Medical Specialties Commons^™

Loss Of Ptdss1 In Tumor Cells Improves Immunogenicity And Response To Anti-Pd-1 Therapy, Jielin Liu, Shelley Herbrich, Sreyashi Basu, Yulong Chen, Ashwat Nagarajan, Swetha Anandhan, Sangeeta Goswami, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma

Faculty, Staff and Student Publications

PTDSS1 (phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of Ptdss1 in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-γ stimulation in vitro. Loss of Ptdss1 in tumor cells also led to increased expression of MHC-I, enhanced cytotoxicity of CD8+ T cells, and increased frequency of an iNOS+ myeloid subset. A gene signature derived from the …

The Colonic Crypt: Cellular Dynamics And Signaling Pathways In Homeostasis And Cancer, Anh L. Nguyen, Molly A. Lausten, Bruce M. Boman

College of Life Sciences Faculty Papers

The goal of this review is to expand our understanding of how the cellular organization of the normal colonic crypt is maintained and elucidate how this intricate architecture is disrupted during tumorigenesis. Additionally, it will focus on implications for new therapeutic strategies targeting Epithelial-Mesenchymal Transition (EMT). The colonic crypt is a highly structured epithelial unit that functions in maintaining homeostasis through a complex physiological function of diverse cell types: SCs, transit-amplifying (TA) progenitors, goblet cells, absorptive colonocytes, Paneth-like cells, M cells, tuft cells, and enteroendocrine cells. These cellular subpopulations are spatially organized and regulated by multiple crucial signaling pathways, including …

Neurotransmitter Signaling In Molecular And Behavioral Immune Responses To Pathogens In C Elegans, Benson Otarigho, Alejandro Aballay

Faculty, Staff and Student Publications

Neurotransmitter signaling pathways play major roles in both molecular and behavioral defenses against pathogen invasion, shaping the ability of Caenorhabditis elegans to sense and respond to environmental challenges. Given the conservation of neurotransmitter signaling pathways, their understanding may not only provide insights into the neurobiology of C. elegans but also has broader implications for our understanding of neural-immune interactions and host defense mechanisms in higher organisms. In this review, we discussed the literature on various neurotransmitter signaling pathways, including serotonergic, dopaminergic/octopaminergic, GABAergic, and glutamatergic pathways, and how these pathways modulate molecular and behavioral immune defense against pathogens.

Human Toxocariasis, Susana Lopez-Alamillo, Pravallika Padyala, Megan Carey, Megan M Duffey, Jill E Weatherhead

Faculty, Staff and Students Publications

Human toxocariasis is a globally prevalent zoonotic parasitic infection caused by larvae of Toxocara species, primarily Toxocara canis and Toxocara cati. Toxocariasis is commonly transmitted to humans through the ingestion of embryonated Toxocara eggs found in contaminated soil, water, or on surfaces contaminated with animal feces. Unlike in dogs and cats, humans are not definitive hosts for Toxocara spp., and, as a result, Toxocara larvae do not complete their life cycle in humans. Instead, following accidental oral ingestion of embryonated eggs, Toxocara larvae undergo an aberrant larval migratory cycle to various organs including the lungs, liver, muscles, and central …

National Alliance Of Sickle Cell Centers Consensus Standards For Transition To Adult Care In Sickle Cell Disease, Stephanie Howe Guarino, Akshat Jain, Mohan Madisetti, Kenneth Rivlin, Payal C. Desai, Julie Kanter, Sophie Lanzkron, Deepa Manwani

Division of Gastroenterology and Hepatology Faculty Papers

Sickle cell disease (SCD), an autosomal recessive hemoglobinopathy, affects ∼100 000 people in the United States.1 The process of transitioning from pediatric to adult SCD health care systems can be disjointed and poorly coordinated, contributing to the high morbidity and mortality seen in this population. There is no universally accepted definition of a successful SCD care transition, nor are there existing standards and recommendations for SCD clinicians. National Alliance of Sickle Cell Centers (NASCC) uses a described modified Delphi process to reach consensus among its members, through which we defined standards and recommendations for transitioning care from pediatric to adult …

