Digital Commons Network^™

Transcranial Direct Current Stimulation For Improving Balance In Healthy Older Adults And Older Adults With Stroke: A Scoping Review, Shih-Chiao Tseng, Sharon Dunnivan-Mitchell, Dana Cherry, Shuo-Hsiu Chang

Faculty, Staff and Student Publications

Background/Objectives: Age-related decline in balance and postural control is common in healthy elders and is escalated in aging adults with stroke. Transcranial direct current stimulation (tDCS) has emerged as one of the promising brain stimulations adjoining therapeutic exercise to enhance the recovery of balance and motor functions in persons with and without neurological disorders. This review aims to summarize and compare the available evidence of the tDCS on improving balance in the older adults without neurological disorders and the older adults with stroke.

Methods: The Ovid (Medline) database was searched from its inception through to 06/15/2024 for randomized …

Left Ventricular Diastolic Dysfunction With Elevated Filling Pressures Is Associated With Embolic Stroke Of Undetermined Source And Atrial Fibrillation, Zubair Bashir, Liqi Shu, Yuqian Guo, Edward W Chen, Shuyuan Wang, Maheen Rana, Xing Dai, Daniel Mandel, Shadi Yaghi, Phinnara Has, Mingxing Xie, Tao Wang, James Simmons, Christopher Song, Philip Haines

Faculty, Staff and Student Publications

Background/Objectives: Left ventricular diastolic dysfunction (LVDD) and elevated left ventricular filling pressure (LVFP) are strong predictors of clinical outcomes across various populations. However, their diagnostic utility in embolic stroke of undetermined source (ESUS) remains unclear. We hypothesized that LVDD with elevated LVFP (based on echocardiography) was more likely to be prevalent in ESUS compared to non-cardioembolic stroke (NCE) and to be associated with atrial fibrillation (AF) on follow-up monitoring.

Methods: This is a single-center retrospective study that included adult patients with a diagnosis of acute ischemic stroke between January 2016 and June 2017. LV function was assessed by …

Interleukin-1 Receptor-Associated Kinase 1 In Cancer Metastasis And Therapeutic Resistance: Mechanistic Insights And Translational Advances, Hui-Wen Lo

Faculty, Staff and Student Publications

Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is a serine/threonine kinase that plays a critical role as a signaling transducer of the activated Toll-like receptor (TLR)/Interleukin-1 receptor (IL-1R) signaling pathway in both immune cells and cancer cells. Upon hyperphosphorylation by IRAK4, IRAK1 forms a complex with TRAF6, which results in the eventual activation of the NF-κB and MAPK pathways. IRAK1 can translocate to the nucleus where it phosphorylates STAT3 transcription factor, leading to enhanced IL-10 gene expression. In immune cells, activated IRAK1 coordinates innate immunity against pathogens and mediates inflammatory responses. In cancer cells, IRAK1 is frequently activated, and the activation …

Pain After Licorice Or Sugar-Water Gargling In Patients Recovering From Oropharyngeal Surgery-A Randomized, Double-Blind Trial, Marita Windpassinger, Michal Prusak, Jana Gemeiner, Olga Plattner, Stefan Janik, Gerold Besser, Wolfgang Gstoettner, Pu Xuan, Daniel I Sessler, Kurt Ruetzler

Faculty, Staff and Student Publications

Background: Glycyrrhiza glabrata (licorice) is used in traditional medicine and herbal remedies and reduces sore throats consequent to intubation, but whether it is protective for more intense pain after oropharyngeal surgery remains unclear. We thus tested the joint hypothesis that gargling with licorice, which has anti-inflammatory and antioxidant properties, reduces postoperative pain and morphine consumption.

