Digital Commons Network^™

Mitochondrial Reprogramming By Activating Oxphos Via Glutamine Metabolism In African American Patients With Bladder Cancer, Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Vasanta Putluri, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Jun Xu, Daniel Kraushaar, Shixia Huang, Sung Yun Jung, Livia S Eberlin, Jabril R Johnson, Rick A Kittles, Leomar Y Ballester, Krishna Parsawar, M Minhaj Siddiqui, Jianjun Gao, Adriana Langer Gramer, Roni J Bollag, Martha K Terris, Yair Lotan, Chad J Creighton, Seth P Lerner, Arun Sreekumar, Benny Abraham Kaipparettu, Nagireddy Putluri

Faculty, Staff and Students Publications

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further …

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 …

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 …

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), …

Treatment Of Acute Myeloid Leukemia In The Community Setting, Taha Al-Juhaishi, Servillano Dela Cruz, Rohan Gupta, Gina Keiffer, Vicki Morrison, Iuliana Shapira, Ashley Woods, Kelly Norsworthy, Romeo Angelo De Claro, Marc Theoret, Ravin Garg, Elizabeth Dianne Pulte

Kimmel Cancer Center Faculty Papers

The treatment landscape for acute myeloid leukemia (AML) is rapidly changing. Many new agents and lower-intensity regimens have been approved and can be safely used by hematologists and oncologists in both academic and community settings. The US Food and Drug Administration (FDA) held a virtual symposium on AML treatment in the community in November 2022. Several members of the FDA, along with practicing hematologists and oncologists in both academic and community settings, participated in the symposium. The goal of the symposium was to discuss challenges and opportunities in the treatment of patients with AML in community oncology settings. A summary …

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 …

Substitution Of A Single Non-Coding Nucleotide Upstream Of Tmem216 Causes Non-Syndromic Retinitis Pigmentosa And Is Associated With Reduced Tmem216 Expression, Samantha Malka, Pooja Biswas, Anne-Marie Berry, Riccardo Sangermano, Mukhtar Ullah, Siying Lin, Matteo D'Antonio, Aleksandr Jestin, Xiaodong Jiao, Mathieu Quinodoz, Lori Sullivan, Jessica C Gardner, Emily M Place, Michel Michaelides, Karolina Kaminska, Omar A Mahroo, Elena Schiff, Genevieve Wright, Francesca Cancellieri, Veronika Vaclavik, Cristina Santos, Atta Ur Rehman, Sudeep Mehrotra, Hafiz Muhammad Azhar Baig, Muhammad Iqbal, Muhammad Ansar, Luisa Coutinho Santos, Ana Berta Sousa, Viet H Tran, Hiroko Matsui, Anjana Bhatia, Muhammad Asif Naeem, Shehla J Akram, Javed Akram, Sheikh Riazuddin, Carmen Ayuso, Eric A Pierce, Alison J Hardcastle, S Amer Riazuddin, Kelly A Frazer, J Fielding Hejtmancik, Carlo Rivolta, Kinga M Bujakowska, Gavin Arno, Andrew R Webster, Radha Ayyagari

Faculty, Staff and Student Publications

Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation …

Current Diagnostic And Quantitative Techniques In The Field Of Lymphedema Management: A Critical Review, Mary Vargo, Melissa Aldrich, Paula Donahue, Emily Iker, Louise Koelmeyer, Rachelle Crescenzi, Andrea Cheville

The Brown Foundation: Institute of Molecular Medicine

Lymphedema evaluation entails multifaceted considerations for which options continue to evolve and emerge. This paper provides a critical review of the current status of diagnostic and quantitative measures for lymphedema, from traditional and novel bedside assessment tools for volumetric and fluid assessment, to advanced imaging modalities. Modalities are contrasted with regard to empirical support and feasibility of clinical implementation. The manuscript proposes a grid framework for comparing the ability of each modality to quantify specific lymphedema characteristics, including distribution, dysmorphism, tissue composition and fluid content, lymphatic anatomy and function, metaplasia, clinical symptoms, and quality of life and function. This review …

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 …

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 …

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

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 …

Preexisting Skin-Resident Cd8 And Γδ T-Cell Circuits Mediate Immune Response In Merkel Cell Carcinoma And Predict Immunotherapy Efficacy, Zachary Z Reinstein, Yue Zhang, Oscar E Ospina, Matt D Nichols, Victoria A Chu, Alvaro De Mingo Pulido, Karol Prieto, Jonathan V Nguyen, Rui Yin, Carlos Moran Segura, Ahmed Usman, Brittney Sell, Spencer Ng, Janis V De La Iglesia, Sunandana Chandra, Jeffrey A Sosman, Raymond J Cho, Jeffrey B Cheng, Ellie Ivanova, Sergei B Koralov, Robbert J C Slebos, Christine H Chung, Nikhil I Khushalani, Jane L Messina, Amod A Sarnaik, Jonathan S Zager, Vernon K Sondak, Charles Vaske, Sungjune Kim, Andrew S Brohl, Xinlei Mi, Brian G Pierce, Xuefeng Wang, Brooke L Fridley, Kenneth Y Tsai, Jaehyuk Choi

Staff and Researcher Publications

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL-1. Responders have increased type I/II interferons and pre-existing tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs. Spatial …

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 …

Diurnal Rhythms In Varicella Vaccine Effectiveness, Dana Danino, Yoav Kalron, Jeffrey A. Haspel, Guy Hazan

2020-Current year OA Pubs

BACKGROUNDImmune processes are influenced by circadian rhythms. We evaluate the association between varicella vaccine administration time of day and vaccine effectiveness.METHODSA national cohort, children younger than 6 years, were enrolled between January 2002 and December 2023. We compared children vaccinated during morning (7:00-10:59), late morning to afternoon (11:00-15:59), or evening hours (16:00-19:59). A Cox proportional hazards regression model was used to adjust for ethnicity, sex, and comorbidities. The first varicella infection occurring at least 14 days after vaccination and a second dose administration were treated as terminal events.RESULTSOf 251,141 vaccinated children, 4,501 (1.8%) experienced breakthrough infections. Infection rates differed based …

Proteomic Correlates And Prognostic Significance Of Kidney Injury In Heart Failure With Preserved Ejection Fraction, Oday Salman, Ali Javaheri, Douglas L Mann, Et Al.

2020-Current year OA Pubs

BACKGROUND: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear.

METHODS AND RESULTS: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death …

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. …

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.

Racial And Ethnic Representation In Food Allergen Immunotherapy Trial Participants: A Systematic Review., Hannah Suffian, Aarti Pandya, Lauren Davidson, Vincent Staggs, Bridgette Jones

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: The lack of inclusion of diverse population samples in food allergy immunotherapy clinical trials not only leads to decreased applicability to the general population in terms of results and treatments but can also be seen as a broader social injustice contributing to inequity within the health care system.

OBJECTIVES: To investigate the racial and ethnic distribution of participants included in food allergy immunotherapy clinical trials, and determine whether the racial and ethnic representation in trials accurately reflects the patients who experience food allergy.

EVIDENCE REVIEW: Data were collected from articles found on PubMed and ClinicalTrials.gov using key terms of …

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.