Innate And Adaptive Immune Features Associated With Immune-Related Adverse Events, Shaheen Khan, Venkat S Malladi, Mitchell S Von Itzstein, Hong Mu-Mosley, Farjana J Fattah, Yang Liu, Mary E Gwin, Jason Y Park, Suzanne M Cole, Sheena Bhalla, Jay Lohrey, David Hsiehchen, Angela Moses, Tao Wang, Yaming Xue, Angela B Mobley, J David Farrar, Marjaan Imam, Michelle Wu, Quan-Zhen Li, Edward K Wakeland, Yang Xie, Jeffrey A Sorelle, David E Gerber

Faculty, Staff and Student Publications

Background: While highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potentially severe immune-related adverse events (irAEs), underscoring the need to understand irAE biology.

Methods: We used a multidimensional approach incorporating single-cell RNA sequencing, mass cytometry, multiplex cytokine assay, and antinuclear antibody (ANA) profiling to characterize the peripheral immune landscape of patients receiving ICI therapy according to irAE development.

Results: Analysis of 162 patients revealed that individuals who developed clinically significant irAEs exhibited a baseline proinflammatory, autoimmune-like state characterized by a significantly higher abundance of CD57+ T and natural killer (NK) T cells, plasmablasts, proliferating and …

Infectious Prions In Brains And Muscles Of Domestic Pigs Experimentally Challenged With The Bse, Scrapie, And Cwd Agents, Francisca Bravo-Risi, Fraser Brydon, Angela Chong, Kane Spicker, Justin J Greenlee, Glenn Telling, Claudio Soto, Sandra Pritzkow, Marcelo A Barria, Rodrigo Morales

Faculty, Staff and Student Publications

Experimental studies suggest that animal species not previously described as naturally infected by prions are susceptible to prion diseases affecting sheep, cattle, and deer. These interspecies transmissions may generate prions with unknown host ranges. Pigs are susceptible to prions from different origins, including deer chronic wasting disease (CWD), sheep scrapie, and bovine spongiform encephalopathy (BSE). Here, we studied prions in brains and muscles from pigs previously infected with these different prion sources. Specifically, we measured the total prion protein (PrP) and PK-resistant PrP by western blot. Seeding activity in these tissues was evaluated using the protein misfolding cyclic amplification (PMCA) …

High Beta Power In The Ventrolateral Prefrontal Cortex Indexes Human Approach Behavior: A Case Study, Nicole R Provenza, Sameer V Rajesh, Gabriel Reyes, Kalman A Katlowitz, Lokesha S Pugalenthi, Raphael A Bechtold, Nabeel Diab, Sandesh Reddy, Anthony K Allam, Ajay D Gandhi, Katherine E Kabotyanski, Kasra A Mansourian, Jonathan H Bentley, Jordan R Altman, Saurabh Hinduja, Nisha Giridharan, Garrett P Banks, Mohammed Hasen, Ben Shofty, Sarah R Heilbronner, Jeffrey F Cohn, David A Borton, Eric A Storch, Jeffrey A Herron, Benjamin Y Hayden, Mary L Phillips, Wayne K Goodman, Sameer A Sheth

Faculty, Staff and Students Publications

Deep brain stimulation (DBS) of the ventral capsule and ventral striatum (VC/VS) is an effective therapy for treatment-resistant obsessive–compulsive disorder (trOCD). DBS initiation often produces acute improvements in mood and energy. These acute behavioral changes, which we refer to as “approach behaviors,” include increased social engagement and talkativeness. We investigated the relationship between stimulation amplitude, spectral power in the ventrolateral prefrontal cortex (vlPFC), and speech rate in one male patient with trOCD implanted with bilateral VC/VS DBS leads and subdural electrodes adjacent to the orbitofrontal cortex and vlPFC. Several times over the first 24 weeks of therapy, we conducted experiments …