Methods: We enrolled patients having elective oropharyngeal surgery. Participants were randomly allocated to gargle with either 1 g licorice or a sugar placebo before and for up to three days after surgery. A numerical rating scale (NRS) for pain along with morphine consumption was evaluated …

Multivariable Mendelian Randomization With Incomplete Measurements On The Exposure Variables In The Hispanic Community Health Study/Study Of Latinos, Heather M Highland, Carolina G Downie, Christy L Avery, Bing Yu, Kristin L Young, Victoria L Buchanan, Robert Kaplan, Lifang Hou, Brian Thomas Joyce, Qibin Qi, Tamar Sofer, Jee-Young Moon, Dan-Yu Lin

Faculty, Staff and Student Publications

Multivariable Mendelian randomization allows simultaneous estimation of direct causal effects of multiple exposure variables on an outcome. When the exposure variables of interest are quantitative omic features, obtaining complete data can be economically and technically challenging: the measurement cost is high, and the measurement devices may have inherent detection limits. In this paper, we propose a valid and efficient method to handle unmeasured and undetectable values of the exposure variables in a one-sample multivariable Mendelian randomization analysis with individual-level data. We estimate the direct causal effects with maximum likelihood estimation and develop an expectation-maximization algorithm to compute the estimators. We …

Impact Of Age On Pharmacogenomics And Treatment Outcomes Of B-Cell Acute Lymphoblastic Leukemia, Satoshi Yoshimura, Zhenhua Li, Yoshihiro Gocho, Wenjian Yang, Kristine R Crews, Kathryn G Roberts, Mary V Relling, Jiyang Yu, Allen E J Yeoh, Mignon L Loh, Caner Saygin, Mark R Litzow, Sima Jeha, Seth E Karol, Hiroto Inaba, Ching-Hon Pui, Marina Konopleva, Nitin Jain, Wendy Stock, Elisabeth Paietta, Elias Jabbour, Steven M Kornblau, William E Evans, Jun J Yang

Faculty, Staff and Student Publications

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations …

Rare Variant Contribution To The Heritability Of Coronary Artery Disease, Alanna C Morrison, Kruthika R Iyer, Erica P Young, Nathan O Stitziel, Goo Jun, Cecelia Laurie, Jai G Broome, Alyna T Khan, Donna K Arnett, Lewis C Becker, Joshua C Bis, Eric Boerwinkle, Donald W Bowden, April P Carson, Patrick T Ellinor, Myriam Fornage, Nora Franceschini, Barry I Freedman, Lifang Hou, Yii-Der Ida Chen, Eimear E Kenny, Charles Kooperberg, Brian G Kral, Ruth J F Loos, Sharon M Lutz, Joann E Manson, Lisa W Martin, Braxton D Mitchell, Rami Nassir, Nicholette D Palmer, Wendy S Post, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Elizabeth A Regan, Stephen S Rich, Jennifer A Smith, Kent D Taylor, Lisa R Yanek, Kendra A Young, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Austin T Hilliard, Catherine Tcheandjieu, Patricia A Peyser, Ramachandran S Vasan, Jerome I Rotter, Clint L Miller, Themistocles L Assimes, Paul S De Vries, Ron Do

Faculty, Staff and Student Publications

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin …

Phase I/Ii Study Of Bms-986156 With Ipilimumab Or Nivolumab With Or Without Stereotactic Ablative Radiotherapy In Patients With Advanced Solid Malignancies, Joe Y Chang, Xinyan Xu, Girish S Shroff, Nathan I Comeaux, Wei Li, Daniel D Karp, Vivek Verma, Aileen Chen, James Welsh, David S Hong

Faculty, Staff and Student Publications

Background: BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043).

Methods: This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 …

Molecular And Clinical Features Of Pancreatic Acinar Cell Carcinoma: A Single-Institution Case Series, Ashwathy Balachandran Pillai, Mahmoud Yousef, Abdelrahman Yousef, Kristin D Alfaro-Munoz, Brandon G Smaglo, Robert A Wolff, Mark W Hurd, Anirban Maitra, Huamin Wang, Matthew Harold G Katz, Laura R Prakash, Ching-Wei D Tzeng, Rebecca Snyder, Luca F Castelnovo, Anthony Chen, Andrey Kravets, Kseniia Kudriavtseva, Artem Tarasov, Kirill Kryukov, Haoqiang Ying, John Paul Shen, Dan Zhao

Faculty, Staff and Student Publications

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods: We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023-2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing …

