Digital Commons Network^™

Oropharyngeal Cancer Outcomes Correlate With P16 Status, Multinucleation And Immune Infiltration, David C Wilde, Patricia D Castro, Kaustav Bera, Syeling Lai, Anant Madabhushi, German Corredor, Can Koyuncu, James S Lewis, Cheng Lu, Mitchell J Frederick, Allan M Frederick, Avery E Haugen, Jose P Zevallos, Erich M Sturgis, Justin Shi, Andrew T Huang, David J Hernandez, Heath D Skinner, Jan O Kemnade, Wendong Yu, Andrew G Sikora, Vlad C Sandulache

Faculty, Staff and Students Publications

Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells …

Chronic Granulomatous Disease-Like Presentation Of A Child With Autosomal Recessive Pkcδ Deficiency, Anna-Lena Neehus, Karen Tuano, Tom Le Voyer, Sarada L Nandiwada, Kruthi Murthy, Anne Puel, Jean-Laurent Casanova, Javier Chinen, Jacinta Bustamante

Faculty, Staff and Students Publications

BACKGROUND: Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS).

MATERIAL AND METHODS: We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient.

RESULTS: Consistent with a history suggestive of …

Integrated Multi-Omic Characterization Of Congenital Heart Disease, Matthew C Hill, Zachary A Kadow, Hali Long, Yuka Morikawa, Thomas J Martin, Emma J Birks, Kenneth S Campbell, Jeanne Nerbonne, Kory Lavine, Lalita Wadhwa, Jun Wang, Diwakar Turaga, Iki Adachi, James F Martin

Faculty, Staff and Students Publications

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We …

A Large-Scale Genome-Wide Gene-Gene Interaction Study Of Lung Cancer Susceptibility In Europeans With A Trans-Ethnic Validation In Asians, Ruyang Zhang, Sipeng Shen, Yongyue Wei, Ying Zhu, Yi Li, Jiajin Chen, Jinxing Guan, Zoucheng Pan, Yuzhuo Wang, Meng Zhu, Junxing Xie, Xiangjun Xiao, Dakai Zhu, Yafang Li, Demetrios Albanes, Maria Teresa Landi, Neil E Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angela Cox, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Juncheng Dai, Hongxia Ma, Yang Zhao, Zhibin Hu, Rayjean J Hung, Christopher I Amos, Hongbing Shen, Feng Chen, David C Christiani

Faculty, Staff and Students Publications

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms …

Cross-Ancestry Genome-Wide Meta-Analysis Of 61,047 Cases And 947,237 Controls Identifies New Susceptibility Loci Contributing To Lung Cancer, Jinyoung Byun, Younghun Han, Yafang Li, Jun Xia, Erping Long, Jiyeon Choi, Xiangjun Xiao, Meng Zhu, Wen Zhou, Ryan Sun, Yohan Bossé, Zhuoyi Song, Ann Schwartz, Christine Lusk, Thorunn Rafnar, Kari Stefansson, Tongwu Zhang, Wei Zhao, Rowland W Pettit, Yanhong Liu, Xihao Li, Hufeng Zhou, Kyle M Walsh, Ivan Gorlov, Olga Gorlova, Dakai Zhu, Susan M Rosenberg, Susan Pinney, Joan E Bailey-Wilson, Diptasri Mandal, Mariza De Andrade, Colette Gaba, James C Willey, Ming You, Marshall Anderson, John K Wiencke, Demetrius Albanes, Stephan Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig Bojeson, Hermann Brenner, Maria Teresa Landi, Stephen J Chanock, Mattias Johansson, Thomas Muley, Angela Risch, H-Erich Wichmann, Heike Bickeböller, David C Christiani, Gad Rennert, Susanne Arnold, John K Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Hongbing Shen, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Alpa Patel, Qing Lan, Nathaniel Rothman, Fiona Taylor, Linda Kachuri, John S Witte, Lori C Sakoda, Margaret Spitz, Paul Brennan, Xihong Lin, James Mckay, Rayjean J Hung, Christopher I Amos