Development Of A Patient-Centered Outcome Tool For Blepharospasm: A Stepwise Modified Delphi Study, Brian D Berman, Fares Qeadan, Amanda D Henderson, Andrew R Harrison, Giovanni Defazio, Mark Hallett, Gamze Kilic-Berkmen, Laura Wright, Samantha Pentecost, Paul Reyes, Anna Tingin, Joseph Jankovic, Jane Boyd, Charlene Hudgins, Janet Hieshetter, Joel S Perlmutter, Hyder A Jinnah, Sarah Pirio Richardson

Faculty, Staff and Students Publications

Blepharospasm (BSP) is characterized by excessive orbicularis oculi muscle activity leading to abnormal blinking and involuntary eyelid closure. Botulinum neurotoxin (BoNT) injections are the main treatment for BSP, but they only partially and transiently relieve symptoms, leading to a waxing and waning therapeutic response. A patient-centered outcome (PCO) tool that measures BSP symptoms in a simple and efficient way could inform the development of better treatments. Using a stepwise modified Delphi approach, potential PCO items were first identified using the Dystonia Coalition Database with data from over 200 individuals with BSP who had provided responses to existing clinical assessment scales. …

Up-Front Alternative Donor Hct In Severe Aplastic Anemia: Gaps And Opportunities To Translate Evidence Into Practice., Neel S Bhatt, Azra Borogovac, Yvonne A Efebera, Anna Desalvo, Steven M Devine, Amy Foley, Valerie Greco-Stewart, Betty K Hamilton, Mykala Heuer, Todd Molfenter, John P Plastaras, Brittany K Ragon, Sarah A Wall, Larisa Broglie, Mark B Juckett, Nandita Khera, Mary M Horowitz, Amy E Dezern

Oncology Articles

Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). …

Computationally Resolved Neuroprogenitor Cell Biomarkers Associate With Human Disorders, Gerarda Cappuccio, William T Choi, Fatih Semerci, Jill A Rosenfeld, Toni Claire Tacorda, Guantong Qi, Anthony W Zoghbi, Yi Zhong, Hu Chen, Pengfei Liu, Zhandong Liu, Mirjana Maletić-Savatić

Duncan NRI Faculty and Staff Publications

Adult hippocampal neurogenesis, the process of generating new neurons, relies on a rare population of neural stem and progenitor cells (NPCs) within the dentate gyrus complex microenvironment. Discovering the specific genes that define these cells is vital yet challenging due to overlapping expression patterns, limiting detection of rare cell populations using traditional approaches. By employing the computational digital sorting algorithm (DSA) that deconvolves complex gene expression data based on pattern recognition, we identified 129 genes enriched in murine NPCs. We validated these genes against published single-cell RNA sequencing (scRNA-seq) data and discovered that 25 human orthologs were known to cause …

Evaluation Of In Vivo Car Transgene Levels In Tisagenlecleucel-Treated Patients With Relapsed/Refractory B-All And Dlbcl., Rakesh Awasthi, Stephan A. Grupp, Edward R. Waldron, Gregory A. Yanik, Constantine S. Tam, Susana Rives, Joseph P. Mcguirk, Michael A. Pulsipher, Ulrich Jaeger, Douglas Myers, Peter Borchmann, Stephen J. Schuster, Heather E. Stefanski, Michael R. Bishop, Abhijit Chakraborty, Aisha Masood, André Baruchel, Edmund K. Waller

Manuscripts, Articles, Book Chapters and Other Papers

Tisagenlecleucel is a CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy. Quantitative polymerase chain reaction assays are highly sensitive in defining in vivo kinetics by measuring CAR transgene in peripheral blood. This study aimed to identify clinically meaningful CAR T-cell blood levels that correlated with response/relapse. In pediatric/young adult patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), maximum CAR T-cell blood levels were higher in patients with ongoing complete remission and in patients with CD19- relapse relative to those with CD19+ relapse. In adult patients with R/R diffuse large B-cell lymphoma (DLBCL), no apparent association between in vivo kinetics …

