Medical Specialties Commons^™

Reimagining Critical Care: Trends And Shifts In 21st Century Medicine, Sai Doppalapudi, Bilal Khan, Muhammad Adrish

Faculty, Staff and Students Publications

Critical care medicine has undergone significant evaluation in the 21st century, primarily driven by advancements in technology, changes in healthcare delivery, and a deeper understanding of disease processes. Advancements in technology have revolutionized patient monitoring, diagnosis, and treatment in the critical care setting. From minimally invasive procedures to advances imaging techniques, clinicians now have access to a wide array of tools to assess and manage critically ill patients more effectively. In this editorial we comment on the review article published by Padte S et al wherein they concisely describe the latest developments in critical care medicine.

Traumatic Brain Injury And Variants Of Shock Index, Sai Doppalapudi, Muhammad Adrish

Faculty, Staff and Students Publications

Traumatic Brain Injury is a major cause of death and long-term disability. The early identification of patients at high risk of mortality is important for both management and prognosis. Although many modified scoring systems have been developed for improving the prediction accuracy in patients with trauma, few studies have focused on prediction accuracy and application in patients with traumatic brain injury. The shock index (SI) which was first introduced in the 1960s has shown to strongly correlate degree of circulatory shock with increasing SI. In this editorial we comment on a publication by Carteri et al wherein they perform a …

Early Identification Of Hepatocellular Carcinoma Patients At High-Risk Of Recurrence Using The Adv Score: A Multicenter Retrospective Study, Shuya Cao, Zheyu Zhou, Chaobo Chen, Wenwen Li, Jinsong Liu, Jiawei Xu, Chunlong Zhao, Yihang Yuan, Zhenggang Xu, Huaiyu Wu, Guwei Ji, Xiaoliang Xu, Ke Wang

Faculty, Staff and Student Publications

BACKGROUND: Postoperative recurrence is a vital reason for poor 5-year overall survival in hepatocellular carcinoma (HCC) patients. The ADV score is considered a parameter that can quantify HCC aggressiveness. This study aimed to identify HCC patients at high-risk of recurrence early using the ADV score.

METHODS: The medical data of consecutive HCC patients undergoing hepatectomy from The First Affiliated Hospital of Nanjing Medical University (TFAHNJMU) and Nanjing Drum Tower Hospital (NJDTH) were retrospectively reviewed. Based on the status of microvascular invasion and the Edmondson-Steiner grade, HCC patients were divided into three groups: low-risk group (group 1: no risk factor exists), …

Single-Cell Chromatin Accessibility Reveals Malignant Regulatory Programs In Primary Human Cancers, Laksshman Sundaram, Arvind Kumar, Matthew Zatzman, Adriana Salcedo, Neal Ravindra, Shadi Shams, Bryan H Louie, S Tansu Bagdatli, Matthew A Myers, Shahab Sarmashghi, Hyo Young Choi, Won-Young Choi, Kathryn E Yost, Yanding Zhao, Jeffrey M Granja, Toshinori Hinoue, D Neil Hayes, Andrew Cherniack, Ina Felau, Hani Choudhry, Jean C Zenklusen, Kyle Kai-How Farh, Andrew Mcpherson, Christina Curtis, Peter W Laird, Cancer Genome Atlas Analysis Network, John A Demchok, Liming Yang, Roy Tarnuzzer, Samantha J Caesar-Johnson, Zhining Wang, Ashley S Doane, Ekta Khurana, Mauro A A Castro, Alexander J Lazar, Bradley M Broom, John N Weinstein, Rehan Akbani, Shwetha V Kumar, Benjamin J Raphael, Christopher K Wong, Joshua M Stuart, Rojin Safavi, Christopher C Benz, Benjamin K Johnson, Cindy Kyi, Hui Shen, M Ryan Corces, Howard Y Chang, William J Greenleaf

