Medical Specialties Commons^™

Genome-Wide Association Study Meta-Analysis Of Neurofilament Light (Nfl) Levels In Blood Reveals Novel Loci Related To Neurodegeneration, Shahzad Ahmad, Mohammad Aslam Imtiaz, Aniket Mishra, Ruiqi Wang, Marisol Herrera-Rivero, Joshua C Bis, Myriam Fornage, Gennady Roshchupkin, Edith Hofer, Mark Logue, W T Longstreth, Rui Xia, Vincent Bouteloup, Thomas Mosley, Lenore J Launer, Michael Khalil, Jens Kuhle, Robert A Rissman, Genevieve Chene, Carole Dufouil, Luc Djoussé, Michael J Lyons, Kenneth J Mukamal, William S Kremen, Carol E Franz, Reinhold Schmidt, Stephanie Debette, Monique M B Breteler, Klaus Berger, Qiong Yang, Sudha Seshadri, N Ahmad Aziz, Mohsen Ghanbari, M Arfan Ikram

Faculty, Staff and Student Publications

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify …

Parp-1 Selectively Impairs Kras-Driven Phenotypic And Molecular Features In Intrahepatic Cholangiocarcinoma, Friederike L Keggenhoff, Darko Castven, Diana Becker, Stojan Stojkovic, Jovana Castven, Carolin Zimpel, Beate K Straub, Tiemo Gerber, Harald Langer, Patricia Hähnel, Thomas Kindler, Jörg Fahrer, Colm J O'Rourke, Ursula Ehmer, Anna Saborowski, Lichun Ma, Xin Wei Wang, Timo Gaiser, Matthias S Matter, Christian Sina, Stefanie Derer, Ju-Seog Lee, Stephanie Roessler, Bernd Kaina, Jesper B Andersen, Peter R Galle, Jens U Marquardt

Faculty, Staff and Student Publications

Objective: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined.

Design: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular …

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

Fibrotic Response To Anti-Csf-1r Therapy Potentiates Glioblastoma Recurrence, Spencer S Watson, Anoek Zomer, Nadine Fournier, Joao Lourenco, Manfredo Quadroni, Agnieszka Chryplewicz, Sina Nassiri, Pauline Aubel, Simona Avanthay, Davide Croci, Erik Abels, Marike L D Broekman, Douglas Hanahan, Jason T Huse, Roy T Daniel, Monika E Hegi, Krisztian Homicsko, Giulia Cossu, Andreas F Hottinger, Johanna A Joyce

Faculty, Staff and Student Publications

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment …

Training Robust T1-Weighted Magnetic Resonance Imaging Liver Segmentation Models Using Ensembles Of Datasets With Different Contrast Protocols And Liver Disease Etiologies, Nihil Patel, Adrian Celaya, Mohamed Eltaher, Rachel Glenn, Kari Brewer Savannah, Kristy K Brock, Jessica I Sanchez, Tiffany L Calderone, Darrel Cleere, Ahmed Elsaiey, Matthew Cagley, Nakul Gupta, David Victor, Laura Beretta, Eugene J Koay, Tucker J Netherton, David T Fuentes

Faculty, Staff and Student Publications

Image segmentation of the liver is an important step in treatment planning for liver cancer. However, manual segmentation at a large scale is not practical, leading to increasing reliance on deep learning models to automatically segment the liver. This manuscript develops a generalizable deep learning model to segment the liver on T1-weighted MR images. In particular, three distinct deep learning architectures (nnUNet, PocketNet, Swin UNETR) were considered using data gathered from six geographically different institutions. A total of 819 T1-weighted MR images were gathered from both public and internal sources. Our experiments compared each architecture's testing performance when trained both …

Project Give: Using A Virtual Genetics Service Platform To Reduce Health Inequities And Improve Access To Genomic Care In An Underserved Region Of Texas, Blake Vuocolo, Roberta Sierra, Daniel Brooks, Christopher Holder, Lauren Urbanski, Keila Rodriguez, Jose David Gamez, Surya Narayan Mulukutla, Ana Hernandez, Alberto Allegre, Humberto Hidalgo, Sarah Rodriguez, Sandy Magallan, Jeremy Gibson, Juan Carlos Bernini, Melanie Watson, Robert Nelson, Lizbeth Mellin-Sanchez, Nancy Garcia, Lori Berry, Hongzheng Dai, Claudia Soler-Alfonso, Kent Carter, Brendan Lee, Seema R Lalani