The Impact Of A Web-Based Prognostic Calculator On Prognostic Confidence In Outpatient Palliative Care, David Hui, John P Maxwell, Allison De La Rosa, Kristofer Jennings, Marieberta Vidal, Ahsan Azhar, Kimberson Tanco, Yvonne Heung, Marvin Delgado-Guay, Donna Zhukovsky, Joseph Arthur, Suresh Reddy, Sriram Yennu, Amy Ontai, Eduardo Bruera

Faculty, Staff and Student Publications

Purpose: Clinicians are often uncertain about their prognostic estimates, which may impede prognostic communication and clinical decision-making. We assessed the impact of a web-based prognostic calculator on physicians' prognostic confidence.

Methods: In this prospective study, palliative care physicians estimated the prognosis of patients with advanced cancer in an outpatient clinic using the temporal, surprise, and probabilistic approaches for 6 m, 3 m, 2 m, 1 m, 2 w, 1 w, and 3 d. They then reviewed information from www.predictsurvival.com , which calculated survival estimates from seven validated prognostic scores, including the Palliative Prognostic Score, Palliative Prognostic Index, and Palliative Performance …

Development And Assessment Of A Point-Of-Care Application (Genomic Medicine Guidance) For Heritable Thoracic Aortic Disease

Faculty, Staff and Student Publications

Background: Genetic testing can determine familial and personal risks for heritable thoracic aortic aneurysms and dissections (TAD). The 2022 American College of Cardiology/American Heart Association guidelines for TAD recommend management decisions based on the specific gene mutation. However, many clinicians lack sufficient comfort or insight to integrate genetic information into clinical practice.

Objective: We therefore developed the Genomic Medicine Guidance (GMG) application, an interactive point-of-care tool to inform clinicians and patients about TAD diagnosis, treatment, and surveillance. GMG is a REDCap-based application that combines publicly available genetic data and clinical recommendations based on the TAD guidelines into one translational education …

Impact Of Cancer Therapy On Clonal Hematopoiesis Mutations And Subsequent Clinical Outcomes, Kevin T Nead, Taebeom Kim, Lijin Joo, Tina L Mcdowell, Justin W Wong, Elizabeth Brock, Ting Xu, Chad Tang, Chang-Lung Lee, Jun-Ichi Abe, Kelly L Bolton, Zhongxing Liao, Paul A Scheet, Steven H Lin

Faculty, Staff and Student Publications

Exposure to cancer therapies is associated with an increased risk of clonal hematopoiesis (CH). The objective of our study was to investigate the genesis and evolution of CH after cancer therapy. In this prospective study, we undertook error-corrected duplex DNA sequencing in blood samples collected before and at 2 time points after chemoradiation in patients with esophageal or lung cancer recruited from 2013 to 2018. We applied a customized workflow to identify the earliest changes in CH mutation count and clone size and determine their association with clinical outcomes. Our study included 29 patients (87 samples). Their median age was …

Rapid Hyperspectral Photothermal Mid-Infrared Spectroscopic Imaging From Sparse Data For Gynecologic Cancer Tissue Subtyping, Reza Reihanisaransari, Chalapathi Charan Gajjela, Xinyu Wu, Ragib Ishrak, Sara Corvigno, Jinsong Liu, David Mayerich, Sebastian Berisha, Rohith Reddy

Faculty, Staff and Student Publications

Ovarian cancer detection has traditionally relied on a multistep process that includes biopsy, tissue staining, and morphological analysis by experienced pathologists. While widely practiced, this conventional approach suffers from several drawbacks: it is qualitative, time-intensive, and heavily dependent on the quality of staining. Mid-infrared (MIR) hyperspectral photothermal imaging is a label-free, biochemically quantitative technology that, when combined with machine learning algorithms, can eliminate the need for staining and provide quantitative results comparable to traditional histology. However, this technology is slow. This work presents a novel approach to MIR photothermal imaging that enhances its speed by an order of magnitude. This …