Faculty, Staff and Student Publications

To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting …

Identification Of A Clade-Specific Hla-C*03:02 Ctl Epitope Gy9 Derived From The Hiv-1 P17 Matrix Protein, Samuel Kyobe, Savannah Mwesigwa, Gyaviira Nkurunungi, Gaone Retshabile, Moses Egesa, Eric Katagirya, Marion Amujal, Busisiwe C Mlotshwa, Lesedi Williams, Hakim Sendagire, On Behalf Of The Cafgen Consortium, Dithan Kiragga, Graeme Mardon, Mogomotsi Matshaba, Neil A Hanchard, Jacqueline Kyosiimire-Lugemwa, David Robinson

Faculty, Staff and Students Publications

Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02 CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope potentially restricted to HLA-C*03:02. Residues …

Correction: Facilitators And Barriers To Initiating And Completing Tuberculosis Preventive Treatment Among Children And Adolescents Living With Hiv In Uganda: A Qualitative Study Of Adolescents, Caretakers And Health Workers, Pauline Mary Amuge, Denis Ndekezi, Moses Mugerwa, Dickson Bbuye, Diana Antonia Rutebarika, Lubega Kizza, Christine Namugwanya, Angella Baita, Peter James Elyanu, Patricia Nahirya Ntege, Dithan Kiragga, Carol Birungi, Adeodata Rukyalekere Kekitiinwa, Agnes Kiragga, Moorine Peninah Sekadde, Nicole Salazar-Austin, Anna Maria Mandalakas, Philippa Musoke

Faculty, Staff and Students Publications

No abstract provided.

A Rapid Non-Invasive Wearable Device For Assessing Cardiac Troponin, William Franklin Peacock, Karina Melissa Soto-Ruiz, Allan S Jaffe, Brian R Tiffany, Simon A Mahler, Brian W Patterson, Alan Hb Wu, Robert Christenson

Faculty, Staff and Students Publications

Background: Chest pain, a common emergency department 35 (ED) presentation, requires rapid evaluation. Optical technology-based non-invasive wearable devices (Infrasensor, RCE, Carlsbad, CA) rapidly and transcutaneously assesses cardiac Troponin I (cTnI).

Objectives: To perform a pilot study describing the performance of the Infrasensor in cTnI defined cohorts.

Methods: This was a 10-hospital prospective observational study in healthy US subjects with a normal cTnI, and in patients with an elevated local cTnI. Healthy subjects were without disease, defined by a negative questionnaire and bloodwork, had a 3-minute Infrasensor measurement and blood samples for high-sensitivity cardiac troponin I (hs-cTnI), n-terminal pro-B-type natriuretic peptide …

A Systematic Review Of The Timing Of Therapeutic Anticoagulation In Adult Patients With Acute Traumatic Brain Injury: Narrative Synthesis Of Observational Studies, Sophie Samuel, Jennifer Cortes, Eugene Uh, Huimahn Alex Choi

Library Staff Publications

Traumatic brain injury (TBI) presents complex management scenarios, particularly in patients requiring anticoagulation for concurrent conditions such as venous thromboembolism (VTE) or atrial fibrillation (AF). A systematic search of PubMed/MEDLINE, Embase, and the Cochrane Library databases was conducted to identify relevant studies. Inclusion criteria encompassed studies assessing the effects of anticoagulation therapy on outcomes such as re-hemorrhage, hematoma expansion, thrombotic events, and hemorrhagic events in TBI patients with subdural hematomas (SDH). This systematic review critically addresses two key questions: the optimal timing for initiating anticoagulation therapy and the differential impact of this timing based on the type of intracranial bleed, …

Small Gtp-Binding Protein Gdp Dissociation Stimulator Influences Cisplatin-Induced Acute Kidney Injury Via Perk-Dependent Er Stress, Yuxue Yang, Ting Xiong, Ti Wang, Xiwei Chen, Ziwei Ma, Bangyun Zuo, Dong Ning, Ruilong Song, Xuesong Liu, Daxin Wang

Children’s Nutrition Research Center Staff Publications

Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK …

90y Sir-Spheres Activity Measurement With New Siros D-Vial Delivery Kit, Benjamin P Lopez, S Cheenu Kappadath

Faculty, Staff and Student Publications

A new 90Y SIR-Spheres delivery kit (SIROS D-vial and shield) has been introduced with a different physical form from the legacy V-Vial kit. Here, we establish the dose calibrator settings and exposure-rate-to-activity conversion factor to assay 90Y SIR-Spheres activity in the new SIROS kit.