A Phase 2 Study Of Obinutuzumab Combined With Lenalidomide In Previously Untreated High Tumor Burden Follicular Lymphoma, Neha Akkad, Lei Feng, Jason R Westin, Fredrick B Hagemeister, Hun Ju Lee, Luis Fayad, Sairah Ahmed, Ranjit Nair, Maria Alma Rodriguez, Paolo Strati, Dai Chihara, Christopher R Flowers, Linda Claret, Karina Ibanez, Michael Wang, Nathan H Fowler, Jared Henderson, R Eric Davis, Sattva S Neelapu, Michael Green, Loretta J Nastoupil

Faculty, Staff and Student Publications

Follicular lymphoma (FL) has a clinical course that is often characterized by high response rates to first-line therapy, followed by multiple relapses over a prolonged natural history. Currently, there are multiple possible approaches to frontline therapy for untreated advanced-stage FL, but there is an ongoing debate around what is the preferred approach. Based on the benefits seen with combining lenalidomide, an immunomodulatory agent, with rituximab, an anti-CD20 antibody, we aimed to evaluate the safety and efficacy of lenalidomide in combination with obinuzutumab, an anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity. The eligibility criteria included a diagnosis of FL, grade 1 …

Fruquintinib In Less Pretreated Patients: Multivariate Profile-Matching Analysis Of Fresco-2 To Fresco, Arvind Dasari, Cathy Eng, Sara Lonardi, Rocio Garcia-Carbonero, Toshiki Masuishi, Chiara Cremolini, François Ghiringhelli, Joleen Hubbard, Tanios Bekaii-Saab, Jeremy Jones, Rui-Hua Xu, Lin Shen, Jianming Xu, Yuxian Bai, Yanhong Deng, Ying Yuan, Wei Wei, Jianchang Lin, Lucy Chen, Zhao Yang, William R Schelman, Shukui Qin, Jin Li

Faculty, Staff and Student Publications

Background: In the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) studies, fruquintinib vs placebo, plus best supportive care, significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). These studies were conducted in temporally and geographically diverse populations that received distinct prior therapies; FRESCO patients were less pretreated than FRESCO-2 patients. This analysis assessed the efficacy and safety of fruquintinib in a less pretreated global population than the FRESCO-2 intention-to-treat (ITT) population.

Methods: In FRESCO and FRESCO-2, patients were randomized 2:1 to receive oral fruquintinib 5 mg or matched placebo. Profile matching was undertaken …

Dissecting The Effect Of Mitochondrial Bcat Inhibition In Methylmalonic Acidemia, Madeline G Hemmingsen, Guo-Fang Zhang, Yunhan Ma, Hannah Marchuk, Kalyani R Patel, Tong Chen, Xinning Li, Mark Chapman, Sabrina Collias, Dolores H Lopez-Terrada, James Beasley, Ashlee R Stiles, Randy J Chandler, Charles P Venditti, Sarah P Young, Mercedes Barzi, Beatrice Bissig-Choisat, Doug Krafte, Christopher B Newgard, Karl-Dimiter Bissig

Faculty, Staff and Students Publications

Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic …

Defining Breast Epithelial Cell Types In The Single-Cell Era, G Kenneth Gray, Eric G Carlson, Tatyana Lev, Bailey Marshall, Austin D Reed, Alex P Sánchez-Covarrubias, Alecia-Jane Twigger, Aleix Puig-Barbe, Aatish Thennavan, Ayodele Omotoso, Lyndsay M Murrow, Deeptiman Chatterjee, Siyuan He, Sara Pensa, Brian Aevermann, Norbert K Tavares, Natalie Chen, Jason A Hilton, Kerrigan Blake, Yunlong Liu, Kiet Phong, Zev J Gartner, Devon A Lawson, Alexander Swarbrick, Camila O Dos Santos, Sophia H L George, Joan S Brugge, Mark A Labarge, Harikrishna Nakshatri, Nicholas Navin, Kai Kessenbrock, Walid T Khaled

Faculty, Staff and Student Publications

Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors. Our proposals and their underlying thought processes aim to catalyze the adoption of a shared model for this tissue and to serve as guidance for other investigators facing similar challenges.