Dna Methylation Near Mad1l1, Kdm2b, And Socs3 Mediates The Effect Of Socioeconomic Status On Elevated Body Mass Index In African American Adults, Brooke S Staley, Kendra Ferrier, Jan Bressler, Laura Loehr, Laura M Raffield, Mario Sims, Kari E North, Lindsay Fernández-Rhodes

Faculty, Staff and Student Publications

Obesity and poverty disproportionally affect African American persons. Epigenetic mechanisms could partially explain the association between socioeconomic disadvantage and body mass index (BMI). We examined the extent to which epigenetic mechanisms mediate the effect of socioeconomic status (SES) on BMI. Using data from African American adults from the Atherosclerosis Risk in Communities (ARIC) Study (n = 2664, mean age = 57 years), education, income, and occupation were used to create a composite SES score at visit 1 (1987-1989). We conducted two methylation-wide association analyses to identify associations between SES (visit 1), BMI and cytosine-phosphate-guanine (CpG) sites measured at a subsequent …

Conserved Signaling Modules Regulate Filamentous Growth In Fungi: A Model For Eukaryotic Cell Differentiation, Matthew D Vandermeulen, Michael C Lorenz, Paul J Cullen

Faculty, Staff and Student Publications

Eukaryotic organisms are composed of different cell types with defined shapes and functions. Specific cell types are produced by the process of cell differentiation, which is regulated by signal transduction pathways. Signaling pathways regulate cell differentiation by sensing cues and controlling the expression of target genes whose products generate cell types with specific attributes. In studying how cells differentiate, fungi have proved valuable models because of their ease of genetic manipulation and striking cell morphologies. Many fungal species undergo filamentous growth-a specialized growth pattern where cells produce elongated tube-like projections. Filamentous growth promotes expansion into new environments, including invasion into …

Immunologic Signatures Of Response And Resistance To Nivolumab With Ipilimumab In Advanced Metastatic Cancer, Apostolia M Tsimberidou, Farah A Alayli, Kwame Okrah, Alexandra Drakaki, Danny N Khalil, Saad A Khan, David Y Oh, Christopher R Cabanski, Shikha Gautam, Stefanie L Meier, Meelad Amouzgar, Shannon M Pfeiffer, Robin Kageyama, Enjun Yang, Marko Spasic, Michael T Tetzlaff, Wai Chin Foo, Travis J Hollmann, Yanyun Li, Matthew Adamow, Phillip Wong, Jonni S Moore, Sharlene Velichko, Richard O Chen, Dinesh Kumar, Samantha Bucktrout, Ramy Ibrahim, Ute Dugan, Lisa Salvador, Vanessa M Hubbard-Lucey, Jill O'Donnell-Tormey, Sandra Santulli-Marotto, Lisa H Butterfield, Diane M Da Silva, Justin Fairchild, Theresa M Lavallee, Lacey J Padrón, Padmanee Sharma

Faculty, Staff and Student Publications

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

An Iron-Rich Subset Of Macrophages Promotes Tumor Growth Through A Bach1-Ednrb Axis, Ian W Folkert, William A Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S Molina, Hesham Mohei, Md Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J Lazar, Khalida Wani, William P Israel, Zhan Zhang, Venkata S Chaluvadi, Robert J Norgard, Ying Liu, Ashley M Fuller, Mai T Dang, Robert E Roses, Giorgos C Karakousis, John T Miura, Douglas L Fraker, T S Karin Eisinger-Mathason, M Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar

Faculty, Staff and Student Publications

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional …

Hybrid Quantification Of Absolute Perfusion Requires Accurate Measurement Of Myocardial Mass

Faculty, Staff and Student Publications

No abstract provided.