Faculty, Staff and Students Publications

BACKGROUND: The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services. Funded by the National Center for Advancing Translational Sciences, Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to reduce the time to diagnosis and increase provider knowledge of genomics in this region, with the goal of …

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 …

Conducting Comparative Effectiveness, Multisite Palliative Care And Advance Care Planning Trials: Lessons Learned And Future Directions From Pcori-Funded Studies, Areej El-Jawahri, Brittany Waterman, Susan Enguidanos, Lisa Gibbs, Victor Navarro, Maren Olsen, Jennifer Temel, Annette Totten, Corita R. Grudzen

Department of Medicine Faculty Papers

The Patient-Centered Outcomes Research Institute (PCORI) funded multiple large-scale comparative effectiveness clinical trials evaluating palliative care (PC) and advance care planning (ACP) healthcare delivery models. This article provides an overview of the most common barriers our investigative teams encountered while implementing these trials and the strategies we utilized to overcome these challenges, with particular attention to identifying research partners for multisite trials; addressing contracting and regulatory issues; creating a team governance structure; training and engaging study staff across sites; recruiting, consenting, and enrolling study participants; collecting PC and ACP data and study outcomes; and managing multisite collaborations. The goal of …

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, …

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 …

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 …

Intracellular Islatravir-Triphosphate Half-Life Supports Extended Dosing Intervals, Xiaowei Zang, Wendy Ankrom, Walter K. Kraft, Ryan Vargo, S Aubrey Stoch, Marian Iwamoto, Randolph P Matthews

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 …

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 …

Residual Stroke Risk Among Patients With Atrial Fibrillation Prescribed Oral Anticoagulants: A Patient-Level Meta-Analysis From Combine Af, Linda Johnson, Alexander Benz, Ashkan Shoamanesh, John W Eikelboom, Michael Ezekowitz, Robert Giugliano, Lars Wallentin, Christian Ruff, Renato Lopes, Sanjit Jolly, Richard Whitlock, Christopher Granger, Stuart Connolly, Jeffrey Healey

Division of Cardiology Faculty Papers

Background: Despite oral anticoagulation, patients with atrial fibrillation (AF) remain at risk of ischemic stroke and systemic embolism (SE) events. For patients whose residual risk is sufficiently high, additional therapies might be useful to mitigate stroke risk.

Methods and results: Individual patient data from 5 landmark trials testing oral anticoagulation in AF were pooled in A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in AF (COMBINE AF). We calculated the rate of ischemic stroke/SE among oral anticoagulation-treated patients with a CHA₂DS₂-VASc score≥2, across strata of CHA₂DS₂-VASc …

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 …

Association Between Obesity And Risk Of Total And Obesity-Related Cancer In People With Incident Cardiovascular Disease., Sarah Malik, Avirup Guha, Xiaoling Wang, Neal L. Weintraub, Ryan Harris, Biplab Datta, Justin Moore, Priyanshu Nain, Sagar A. Patel, Steven Coughlin, Elizabeth Polter, Anna Prizment, Anne Blaes, Roberta Florido, Shelby Kutty, Alvaro Alonso, Corinne E. Joshu, Elizabeth A. Platz

Markey Cancer Center Faculty Publications

BACKGROUND: Cardiovascular disease (CVD) and cancer frequently co-occur due to shared risk factors such as obesity, which is linked to CVD and 14 cancer types. This study explores whether CVD pathophysiologies, combined with obesity, increase cancer risk, impacting clinical management.

METHODS AND RESULTS: Data from the ARIC (Atherosclerosis Risk in Communities) study, spanning 28 years, were analyzed. The cohort included 5127 participants with incident CVD (myocardial infarction, stroke, heart failure, coronary heart disease), of whom 1511 developed a first primary cancer. Follow-up began at CVD diagnosis after Visit 1. Obesity was assessed using body mass index, waist circumference, and waist-to-hip …