Gene Context Drift Identifies Drug Targets To Mitigate Cancer Treatment Resistance, Amir Jassim, Birgit V Nimmervoll, Sabrina Terranova, Erica Nathan, Linda Hu, Jessica T Taylor, Katherine E Masih, Lisa Ruff, Matilde Duarte, Elizabeth Cooper, Gunjan Katyal, Melika Akhbari, Reuben J Gilbertson, Jennifer C Coleman, Joseph S Toker, Colton Terhune, Gabriel Balmus, Stephen P Jackson, Hailong Liu, Tao Jiang, Michael D Taylor, Kui Hua, Jean E Abraham, Mariella G Filbin, Anthony Hill, Anarita Patrizi, Neil Dani, Aviv Regev, Maria K Lehtinen, Richard J Gilbertson

Faculty, Staff and Students Publications

Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments …

Modeling The Impact Of Mmr Vaccination Strategies On Measles Outbreaks In Texas, Kaiming Bi, Thuy Nguyen, Boya Peng, Trudy Krause, Cecilia Ganduglia Cazaban, Janelle Rios, Cici Bauer, Catherine Troisi, Eric Boerwinkle, Aanand D Naik

Faculty, Staff and Student Publications

No abstract provided.

Identifying Bio-Behavioural Signatures Of Persistent Opioid Use Risk In Trauma Injury Patients: A Protocol For A Prospective Cohort Study, Joy M Schmitz, Jin Ho Yoon, Bruno Kluwe-Schiavon, John A Harvin, Preethi H Gunaratne, Darrion Mouton, Kandice Motley, Erin E Fox, Jessica Vincent, Megan Tarbet, Consuelo Walss-Bass

Faculty, Staff and Student Publications

Introduction: Exposure to prescription opioids following traumatic injury can increase the risk of developing tolerance, persistent opioid use and opioid use disorder. The mechanisms underlying opioid tolerance or dependence are not well understood, and no biomarkers predict risk. Opioid exposure causes epigenetic modifications, including alterations in microRNA (miRNA) expression. Several miRNAs, which regulate synaptic plasticity, are hypothesised to underlie substance use disorders and influence µ-opioid receptor levels, modulating opioid tolerance. This project aims to develop a bio-behavioural signature to predict persistent opioid use and chronic pain up to 6 months post-discharge.

Methods and analysis: The study will use a prospective …

Establishing Best Practices Guidelines For Collaborative Research In Global Surgery: Developing A Delphi Survey, Ramitha Eshan Ruwanpathirana, Swati Deshpande, Sophia Abdulhai, Mathilde Djeneba Billau, Sumeja Catic, Theresa L Chin, Julia N Harrison, Pratyush Kumar, Maria Cecilia T Leyson, Helen W Li, Katayoun S Madani, Arthur Serumaga, Margaret Tarpley, Grayson Wright, Nia N Zalamea, Joshua S Ng-Kamstra

Faculty, Staff and Students Publications

Background: Collaborative research in global surgery has resulted in the rapid development of the field via knowledge creation and dissemination, research capacity building, and direct improvements in the delivery of clinical care. Yet the establishment and maintenance of trans-boundary collaborations carries significant risk to health systems, clinicians, patients, and researchers, particularly if such collaborations are not developed thoughtfully and with appropriate guardrails. In recent years, there has been significant growth in the literature on the pervasiveness and impact of neocolonialism on global health research.

Methods: To harness the benefits of global surgery research collaboration while mitigating these risks, we reviewed …

Upper Gastrointestinal Symptoms And Gulf War Illness In A Clinical Cohort Of Us Veterans: A Retrospective, Cross-Sectional Study, Abdelrahman Yousef, Sarah T Ahmed, Theresa H Nguyen Wenker, Alice B S Nono-Djotsa, Stephen H Boyle, Elizabeth J Gifford, Deeksha Malhotra, Helena Chandler, Sandhya Bandi, Drew A Helmer

Faculty, Staff and Students Publications

Objective: Approximately 30% of the 700 000 US Gulf War Veterans (GWVs) report symptoms collectively termed Gulf War Illness (GWI), a multisymptom illness of uncertain pathophysiology. Prior studies in GWI focus on overlap with irritable bowel syndrome. This study examines the associations between upper gastrointestinal (UGI) symptoms, GWI and specialty GI care.