Faculty, Staff and Students Publications

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung …

Pathological Implication Of Protein Post-Translational Modifications In Cancer, Sheng Pan, Ru Chen

Faculty, Staff and Students Publications

Protein post-translational modifications (PTMs) profoundly influence protein functions and play crucial roles in essentially all cell biological processes. The diverse realm of PTMs and their crosstalk is linked to many critical signaling events involved in neoplastic transformation, carcinogenesis and metastasis. The pathological roles of various PTMs are implicated in all aspects of cancer hallmark functions, cancer metabolism and regulation of tumor microenvironment. Study of PTMs has become an important area in cancer research to understand cancer biology and discover novel biomarkers and therapeutic targets. With a limited scope, this review attempts to discuss some PTMs of high frequency with recognized …

Patients With Lung Cancer Of Different Racial Backgrounds Harbor Distinct Immune Cell Profiles, Yitian Xu, Licheng Zhang, Jose Thaiparambil, Sunny Mai, Dimuthu Nuwan Perera, Jilu Zhang, Ping-Ying Pan, Cristian Coarfa, Kenneth Ramos, Shu-Hsia Chen, Randa El-Zein

Faculty, Staff and Students Publications

UNLABELLED: Tumors accumulated with infiltrated immune cells (hot tumors) have a higher response rate to immune checkpoint blockade, when compared with those with minimal T-cell infiltration (cold tumors). We report here that patients with lung cancer with different racial backgrounds harbored distinct immune cell profiles in the tumor microenvironment. Compared with African Americans (AA), Caucasian Americans (CA) exhibited increased immune cell infiltration and vasculature, and increased survival. Changes of survival and immune profile were most pronounced among active smokers and nonsmokers, compared with former smokers and total patients. Neighborhood analysis showed that immune cells accumulated around cancer cells in CAs …

Exome Sequencing Identifies Genetic Variants In Anophthalmia And Microphthalmia, Jingjing Li, Wei Yang, Yuejun Jessie Wang, Chen Ma, Cynthia J Curry, Daniel Mcgoldrick, Deborah A Nickerson, Jessica X Chong, Elizabeth E Blue, James C Mullikin, Jennita Reefhuis, Wendy N Nembhard, Paul A Romitti, Martha M Werler, Marilyn L Browne, Andrew F Olshan, Richard H Finnell, Marcia L Feldkamp, Faith Pangilinan, Lynn M Almli, Mike J Bamshad, Lawrence C Brody, Mary M Jenkins, Gary M Shaw, University Of Washington Center For Mendelian Genomics, Nisc Comparative Sequencing Program, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 …

Selinexor In Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial, Mrinal M Gounder, Brian A Van Tine, Et Al

2020-Current year OA Pubs

PURPOSE: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.

METHODS: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of …

Context-Dependent Pro- And Anti-Resection Roles Of Zkscan3 In The Regulation Of Fork Processing During Replication Stress, Zheng Yang, Delphine Sangotokun Lemacon, Shan Li, Abigael Cheruiyot, Lingzhen Kong, Ke Tan, Chen Cheng, Ecenur Turkay, Dalin He, Zhongsheng You

2020-Current year OA Pubs

Uncontrolled resection of replication forks under stress can cause genomic instability and influence cancer formation. Extensive fork resection has also been implicated in the chemosensitivity of "BReast CAncer gene" BRCA-deficient cancers. However, how fork resection is controlled in different genetic contexts and how it affects chromosomal stability and cell survival remains incompletely understood. Here, we report a novel function of the transcription repressor ZKSCAN3 in fork protection and chromosomal stability maintenance under replication stress. We show disruption of ZKSCAN3 function causes excessive resection of replication forks by the exonuclease Exo1 and homologous DNA recombination/repair protein Mre11 following fork reversal. Interestingly, …

Reoperative Brachial Plexus Neurolysis After Previous Anatomically Complete Supraclavicular Decompression For Neurogenic Thoracic Outlet Syndrome: A 10-Year Single-Center Case Series, Momodou L Jammeh, Alexander Yang, Ahmmad A Abuirqeba, J Westley Ohman, Robert W Thompson

2020-Current year OA Pubs

BACKGROUND: Optimal management of recurrent neurogenic thoracic outlet syndrome (NTOS) remains a considerable challenge.