Methods: Eight D-vials with initial 90Y activities from 1.2 to 6.6 GBq within acrylic shields were assayed with dose calibrators and exposure-rate meters until activities decayed to approximately 0.1 GBq. The dose calibrator settings resulting in the lowest median activity errors and the best-fit slope of exposure rate versus activity were identified.

Results: SIROS D-vial 90Y …

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 …

Rna Interacts With Topoisomerase I To Adjust Dna Topology, Mannan Bhola, Kouki Abe, Paola Orozco, Homa Rahnamoun, Pedro Avila-Lopez, Elijah Taylor, Nefertiti Muhammad, Bei Liu, Prachi Patel, John F Marko, Anne C Starner, Chuan He, Eric L Van Nostrand, Alfonso Mondragón, Shannon M Lauberth

Faculty, Staff and Students Publications

Topoisomerase I (TOP1) is an essential enzyme that relaxes DNA to prevent and dissipate torsional stress during transcription. However, the mechanisms underlying the regulation of TOP1 activity remain elusive. Using enhanced cross-linking and immunoprecipitation (eCLIP) and ultraviolet-cross-linked RNA immunoprecipitation followed by total RNA sequencing (UV-RIP-seq) in human colon cancer cells along with RNA electrophoretic mobility shift assays (EMSAs), biolayer interferometry (BLI), and in vitro RNA-binding assays, we identify TOP1 as an RNA-binding protein (RBP). We show that TOP1 directly binds RNA in vitro and in cells and that most RNAs bound by TOP1 are mRNAs. Using a TOP1 RNA-binding mutant …

Tulips Decorate The Three-Dimensional Genome Of Pfa Ependymoma, Michael J Johnston, John J Y Lee, Bo Hu, Ana Nikolic, Elham Hasheminasabgorji, Audrey Baguette, Seungil Paik, Haifen Chen, Sachin Kumar, Carol C L Chen, Selin Jessa, Polina Balin, Vernon Fong, Melissa Zwaig, Kulandaimanuvel Antony Michealraj, Xun Chen, Yanlin Zhang, Srinidhi Varadharajan, Pierre Billon, Nikoleta Juretic, Craig Daniels, Amulya Nageswara Rao, Caterina Giannini, Eric M Thompson, Miklos Garami, Peter Hauser, Timea Pocza, Young Shin Ra, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa Grajkowska, Marta Perek-Polnik, Sameer Agnihotri, Stephen Mack, Benjamin Ellezam, Alex Weil, Jeremy Rich, Guillaume Bourque, Jennifer A Chan, V Wee Yong, Mathieu Lupien, Jiannis Ragoussis, Claudia Kleinman, Jacek Majewski, Mathieu Blanchette, Nada Jabado, Michael D Taylor, Marco Gallo

Faculty, Staff and Students Publications

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in …

Cyp3a-Mediated Carbon-Carbon Bond Cleavages In Drug Metabolism, Junhui Zhou, Xuan Qin, Shenzhi Zhou, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Cytochrome P450 enzymes (P450s) play a critical role in drug metabolism, with the CYP3A subfamily being responsible for the biotransformation of over 50% of marked drugs. While CYP3A enzymes are known for their extensive catalytic versatility, one intriguing and less understood function is the ability to mediate carbon-carbon (C-C) bond cleavage. These uncommon reactions can lead to unusual metabolites and potentially influence drug safety and efficacy. This review focuses on examining examples of C-C bond cleavage catalyzed by CYP3A, exploring the mechanisms, physiological significance, and implications for drug metabolism. Additionally, examples of CYP3A-mediated ring expansion via C-C bond cleavages are …

