Digital Commons Network^™

Sleep Architecture And Dementia Risk In Adults: An Analysis Of 5 Cohorts From The Sleep And Dementia Consortium, Stephanie Yiallourou, Andree-Ann Baril, Crystal Wiedner, Jeffrey R Misialek, Christopher E Kline, Stephanie Harrison, Ethan Cannon, Qiong Yang, Rebecca Bernal, Alycia Bisson, Dibya Himali, Marina Cavuoto, Antoine Weihs, Alexa Beiser, Rebecca F Gottesman, Yue Leng, Oscar Lopez, Pamela L Lutsey, Shaun M Purcell, Susan Redline, Sudha Seshadri, Katie L Stone, Kristine Yaffe, Sonia Ancoli-Israel, Qian Xiao, Eleni Okeanis Vaou, Jayandra J Himali, Matthew P Pase

Faculty, Staff and Student Publications

Study objectives: Poor sleep may play a role in the risk of dementia. However, few studies have investigated the association between polysomnography (PSG)-derived sleep architecture and dementia incidence. We examined the relationship between sleep architecture and dementia incidence across five US-based cohort studies from the Sleep and Dementia Consortium.

Methods: Percent of time spent in stages of sleep (N1, N2, N3, rapid eye movement sleep), wake after sleep onset, sleep maintenance efficiency, apnea-hypopnea index, and relative delta power were derived from a single night home-based PSG. Dementia was ascertained in each cohort using its cohort-specific criteria. Each cohort performed Cox …

Chemo-Rast With Bortezomib Inhibits Multiple Myeloma Relapse, Anchal Ghai, Alexander Zheleznyak, Christopher Egbulefu, Nicole Blasi, Kvar Black, Rui Tang, Matthew L Cooper, Kiran Vij, Ravi Vij, John Dipersio, Monica Shokeen, Samuel Achilefu

2020-Current year OA Pubs

No abstract provided.

Impacts Of Environmental Distractions And Interruptions On Unsupervised Digital Cognitive Assessments In Older Adults: Cognitive Ecological Momentary Assessment Study, Matthew Welhaf, Hannah Wilks, Andrew J Aschenbrenner, Samhita Katteri, John C Morris, Jason J Hassenstab

2020-Current year OA Pubs

BACKGROUND: Unsupervised cognitive assessments are becoming commonly used in studies of aging and neurodegenerative diseases. As assessments are completed in everyday environments and without a proctor, there are concerns about how common distractions may impact performance and whether these distractions may differentially impact those experiencing the earliest symptoms of dementia.

OBJECTIVE: We examined the impact of self-reported interruptions, testing location, and social context during testing on remote cognitive assessments in older adults.

METHODS: Participants from the Ambulatory Research in Cognition smartphone study were classified as cognitively normal (n=380) or as having very mild dementia (n=37). Participants completed daily tests of …

Postoperative Fluid Restriction To Prevent Delayed Hyponatremia After Endoscopic Transsphenoidal Surgery, Doriann Klaassen, Shinghei Mok, Jenie Y Hwang, Kelley J Williams, Brendan M Fong, Ralph G Dacey, Nyssa F Farrell, Joshua W Osbun, Keith M Rich, Lauren T Roland, John S Schneider, Gregory J Zipfel, Chongliang Luo, Albert H Kim, Julie M Silverstein, Et Al.

2020-Current year OA Pubs

BACKGROUND: Readmission following endoscopic endonasal transsphenoidal surgery (EETS) for pituitary neuroendocrine tumor (PitNET) and other sellar pathology is most commonly due to delayed hyponatremia. Studies suggest postoperative fluid restriction (FR) reduces delayed hyponatremia. We present a prospective randomized controlled study evaluating post-EETS FR.

METHODS: 300 participants were scheduled for EETS (2016-2023) at a single institution. Patients with CKD, CHF, arginine vasopressin deficiency on postoperative day (POD) 3, chronic hyponatremia, and untreated adrenal insufficiency or hypothyroidism were excluded. Groups included control (ad-lib, n = 94), moderate FR (1.8 L/day or 2 L/day weight > 100 kg, n = 39), and strict FR …

Co-Occurrence Of Congenital Anomalies And Childhood Brain Tumors In 22 Million Live Births, Thanh T Hoang, Jeremy M Schraw, Charles Shumate, Tania A Desrosiers, Wendy N Nembhard, Mahsa Yazdy, Eirini Nestoridi, Amanda E Janitz, Russell S Kirby, Jason L Salemi, Jean Paul Tanner, Tiffany M Chambers, Michael D Taylor, Chad D Huff, Sharon E Plon, Philip J Lupo, Michael E Scheurer

Faculty, Staff and Students Publications

Background: Children born with a congenital anomaly have a higher risk of developing a brain tumor during childhood or adolescence, but the co-occurrence between specific types of congenital anomalies and specific types of childhood brain tumors (CBTs) is not well described. This study characterized the associations between specific congenital anomalies and CBTs.