Methods: This cross-sectional study analysed GWVs referred to a Veterans Health Administration clinical War-Related Illness and Injury Study Center (2008-2020). Symptoms, demographics, military service and clinical history were obtained from self-reported intake packets. GWI was defined by the Centers for Disease Control and Prevention criteria requiring moderate-to-severe symptoms …

Implementing A Training Resource For Large-Scale Genomic Data Analysis In The All Of Us Researcher Workbench, Jasmine Baker, Erik Stricker, Julie Coleman, Shamika Ketkar, Taotao Tan, Ashley M Butler, Laterrica Williams, Latanya Hammonds-Odie, Debra Murray, Brendan Lee, Kim C Worley, Elizabeth G Atkinson

Duncan NRI Faculty and Staff Publications

A lack of representation in genomic research and limited access to computational training create barriers for many researchers seeking to analyze large-scale genetic datasets. The All of Us Research Program provides an unprecedented opportunity to address these gaps by offering genomic data from a broad range of participants, but its impact depends on equipping researchers with the necessary skills to use it effectively. The All of Us Biomedical Researcher (BR) Scholars Program at Baylor College of Medicine aims to break down these barriers by providing early-career researchers with hands-on training in computational genomics through the All of Us Evenings with …

Lewy Body Dementia Promotion By Air Pollutants, Xiaodi Zhang, Haiqing Liu, Xiao Wu, Longgang Jia, Kundlik Gadhave, Lena Wang, Kevin Zhang, Hanyu Li, Rong Chen, Ramhari Kumbhar, Ning Wang, Chantelle E Terrillion, Bong Gu Kang, Bin Bai, Minhan Park, Ma Cristine Faye Denna, Shu Zhang, Wenqiang Zheng, Denghui Ye, Xiaoli Rong, Liu Yang, Lili Niu, Han Seok Ko, Weiyi Peng, Lingtao Jin, Mingyao Ying, Liana S Rosenthal, David W Nauen, Alex Pantelyat, Mahima Kaur, Kezia Irene, Liuhua Shi, Rahel Feleke, Sonia García-Ruiz, Mina Ryten, Valina L Dawson, Francesca Dominici, Rodney J Weber, Xuan Zhang, Pengfei Liu, Ted M Dawson, Shizhong Han, Xiaobo Mao

Faculty, Staff and Student Publications

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. Here we showed in a cohort of 56.5 million individuals across the U.S. that PM2.5 exposure raises LBD risk. Mechanistically, we found PM2.5 exposure led to brain atrophy in wild-type mice, an effect not seen in α-synuclein (αSyn)-deficient mice. PM2.5 exposure generated a highly pathogenic αSyn strain, PM-PFF, with enhanced proteinase K-resistance and neurotoxicity, resembling αSyn LBD strains. PM2.5 samples from China, the U.S., and Europe consistently induced proteinase-resistant αSyn strains and in vivo pathology. Transcriptomic analyses revealed shared responses between PM2.5-exposed mice and …

Dissecting Microbial Communities With Single-Cell Transcriptome Analysis, Andrew W Pountain, Itai Yanai

Faculty, Staff and Student Publications

Revealing insights into the function of microbial communities requires moving beyond measuring bulk taxonomic composition to detecting interactions between subpopulations. Following the transformative impact of single-cell gene expression profiling techniques on numerous fields of human biology, recent years have seen increased application to microbes. We review progress in the development of these techniques and discuss challenges in applying them to microbial communities. We highlight applications for dissecting the microbiome in human health and disease that reveal functional heterogeneity within gut communities, antibiotic responses, and the dynamics of mobile genetic elements. As single-cell gene expression technologies continue to develop, they are …