OBJECTIVE: To assess the safety and effectiveness of reoperative brachial plexus neurolysis in patients with recurrent NTOS.

METHODS: From 2009 to 2019, 85 patients underwent reoperative supraclavicular brachial plexus neurolysis for recurrent NTOS after a previous anatomically complete supraclavicular decompression. Data from a prospectively maintained database were analyzed retrospectively.

RESULTS: The mean patient age at reoperation was 36.9 ± 1.3 (range 15-64) years, 75% were female, and the interval after previous primary operation was 2.5 ± 0.2 years. Intervening injury had precipitated recurrent NTOS in 14 …

Il-34 Deficiency Impairs Foxp3+ Treg Function In A Model Of Autoimmune Colitis And Decreases Immune Tolerance Homeostasis, Antoine Freuchet, Marco Colonna, Et Al

2020-Current year OA Pubs

BACKGROUND: Immune homeostasis requires fully functional Tregs with a stable phenotype to control autoimmunity. Although IL-34 is a cytokine first described as mainly involved in monocyte cell survival and differentiation, we recently described its expression by CD8

METHODS: We generated Il34

RESULTS: Here we report that the absence of expression of IL-34 in Il34

CONCLUSION: Altogether, our data emphasize on the crucial necessity of IL-34 for immune homeostasis and for CD4

HIGHLIGHTS: -Absence of expression of IL-34 in Il34

Ligand-Based Design, Synthesis, Computational Insights, And In Vitro Studies Of Novel N-(5-Nitrothiazol-2-Yl)-Carboxamido Derivatives As Potent Inhibitors Of Sars-Cov-2 Main Protease, Mohamed Elagawany, Ayman Abo Elmaaty, Ahmed Mostafa, Noura M Abo Shama, Eman Y Santali, Bahaa Elgendy, Ahmed A Al-Karmalawy

2020-Current year OA Pubs

The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of

Mirna Expression Is Increased In Serum From Patients With Semantic Variant Primary Progressive Aphasia, Maria Serpente, Laura Ghezzi, Chiara Fenoglio, Francesca R Buccellato, Giorgio G Fumagalli, Emanuela Rotondo, Marina Arcaro, Andrea Arighi, Daniela Galimberti

2020-Current year OA Pubs

Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants is not fully understood, including the role of micro (mi)RNAs which were previously shown to play a role in several neurodegenerative diseases. Using a two-step analysis (array and validation through real-time PCR), we investigated the miRNA expression pattern in serum from 54 PPA patients and 18 controls. In the svPPA cohort, we observed a generalized upregulation of miRNAs with miR-106b-5p and miR-133a-3p reaching statistical significance (miR-106b-5p: 2.69 …

Maladaptive Positive Feedback Production Of Chrebpβ Underlies Glucotoxic Β-Cell Failure, Liora S Katz, Gabriel Brill, Pili Zhang, Anil Kumar, Sharon Baumel-Alterzon, Lee B Honig, Nicolás Gómez-Banoy, Esra Karakose, Marius Tanase, Ludivine Doridot, Alexandra Alvarsson, Bennett Davenport, Peng Wang, Luca Lambertini, Sarah A Stanley, Dirk Homann, Andrew F Stewart, James C Lo, Mark A Herman, Adolfo Garcia-Ocaña, Donald K Scott