Methods: We leveraged a population-based registry linkage study of births (1990-2018), congenital anomalies, and cancer from 9 states (n = 22,599,099 births). Congenital anomalies were classified as major structural without a known chromosomal or genetic syndrome, chromosomal, neurofibromatosis, and/or tuberous sclerosis complex. CBT classification was based on the …

Identification Of Cobra And Viper Bites In Southern India Using Enzyme-Linked Immunosorbent Assay, Tejeswara Rao Asuru, Raskin Erusan Rajagopal, Albert Rajendran, Gulistan Parveen, Anushka Das, Pabitha Devi, Swapan K Dasgupta, Shantaraman Kalyanaraman, Prasenjit Guchhait, Perumal Thiagarajan

Faculty, Staff and Students Publications

Introduction: Snakebite-related deaths are major concerns in populations worldwide that lack access to medical care. Current treatment of snakebites includes administration of polyspecific and polyvalent heterologous equine antiserum. Swift diagnosis of the species of snake responsible is essential to initiate a specific treatment.

Methods: We generated murine monoclonal and rabbit polyclonal antibodies against the venom of the 3 most common venomous snakes in southern India: the Russell viper, the saw-scaled viper, and the Indian cobra. We developed an enzyme-linked immunosorbent assay to distinguish the snake by analyzing the exudates from the snakebite wound.

Results: Monoclonal antibody EC3 reacts specifically with …

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.

Integrative Analysis Of Lung Adenocarcinoma Across Diverse Ethnicities And Exposures, Shankha Satpathy, Natalie M Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, David I Heiman, Indranil Paul, Hanbyul Cho, Michelle Hollenberg, Giacomo B Marino, Kuen-Tyng Lin, Rahul Mannan, C Jackson White, Joe Allen, Shayan C Avanessian, M Harry Kane, Ashley Wolfe, Miloni Kinarivala, Wenke Liu, Shankara Anand, Mong-Wei Lin, Moe Haines, Erik J Bergstrom, Grant Hussey, Ginny Xiaohe Li, Deepak C Mani, Hao Fang, Eric J Jaehnig, Hasmik Keshishian, Brecca Miller, Kang-Yi Su, Yi-Jing Hsiao, Hsao-Hsun Hsu, Min-Shu Hsieh, Kuo-Hsuan Hsu, Alexi Monovoukas, Simone Gohsman, John R Thorup, Yamei Deng, Yo Akiyama, Eden Deng, Eric Sheng-Wen Chen, Azra Krek, Rodrigo Espinoza, Weiping Ma, Daniel Charytonowicz, Robert Sebra, Jyun-Hong Lin, Yan-Si Chen, Yin-Chen Hsu, Ze-Shiang Lin, Kun-Chieh Chen, Chang-Wei Yeh, Yu-Tai Wang, Alexander J Lazar, Mehdi Mesri, Eunkyung An, Xu Zhang, Karl R Clauser, David Fenyö, Arul M Chinnaiyan, Bing Zhang, Li Ding, Kelly Ruggles, Chelsea Newton, Hui Zhang, Pei Wang, Galen Hostetter, Gilbert S Omenn, Chandan Kumar-Sinha, Mathangi Thiagarajan, Ramaswamy Govindan, Paul Paik, Abhijit Parolia, Qing K Li, Avi Ma'ayan, Gad A Getz, Saravana M Dhanasekaran, Ana I Robles, Gee-Chen Chang, Pan-Chyr Yang, Sung-Liang Yu, Hsuan-Yu Chen, Alexey I Nesvizhskii, Steven A Carr, D R Mani, Marcin P Cieslik, Yu-Ju Chen, Michael A Gillette, Taiwan Cancer Moonshot Program, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology …

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 …

Blue Light As An Anti-Inflammatory And Analgesic Strategy In Thoracic Trauma (Blaastt): Protocol For A Randomised Controlled Trial In Adult Trauma Inpatients With Painful Rib Fractures, Rebecca E Kotcher, Matthew R Rosengart, Luca La Colla, Hsing-Hua Sylvia Lin, Keith M Vogt, Yan Xu, Matthew D Neal

2020-Current year OA Pubs

INTRODUCTION: Blue light (peak wavelength 442 nm) has been shown to modulate the immune response in preclinical models of intra-abdominal sepsis and pneumonia.

METHODS AND ANALYSIS: This is a randomised controlled trial in which adult trauma inpatients (

ETHICS AND DISSEMINATION: Full ethical approval for this trial has been granted by the University of Pittsburgh Institutional Review Board. On study completion, results will be published in the peer-reviewed literature and at ClinicalTrials.gov.