Multiregional Transcriptomic Profiling Provides Improved Prognostic Insight In Localized Non-Small Cell Lung Cancer, Chenyang Li, Thinh T Nguyen, Jian-Rong Li, Xingzhi Song, Junya Fujimoto, Curtis Gumb, Ignacio I Wistuba, Andrew P Futreal, Jianhua Zhang, Shawna M Hubert, John V Heymach, Jia Wu, Christopher I Amos, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with …

Cd28 Costimulation Augments Car Signaling In Nk Cells Via The Lck/Cd3Ζ/Zap70 Signaling Axis, Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Emily Ensley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, …

Tissue-Agnostic Targeting Of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals And Future Directions, Mohamed A Gouda, Kyaw Z Thein, David S Hong

Faculty, Staff and Student Publications

NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition …

Biologic And Clinical Analysis Of Childhood Gamma Delta T-All Identifies Lmo2/Stag2 Rearrangements As Extremely High Risk, Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Elizabeth D Arnold, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A De Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan

Faculty, Staff and Student Publications

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in …

The History Of Chromosomal Instability In Genome-Doubled Tumors, Toby M Baker, Siqi Lai, Andrew R Lynch, Tom Lesluyes, Haixi Yan, Annelien Verfaillie, Amy L Bowes, Nischalan Pillay, Adrienne M Flanagan, Charles Swanton, Paul T Spellman, Maxime Tarabichi, Peter Van Loo

Faculty, Staff and Student Publications

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe Gain Route Identification and Timing In Cancer (GRITIC), a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains …

Whole-Genome Sequencing In 333,100 Individuals Reveals Rare Non-Coding Single Variant And Aggregate Associations With Height, Xihao Li, Allison E Ashley-Koch, Aneel A Ashrani, Kathleen C Barnes, Eric Boerwinkle, Jennifer A Brody, April P Carson, Nathalie Chami, Yii-Der Ida Chen, Mina K Chung, Joanne E Curran, Dawood Darbar, Patrick T Ellinor, Myrian Fornage, Victor R Gordeuk, Xiuqing Guo, Jiang He, Chii-Min Hwu, Robert Kaplan, Sharon L R Kardia, Charles Kooperberg, Ruth J F Loos, Steven A Lubitz, Ryan L Minster, Take Naseri, Satupa'itea Viali, Braxton D Mitchell, Joanne M Murabito, Nicholette D Palmer, Bruce M Psaty, Susan Redline, M Benjamin Shoemaker, Edwin K Silverman, Marilyn J Telen, Scott T Weiss, Lisa R Yanek, Hufeng Zhou, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Ching-Ti Liu, Kari E North, Anne E Justice, Jonathan M Locke, Nick Owens, Anna Murray, Kashyap Patel, Timothy M Frayling, Caroline F Wright, Andrew R Wood, Xihong Lin, Alisa Manning, Michael N Weedon

Faculty, Staff and Student Publications

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6×10-10" role="presentation" style="box-sizing: inherit; display: inline-block; line-height: 0; font-size: 18.08px; font-size-adjust: none; overflow-wrap: normal; text-wrap-mode: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; margin: 0px; padding: 1px 0px; color: rgb(33, 33, 33); font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; position: relative;">6×10−106×10-10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in …

Likelihood Adaptively Incorporated External Aggregate Information With Uncertainty For Survival Data, Ziqi Chen, Yu Shen, Jing Qin, Jing Ning

Faculty, Staff and Student Publications

Population-based cancer registry databases are critical resources to bridge the information gap that results from a lack of sufficient statistical power from primary cohort data with small to moderate sample size. Although comprehensive data associated with tumor biomarkers often remain either unavailable or inconsistently measured in these registry databases, aggregate survival information sourced from these repositories has been well documented and publicly accessible. An appealing option is to integrate the aggregate survival information from the registry data with the primary cohort to enhance the evaluation of treatment impacts or prediction of survival outcomes across distinct tumor subtypes. Nevertheless, for rare …

Semi-Supervised Machine Learning Method For Predicting Homogeneous Ancestry Groups To Assess Hardy-Weinberg Equilibrium In Diverse Whole-Genome Sequencing Studies, Eric Boerwinkle, Richard A Gibbs, Ira Hall, Tara Matise, Catherine Reeves, Nathan O Stitziel, Michael Zody, Benjamin M Neale, Xihong Lin