Faculty, Staff and Students Publications

Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPβ is necessary for adaptive β-cell expansion in response to metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression of ChREBPβ results in loss of β-cell identity, apoptosis, loss of β-cell mass, and diabetes. Furthermore, β-cell "glucolipotoxicity" can be prevented by deletion of ChREBPβ. Moreover, ChREBPβ-mediated cell death is …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer's Disease., Jaclyn M Eissman, Logan Dumitrescu, Emily R Mahoney, Alexandra N Smith, Shubhabrata Mukherjee, Michael L Lee, Phoebe Scollard, Seo Eun Choi, William S Bush, Corinne D Engelman, Qiongshi Lu, David W Fardo, Emily H Trittschuh, Jesse Mez, Catherine C Kaczorowski, Hector Hernandez Saucedo, Keith F Widaman, Rachel F Buckley, Michael J Properzi, Elizabeth C Mormino, Hyun Sik Yang, Theresa M Harrison, Trey Hedden, Kwangsik Nho, Shea J Andrews, Douglas Tommet, Niran Hadad, R Elizabeth Sanders, Douglas M Ruderfer, Katherine A Gifford, Xiaoyuan Zhong, Neha S Raghavan, Badri N Vardarajan, Margaret A Pericak-Vance, Lindsay A Farrer, Li San Wang, Carlos Cruchaga, Gerard D Schellenberg, Nancy J Cox, Jonathan L Haines, C Dirk Keene, Andrew J Saykin, Eric B Larson, Reisa A Sperling, Richard Mayeux, Michael L Cuccaro, David A Bennett, Julie A Schneider, Paul K Crane, Angela L Jefferson, Timothy J Hohman

Faculty Research 2022

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer's Disease, Jaclyn M Eissman, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Predicting Which Genes Will Respond To Transcription Factor Perturbations, Yiming Kang, Wooseok J Jung, Michael R Brent

2020-Current year OA Pubs

The ability to predict which genes will respond to the perturbation of a transcription factor serves as a benchmark for our systems-level understanding of transcriptional regulatory networks. In previous work, machine learning models have been trained to predict static gene expression levels in a biological sample by using data from the same or similar samples, including data on their transcription factor binding locations, histone marks, or DNA sequence. We report on a different challenge-training machine learning models to predict which genes will respond to the perturbation of a transcription factor without using any data from the perturbed cells. We find …

The University Of Pennsylvania Glioblastoma (Upenn-Gbm) Cohort: Advanced Mri, Clinical, Genomics, & Radiomics, Spyridon Bakas, Aristeidis Sotiras, Sung Min Ha, Et Al

2020-Current year OA Pubs

Glioblastoma is the most common aggressive adult brain tumor. Numerous studies have reported results from either private institutional data or publicly available datasets. However, current public datasets are limited in terms of: a) number of subjects, b) lack of consistent acquisition protocol, c) data quality, or d) accompanying clinical, demographic, and molecular information. Toward alleviating these limitations, we contribute the "University of Pennsylvania Glioblastoma Imaging, Genomics, and Radiomics" (UPenn-GBM) dataset, which describes the currently largest publicly available comprehensive collection of 630 patients diagnosed with de novo glioblastoma. The UPenn-GBM dataset includes (a) advanced multi-parametric magnetic resonance imaging scans acquired during …

Implication Of Melanocortin Receptor Genes In The Familial Comorbidity Of Type 2 Diabetes And Depression., Mutaz Amin, Jurg Ott, Rongling Wu, Teodor T Postolache, Claudia Gragnoli

Division of Endocrinology, Diabetes and Metabolic Diseases Faculty Papers

The melanocortin receptors are G-protein-coupled receptors, which are essential components of the hypothalamic–pituitary–adrenal axis, and they mediate the actions of melanocortins (melanocyte-stimulating hormones: α-MSH, β-MSH, and γ-MSH) as well as the adrenocorticotropin hormone (ACTH) in skin pigmentation, adrenal steroidogenesis, and stress response. Three melanocortin receptor genes (MC1R, MC2R, and MC5R) contribute to the risk of major depressive disorder (MDD), and one melanocortin receptor gene (MC4R) contributes to the risk of type 2 diabetes (T2D). MDD increases T2D risk in drug-naïve patients; thus, MDD and T2D commonly coexist. The five melanocortin receptor genes might confer risk for both disorders. However, they …