Human Papillomavirus Integration Induces Oncogenic Host Gene Fusions In Oropharyngeal Cancers, Nusrat Khan, Keiko Akagi, Shiming Jiang, Joe Dan Dunn, Bo Jiang, Weihong Xiao, Madison P O'Hara, Li Shen, Qi Wang, Vakul Mohanty, Jing Wang, Sara Goodwin, Jamie L Hutchins, Kevin R Coombes, Jagannadha K Sastry, David E Symer, Maura L Gillison

Faculty, Staff and Student Publications

HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host fusion genes, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of …

Detection Of Cancers Three Years Prior To Diagnosis Using Plasma Cell-Free Dna, Yuxuan Wang, Corinne E Joshu, Samuel D Curtis, Christopher Douville, Vernon A Burk, Meng Ru, Maria Popoli, Janine Ptak, Lisa Dobbyn, Natalie Silliman, Josef Coresh, Eric Boerwinkle, Anna Prizment, Chetan Bettegowda, Kenneth W Kinzler, Nickolas Papadopoulos, Elizabeth A Platz, Bert Vogelstein

Faculty, Staff and Student Publications

To explore how early can cancers be detected prior to clinical signs or symptoms, we assessed prospectively collected serial plasma samples from the Atherosclerosis Risk in Communities (ARIC) study, including 26 participants diagnosed with cancer and 26 matched controls. At the index time point, eight of these 52 participants scored positively with a multicancer early detection (MCED) test. All eight participants were diagnosed with cancer within 4 months after blood collection. In six of these 8 participants, we were able to assess an earlier plasma sample collected 3.1 to 3.5 years prior to clinical diagnosis. In four of these six …

The Causal Pivot: A Structural Approach To Genetic Heterogeneity And Variant Discovery In Complex Diseases, Chad A Shaw, C J Williams, Taotao Tan, Daniel Illera, Nicholas Di, Joshua M Shulman, John W Belmont

Center on Aging Staff Publications

We present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages an established causal factor or factors to detect the contribution of additional suspected causes. Specifically, polygenic risk scores (PRSs) serve as known causes, while rare variants (RVs) or RV ensembles are evaluated as candidate causes. The CP incorporates outcome-induced association by conditioning on disease status. We derive a conditional maximum-likelihood procedure for binary and quantitative traits and develop the Causal Pivot likelihood ratio test (CP-LRT) to detect causal signals. Through simulations, we demonstrate the CP-LRT’s robust power and …

An Allele-Agnostic Mutant-Kras Inhibitor Suppresses Tumor Maintenance Signals And Reprograms Tumor Immunity In Pancreatic Cancer, Kathleen M Mcandrews, Francesca Paradiso, Clint A Stalnecker, Benson S Chellakkan, Fredrik I Thege, David H Peng, Barbara A Moreno Diaz, Hikaru Sugimoto, Sarah I Patel, Krishnan K Mahadevan, Michelle L Kirtley, Danielle Wills, Amari M Sockwell, Andre Luis F Fonseca, Yunhe Liu, Kimal I Rajapakshe, Nathaniel G Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E Deckard, Linghua Wang, Channing J Der, Christopher Vellano, Paola A Guerrero, Timothy P Heffernan, Raghu Kalluri, Anirban Maitra

Faculty, Staff and Student Publications

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 a panKRASi, a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse …

An Isoform-Specific Runx1c-Btg2 Axis Governs Aml Quiescence And Chemoresistance, Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl Mckenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang

Faculty, Staff and Student Publications

Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. …

Amoxicillin Vs Ceftriaxone To Treat Pneumonia Caused By Amoxicillin-Non-Susceptible Streptococcus Pneumoniae, Daniel M Musher

Faculty, Staff and Students Publications

Although the article by J Càmara, I Grau, A González-Díaz, N Santos, et al. (Antimicrob Agents Chemother 69:e00237-25, 2025, https://doi.org/10.1128/aac.00237-25) suggests that ceftriaxone is greatly superior to amoxicillin in treating pneumonia due to pneumococci with an MIC > 2 mg/L, much of the difference in efficacy of the two drugs may have been due to dosage, route, and times of administration of the amoxicillin.