debated. This retrospective study used 2 large lung cancer databases to assess comprehensively diabetes effects on lung cancer OS in diverse demographic populations, including health disparity.

Methods: The University of Texas MD Anderson Cancer Center database (32 643 lung cancer patients with 11 973 patients with diabetes) was extracted from electronic health records (EHRs) using natural language processing (NLP). Associations were between diabetes and lung cancer prognostic features (age, sex, race, body mass index [BMI], insurance status, smoking, stage, and histopathology). Hemoglobin A1C (HgbA1c) and glucose levels assessed …

Scintruler: Guiding The Integration Of Multiple Single-Cell Rna-Seq Datasets With A Novel Statistical Metric, Yue Lyu, Steven H Lin, Hao Wu, Ziyi Li

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Motivation: The growing number of single-cell RNA-seq (scRNA-seq) studies highlights the potential benefits of integrating multiple datasets, such as augmenting sample sizes and enhancing analytical robustness. Inherent diversity and batch discrepancies within samples or across studies continue to pose significant challenges for computational analyses. Questions persist in practice, lacking definitive answers: Should we use a specific integration method or opt for simply merging the datasets during joint analysis? Among all the existing data integration methods, which one is more suitable in specific scenarios?

Result: To fill the gap, we introduce SCIntRuler, a novel statistical metric for guiding the integration of …

Toward Reliable Symptom Coding In Electronic Health Records For Symptom Assessment And Research: Identification And Categorization Of International Classification Of Diseases, Ninth Revision, Clinical Modification Symptom Codes, Tru Cao, Veronica Brady, Meagan Whisenant, Xueying Wang, Yuxuan Gu, Hulin Wu

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To date, symptom documentation has mostly relied on clinical notes in electronic health records or patient-reported outcomes using disease-specific symptom inventories. To provide a common and precise language for symptom recording, assessment, and research, a comprehensive list of symptom codes is needed. The International Classification of Diseases, Ninth Revision or its clinical modification ( International Classification of Diseases, Ninth Revision, Clinical Modification ) has a range of codes designated for symptoms, but it does not contain codes for all possible symptoms, and not all codes in that range are symptom related. This study aimed to identify and categorize the first …

Systematically Assessing The Quality Of Dental Electronic Health Record Data For An Investigation Into Oral Health Care Disparities, Krishna Kumar Kookal, Muhammad F Walji, Ryan Brandon, Ferit Kivanc, Elizabeth Mertz, Aubri Kottek, Joanna Mullins, Shuang Liang, Larry E Jenson, Joel M White

Faculty, Staff and Student Publications

Objectives: This work describes the process by which the quality of electronic health care data for a public health study was determined. The objectives were to adapt, develop, and implement data quality assessments (DQAs) based on the National Institutes of Health Pragmatic Trials Collaboratory (NIHPTC) data quality framework within the three domains of completeness, accuracy, and consistency, for an investigation into oral health care disparities of a preventive care program.

Methods: Electronic health record data for eligible children in a dental accountable care organization of 30 offices, in Oregon, were extracted iteratively from January 1, 2014, through March 31, 2022. …

Ataxia Telangiectasia And Rad3-Related (Atr) Inhibitor Camonsertib Dose Optimization In Patients With Biomarker-Selected Advanced Solid Tumors (Tresr Study), Elisa Fontana, Ezra Rosen, Elizabeth K Lee, Martin Højgaard, Niharika B Mettu, Stephanie Lheureux, Benedito A Carneiro, Gregory M Cote, Louise Carter, Ruth Plummer, Devalingam Mahalingam, Adrian J Fretland, Joseph D Schonhoft, Ian M Silverman, Marisa Wainszelbaum, Yi Xu, Danielle Ulanet, Maria Koehler, Timothy A Yap

Faculty, Staff and Student Publications

BACKGROUND: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects.