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

Faculty, Staff and Student Publications

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 …

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

Faculty, Staff and Student Publications

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 …

Cystic Fibrosis-Related Diabetes Screening At A Large Pediatric Center, Anil K Chokkalla, Pamela Tuley, Miray Kurtca, Herda Ona, Fadel E Ruiz, Sridevi Devaraj

Faculty, Staff and Students Publications

Objective: Cystic Fibrosis Foundation guidelines recommend annual diabetes screening by oral glucose tolerance test (OGTT) in pediatric patients with cystic fibrosis (CF) starting at the age of 10 years. Adherence to these guidelines proves to be challenging, and the nationwide screening rates are still considered suboptimal. The aim of this study was to assess and improve the screening rates at our large pediatric center.

Methods: A 4-year retrospective audit of OGTT completion among pediatric patients with CF of age ≥10 years who are not yet diagnosed with diabetes was conducted. A collaborative working group was formed to identify the barriers …

Parasitic Contamination Of Soil In The Southern United States, Christine Crudo Blackburn, Sally Mingshuang Yan, David Mccormick, Lauren Nicholas Herrera, Roumen Borilov Iordanov, Mark Daniel Bailey, Maria Elena Bottazzi, Peter J Hotez, Rojelio Mejia

Faculty, Staff and Students Publications

Parasites are generally associated with lower income countries in tropical and subtropical areas. Still, they are also prevalent in low-income communities in the southern United States. Studies characterizing the epidemiology of parasites in the United States are limited, resulting in little comprehensive understanding of the problem. This study investigated the environmental contamination of parasites in the southern United States by determining each parasite's contamination rate and burden in five low-income communities. A total of 499 soil samples of approximately 50 g were collected from public parks and private residences in Alabama, Louisiana, Mississippi, South Carolina, and Texas. A technique using …

Myc Induces Oncogenic Stress Through Rna Decay And Ribonucleotide Catabolism In Breast Cancer, Jitendra K Meena, Jarey H Wang, Nicholas J Neill, Dianne Keough, Nagireddy Putluri, Panagiotis Katsonis, Amanda M Koire, Hyemin Lee, Elizabeth A Bowling, Siddhartha Tyagi, Mayra Orellana, Rocio Dominguez-Vidaña, Heyuan Li, Kenneth Eagle, Charles Danan, Hsiang-Ching Chung, Andrew D Yang, William Wu, Sarah J Kurley, Brian M Ho, Joseph R Zoeller, Calla M Olson, Kristen L Meerbrey, Olivier Lichtarge, Arun Sreekumar, Clifford C Dacso, Luke W Guddat, Dominik Rejman, Dana Hocková, Zlatko Janeba, Lukas M Simon, Charles Y Lin, Monica C Pillon, Thomas F Westbrook

Faculty, Staff and Students Publications

Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting …

The Prognostic Effect Of Infiltrating Immune Cells Is Shaped By Proximal M2 Macrophages In Lung Adenocarcinoma, Jian-Rong Li, Vikram Shaw, Yupei Lin, Xiang Wang, Muhammad Aminu, Yong Li, Jia Wu, Jianjun Zhang, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density …

Prospects And Challenges Of Tissue-Derived Extracellular Vesicles, Justin C Lee, Roslyn M Ray, Tristan A Scott

Faculty, Staff and Students Publications

Extracellular vesicles (EVs) are considered a vital component of cell-to-cell communication and represent a new frontier in diagnostics and a means to identify pathways for therapeutic intervention. Recently, studies have revealed the importance of tissue-derived EVs (Ti-EVs), which are EVs present in the interstitial spaces between cells, as they better represent the underlying physiology of complex, multicellular tissue microenvironments in biology and disease. EVs are native, lipid bilayer membraned nano-sized particles produced by all cells that are packaged with varied functional biomolecules including proteins, lipids, and nucleic acids. They are implicated in short- and long-range cellular communication and may elicit …

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. …

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.