TRIAL REGISTRATION NUMBER: NCT06626334.

Post-Translational Modification Of H2b C-Terminal Helix Regulates Nucleosome Interactions And Chromatin Signaling, Yani Zhao, Anh Nguyen, Eyla C Arteaga, Aleksandra Skrajna, Krzysztof Krajewski, Dennis Goldfarb, Robert K Mcginty

2020-Current year OA Pubs

Histone H2B contains a highly conserved C-terminal (H2B αC) helix that has been implicated in chromatin interactions and dynamics. The H2B αC helix comprising residues 105-125 is positioned adjacent to a major site of nucleosome interactions called the acidic patch. Despite individual structural studies highlighting interactions between chromatin proteins and the H2B αC helix, the general role of the helix in mediating nucleosome recognition has not been explored. Moreover, many post-translational modifications (PTMs) have been identified within the H2B αC helix, but significant gaps exist in our understanding of their regulatory potential. In this study, we employed nucleosome affinity proteomics …

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.

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 …

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 …

Risk Of Clonal Hematopoiesis In Families Exposed To Radiation Following The Chornobyl Accident, Mitchell J Machiela, Irenaeus Chan, Kelly Bolton, Et Al.

2020-Current year OA Pubs

Radiation exposure is a well-established risk factor for leukemia. Clonal hematopoiesis (CH), the expansion of mutated hematopoietic cells, is also associated with increased leukemia risk and its frequency is higher in cancer patients following radiotherapy and chemotherapy. We investigated whether low to moderate environmental ionizing radiation determined by state-of-the-art dosimetric analysis was associated with CH in the Chornobyl Family Study (CFS). Our study conducted targeted high-depth sequencing and array genotyping to identify and characterize clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) in 882 participants from 292 CFS families. Fathers had mean bone marrow radiation doses of …

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 …

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 …

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 …

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 …

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 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, Mitchell S. 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 Research 2025

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. …

Handling Hemolytic Blood Samples From High-Risk Clinical Areas: A Call To Action, Alan H B Wu, Jerrold H Levy, W Franklin Peacock, Ramzy Rimawi, Manuel Sanchez Luna, Christopher Farnsworth, Hugo Stiegler, Robert H Christenson

2020-Current year OA Pubs

BACKGROUND: Spectrophotometric testing to detect sample hemolysis is available from central laboratory chemistry analyzers. While the cause and preventative measures are known, hemolysis continues to be a common preanalytical error, especially for specimens collected from the emergency department (ED) and intensive care units (ICUs) where point-of-care analyzers are commonly used for whole blood electrolyte testing. Recently, these analyzers have employed technology to detect hemolysis directly on whole blood samples.

METHODS: Experienced laboratorians and physicians from the clinical laboratory, ED, adult and neonatal ICUs provide a summary of the medical importance of in vitro hemolysis. Causes for in vivo hemolysis are …

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. …

Intronic Fgf14 Gaa Repeat Expansions Impact Progression And Survival In Multiple System Atrophy., Viorica Chelban, David Pellerin, Nirosen Vijiaratnam, Hamin Lee, Yen Yee Goh, Lauren Brown, Sara Sambin, Danielle Seilhean, Stephane Lehericy, Pablo Iruzubieta, Rahema Mohammad, Eleanor Self, Annarita Scardamaglia, Cameron Lee, Miriama Ostrozovicova, Marie-Josée Dicaire, Christine Girges, Emil K. Gustavsson, David Murphy, Toby Curless, Joshua Laß, Joanne Trinh, Timothy Rittman, James B. Rowe, Marios Hadjivassiliou, Neil Archibald, Matt C. Danzi, Catherine Ashton, Virginie Roth, Marion Wandzel, Warren A. Cheung, Djordje O. Gveric, Bart De Vil, Jordan Follett, P Nigel Leigh, Lukas Beichert, Tomi Pastinen, Céline Bonnet, Mathilde Renaud, Wassilios G. Meissner, Anne Sieben, David Crosiers, Patrick Cras, Stephan Zuchner, Jean-Christophe Corvol, Matthew J. Farrer, Matthis Synofzik, Bernard Brais, Tom Warner, Huw R. Morris, Zane Jaunmuktane, Tom Foltynie, Henry Houlden

Manuscripts, Articles, Book Chapters and Other Papers

Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls. The FGF14 repeat locus was genotyped using long-range PCR and bidirectional repeat-primed PCRs, and expansions were confirmed with targeted long-read Oxford Nanopore Technologies sequencing. We identified 19 multiple system atrophy cases carrying an FGF14 …

Revealing Hyperactivated Ifn-Γ Pathways In Perianal Fistulizing Crohn's Disease Using Single-Cell And Spatial Multi-Omics, Siyan Cao, Khai M. Nguyen, Kaiming Ma, Tingyi Tan, Xin Yao, Ta-Chiang Liu, Malek Ayoub, Jalpa Devi, Sami Samaan, Yizhou Liu, Radhika Smith, Matthew L. Silviera, Steven R. Hunt, Paul E. Wise, Matthew G. Mutch, Sean C. Glasgow, William C. Chapman, Michelle L. Cowan, Matthew A. Ciorba, Marco Colonna, Parakkal Deepak, Sparc Ibd Investigators

2020-Current year OA Pubs

Up to 40% patients with Crohn's disease suffer from perianal disease, a debilitating complication with unclear etiology. This study identified unique pathophysiology which may help develop novel therapies.