Faculty, Staff and Student Publications

Large-scale, multi-ethnic whole-genome sequencing (WGS) studies, such as the National Human Genome Research Institute Genome Sequencing Program's Centers for Common Disease Genomics (CCDG), play an important role in increasing diversity for genetic research. Before performing association analyses, assessing Hardy-Weinberg equilibrium (HWE) is a crucial step in quality control procedures to remove low quality variants and ensure valid downstream analyses. Diverse WGS studies contain ancestrally heterogeneous samples; however, commonly used HWE methods assume that the samples are homogeneous. Therefore, directly applying these to the whole dataset can yield statistically invalid results. To account for this heterogeneity, HWE can be tested on …

Regulation Of Fibrinogen Synthesis, Marguerite Neerman-Arbez

Faculty, Staff and Student Publications

The plasma protein fibrinogen is encoded by 3 structural genes (FGA, FGB, and FGG) that are transcribed to mRNA, spliced, and translated to 3 polypeptide chains (Aα, Bβ, and γ, respectively). These chains are targeted for secretion, decorated with post-translational modifications, and assembled into a hexameric “dimer of trimers” (AαBβγ)2. Fully assembled fibrinogen is secreted into the blood as a 340 kDa glycoprotein. Fibrinogen is one of the most prevalent coagulation proteins in blood, and its expression is induced by inflammatory cytokines, wherein circulating fibrinogen levels may increase up to 3-fold during acute inflammatory events. Abnormal …

Ficture: Scalable Segmentation-Free Analysis Of Submicron-Resolution Spatial Transcriptomics, Weiqiu Cheng, Asma Nusrat, Weizhou Zhang, Goo Jun, Sebastian Zöllner, Jun Hee Lee, Hyun Min Kang

Faculty, Staff and Student Publications

Spatial transcriptomics (ST) technologies have advanced to enable transcriptome-wide gene expression analysis at submicron resolution over large areas. However, analysis of high-resolution ST is often challenged by complex tissue structure, where existing cell segmentation methods struggle due to the irregular cell sizes and shapes, and by the absence of segmentation-free methods scalable to whole-transcriptome analysis. Here we present FICTURE (Factor Inference of Cartographic Transcriptome at Ultra-high REsolution), a segmentation-free spatial factorization method that can handle transcriptome-wide data labeled with billions of submicron-resolution spatial coordinates and is compatible with both sequencing-based and imaging-based ST data. FICTURE uses the multilayered Dirichlet model …

Dna Methylation-Derived Immune Cell Proportions And Cancer Risk In Black Participants, Jan Bressler, Elizabeth A Platz, Dominique S Michaud

Faculty, Staff and Student Publications

Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation obscures vital insights into how cancer risk varies across race. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers from blood samples collected at baseline on participants without cancer in the Atherosclerosis Risk in Communities Study. During a mean of 17.5 years of follow-up, 668 incident cancers were diagnosed in 2,467 Black participants. Cox proportional hazards regression was used to examine immune cell subtype proportions and overall cancer incidence and site-specific incidence (lung, breast, and …

Multicohort Epigenome-Wide Association Study Of All-Cause Cardiovascular Disease And Cancer Incidence: A Cardio-Oncology Approach, Karin Haack, Jason G Umans, M Daniele Fallin, Miguel Herreros-Martinez, Marina Pollan, Eric Boerwinkle, Elizabeth A Platz, Miranda R Jones, Jan Bressler, Roby Joehanes, Calen P Ryan, Juan R Gonzalez, Daniel Levy, Daniel W Belsky, Shelley A Cole, Dominique S Michaud, Ana Navas-Acien, Maria Tellez-Plaza

Faculty, Staff and Student Publications

BACKGROUND: Emerging evidence reveals a complex relationship between cardiovascular disease (CVD) and cancer, which share common risk factors and biological pathways.

OBJECTIVES: The aim of this study was to evaluate common epigenetic signatures for CVD and cancer incidence in 3 ethnically diverse cohorts: Native Americans from the SHS (Strong Heart Study), European Americans from the FHS (Framingham Heart Study), and European Americans and African Americans from the ARIC (Atherosclerosis Risk In Communities) study.

METHODS: A 2-stage strategy was used that included first conducting untargeted epigenome-wide association studies for each cohort and then running targeted models in the union set of …