METHODS: Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of …

Identification Of Hypoxia-Alcamhigh Macrophage- Exhausted T Cell Axis In Tumor Microenvironment Remodeling For Immunotherapy Resistance, Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han

Faculty, Staff and Student Publications

Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAM

Ensemble Pretrained Language Models To Extract Biomedical Knowledge From Literature, Zhao Li, Qiang Wei, Liang-Chin Huang, Jianfu Li, Yan Hu, Yao-Shun Chuang, Jianping He, Avisha Das, Vipina Kuttichi Keloth, Yuntao Yang, Chiamaka S Diala, Kirk E Roberts, Cui Tao, Xiaoqian Jiang, W Jim Zheng, Hua Xu

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OBJECTIVES: The rapid expansion of biomedical literature necessitates automated techniques to discern relationships between biomedical concepts from extensive free text. Such techniques facilitate the development of detailed knowledge bases and highlight research deficiencies. The LitCoin Natural Language Processing (NLP) challenge, organized by the National Center for Advancing Translational Science, aims to evaluate such potential and provides a manually annotated corpus for methodology development and benchmarking.

MATERIALS AND METHODS: For the named entity recognition (NER) task, we utilized ensemble learning to merge predictions from three domain-specific models, namely BioBERT, PubMedBERT, and BioM-ELECTRA, devised a rule-driven detection method for cell line and …

Improving Large Language Models For Clinical Named Entity Recognition Via Prompt Engineering, Yan Hu, Qingyu Chen, Jingcheng Du, Xueqing Peng, Vipina Kuttichi Keloth, Xu Zuo, Yujia Zhou, Zehan Li, Xiaoqian Jiang, Zhiyong Lu, Kirk Roberts, Hua Xu

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IMPORTANCE: The study highlights the potential of large language models, specifically GPT-3.5 and GPT-4, in processing complex clinical data and extracting meaningful information with minimal training data. By developing and refining prompt-based strategies, we can significantly enhance the models' performance, making them viable tools for clinical NER tasks and possibly reducing the reliance on extensive annotated datasets.

OBJECTIVES: This study quantifies the capabilities of GPT-3.5 and GPT-4 for clinical named entity recognition (NER) tasks and proposes task-specific prompts to improve their performance.

MATERIALS AND METHODS: We evaluated these models on 2 clinical NER tasks: (1) to extract medical problems, treatments, …

Target Engagement And Immunogenicity Of An Active Immunotherapeutic Targeting Pathological Α-Synuclein: A Phase 1 Placebo-Controlled Trial, Pepijn Eijsvogel, Pinaki Misra, Luis Concha-Marambio, Justin D Boyd, Shuang Ding, Lauren Fedor, Yueh-Ting Hsieh, Yu Shuang Sun, Madeline M Vroom, Carly M Farris, Yihua Ma, Marieke L De Kam, Igor Radanovic, Maurits F J M Vissers, Dario Mirski, Ghazal Shareghi, Mohammad Shahnawaz, Wolfgang Singer, Philip Kremer, Geert Jan Groeneveld, Hui Jing Yu, Jean-Cosme Dodart

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Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks …

Mechanistic Insights Into Metabolic Function Of Dynamin-Related Protein 1, Xin Li, Katherine Pham, Jazmin Ysaguirre, Iqbal Mahmud, Lin Tan, Bo Wei, Long J Shao, Maryam Elizondo, Rabie Habib, Fathima Elizondo, Hiromi Sesaki, Philip L Lorenzi, Kai Sun

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Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, …

An Analysis Of Suspected Microplastics In The Muscle And Gastrointestinal Tissues Of Fish From Sarasota Bay, Fl: Exposure And Implications For Apex Predators And Seafood Consumers, Eric Conger, Miranda Dziobak, Elizabeth J Berens Mccabe, Tita Curtin, Ayushi Gaur, Randall S Wells, John E Weinstein, Leslie B Hart

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Microplastics have been found in the gastrointestinal (GI) fluid of bottlenose dolphins (Tursiops truncatus), inhabiting Sarasota Bay, FL, suggesting exposure by ingestion, possibly via contaminated fish. To better understand the potential for trophic transfer, muscle and GI tissues from 11 species of dolphin prey fish collected from Sarasota Bay were screened for microplastics (particles <5 mm diameter). Suspected microplastics were found in 82% of muscle samples (n=89), and 97% of GI samples (n=86). Particle abundance and shapes varied by species (p<0.05) and foraging habit (omnivore vs. carnivore, p<0.05). Pinfish (Lagodon rhomboides) had the highest particle abundance for both tissue types (muscle: 0.38 …