Mepolizumab Alters Gene Regulatory Networks Of Nasal Airway Type-2 And Epithelial Inflammation In Urban Children With Asthma, Courtney L Gaberino, Michelle A Gill, Jeffrey Stokes, Et Al.

2020-Current year OA Pubs

Mepolizumab (anti-IL5 therapy) reduces asthma exacerbations in urban children with exacerbation-prone eosinophilic asthma. We previously utilized nasal transcriptomics to identify inflammatory pathways (gene co-expression modules) associated with asthma exacerbations despite this therapy. In this study, we applied differential gene correlation analysis on these targeted gene co-expression modules to gain better insight into the treatment effects on correlation structure within gene networks. Mepolizumab treatment resulted in loss of correlation amongst eosinophil-specific genes but conservation and even strengthening of correlation amongst mast cell-specific genes, T2 cytokines, and airway epithelial inflammatory genes. Notably, mepolizumab induced significant gain in correlation of genes associated with …

Risk Of Cardiovascular Events During Delivery Hospitalization Among Pregnant Patients With Mental Health Conditions, Kavya Parekh, R J Waken, Khavya Avula, Katelin B Nickel, Kathryn J Lindley, Cynthia Rogers, Karen E Joynt Maddox

2020-Current year OA Pubs

BACKGROUND: Cardiovascular disease remains the leading cause of maternal mortality. Mental health disorders are risk factors for cardiovascular disease in nonpregnant populations, but their association with delivery outcomes is unknown.

METHODS: This cross-sectional study used delivery hospitalizations from the 2021 National Inpatient Sample. We used generalized estimating equations to fit quasi-Poisson regression models for cardiovascular severe maternal morbidity and mortality (SMM) events as defined by the Centers for Disease Control and Prevention, and non-SMM cardiovascular conditions or complications as defined by the Alliance for Innovation on Maternal Health. Incidence rate ratios were calculated for depression, anxiety, psychosis, bipolar, obsessive-compulsive disorder, …

Neoadjuvant Bms-813160, Nivolumab, Gemcitabine, And Nab-Paclitaxel For Patients With Pancreatic Cancer, Patrick M Grierson, Crystal Wolf, Rama Suresh, Andrea Wang-Gillam, Benjamin R Tan, Lee Ratner, Peter Oppelt, Olivia Aranha, Ashley Frith, Katrina S Pedersen, Jennifer Spann, Nicholas Boice, Amberly Brown, John M Baer, Emily G Butka, Faiz Ahmad, Yifei Xu, Jingxia Liu, David G Denardo, Kian-Huat Lim

2020-Current year OA Pubs

PURPOSE: Targeting tumor-associated macrophages through C-C chemokine receptor type 2 (CCR) in pancreatic ductal adenocarcinoma (PDAC) improves the efficacy of chemotherapy and restores T-cell immunity in preclinical models.

PATIENTS AND METHODS: We conducted a phase I/II single-institution study (NCT03496662) combining chemotherapy gemcitabine and nab-paclitaxel (GnP), CCR2/5 inhibitor BMS-813160, and nivolumab for four 28-day cycles for patients with borderline resectable (BR) or locally advanced (LA) PDAC. The recommended phase II dose of BMS-813160 was established in the 3 + 3 design. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included resection rate, median progression-free survival, and median overall …

Surgery Versus Surveillance: A Quality-Of-Life Analysis Of Patients With Moderately Dilated Aortic Root Or Ascending Aorta, Ming Hao Guo, Puja Kachroo, Et Al.

2020-Current year OA Pubs

OBJECTIVES: The impact of diagnosis and management of ascending thoracic aortic aneurysm (ATAA) on patients' quality of life (QoL) is not well characterized. This study aims to compare QoL with surgery versus surveillance in patients with moderate ATAAs.

METHODS: Treatment In Thoracic Aortic aNeurysm: Surgery versus Surveillance is a multicentre randomized trial for patients with ATAA between 5.0 and 5.4 cm and includes a registry of patients who underwent either surgery or surveillance. From May 2019 to December 2022, 157 patients from 15 centres were enrolled in the surveillance (n = 105) or surgery (n = 52) registry and completed …