Whole Genome Sequence Association Analysis Of Fasting Glucose And Fasting Insulin Levels In Diverse Cohorts From The Nhlbi Topmed Program, Daniel Dicorpo, Sheila M Gaynor, Emily M Russell, Kenneth E Westerman, Laura M Raffield, Timothy D Majarian, Peitao Wu, Chloé Sarnowski, Heather M Highland, Anne Jackson, Natalie R Hasbani, Paul S De Vries, Jennifer A Brody, Bertha Hidalgo, Xiuqing Guo, James A Perry, Jeffrey R O'Connell, Samantha Lent, May E Montasser, Brian E Cade, Deepti Jain, Heming Wang, Ricardo D'Oliveira Albanus, Arushi Varshney, Lisa R Yanek, Leslie Lange, Nicholette D Palmer, Marcio Almeida, Juan M Peralta, Stella Aslibekyan, Abigail S Baldridge, Alain G Bertoni, Lawrence F Bielak, Chung-Shiuan Chen, Yii-Der Ida Chen, Won Jung Choi, Mark O Goodarzi, James S Floyd, Marguerite R Irvin, Rita R Kalyani, Tanika N Kelly, Seonwook Lee, Ching-Ti Liu, Douglas Loesch, Joann E Manson, Ryan L Minster, Take Naseri, James S Pankow, Laura J Rasmussen-Torvik, Alexander P Reiner, Muagututi'a Sefuiva Reupena, Elizabeth Selvin, Jennifer A Smith, Daniel E Weeks, Huichun Xu, Jie Yao, Wei Zhao, Stephen Parker, Alvaro Alonso, Donna K Arnett, John Blangero, Eric Boerwinkle, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, Ravindranath Duggirala, Jiang He, Susan R Heckbert, Sharon L R Kardia, Ryan W Kim, Charles Kooperberg, Simin Liu, Rasika A Mathias, Stephen T Mcgarvey, Braxton D Mitchell, Alanna C Morrison, Patricia A Peyser, Bruce M Psaty, Susan Redline, Alan R Shuldiner, Kent D Taylor, Ramachandran S Vasan, Karine A Viaud-Martinez, Jose C Florez, James G Wilson, Robert Sladek, Stephen S Rich, Jerome I Rotter, Xihong Lin, Josée Dupuis, James B Meigs, Jennifer Wessel, Alisa K Manning

Faculty, Staff and Student Publications

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, …

The Lupus Susceptibility Allele Drb1*03:01 Encodes A Disease-Driving Epitope, Bruna Miglioranza Scavuzzi, Vincent Van Drongelen, Bhavneet Kaur, Jennifer Callahan Fox, Jianhua Liu, Raquel A Mesquita-Ferrari, J Michelle Kahlenberg, Evan A Farkash, Fernando Benavides, Frederick W Miller, Amr H Sawalha, Joseph Holoshitz

Faculty, Staff and Student Publications

The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also triggers a cascade of SLE-associated cellular aberrations, including endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, necroptotic cell death, and production of pro-inflammatory cytokines. Parenteral administration of IFN-γ to naïve DRB1*03:01 transgenic mice causes increased serum levels of anti-double stranded DNA antibodies, glomerular immune complex deposition and histopathological renal …

Structural Network Alterations In Focal And Generalized Epilepsy Assessed In A Worldwide Enigma Study Follow Axes Of Epilepsy Risk Gene Expression, Sara Larivière, Jessica Royer, Raúl Rodríguez-Cruces, Casey Paquola, Maria Eugenia Caligiuri, Antonio Gambardella, Luis Concha, Simon S. Keller, Fernando Cendes, Clarissa L. Yasuda, Leonardo Bonilha, Ezequiel Gleichgerrcht, Niels K. Focke, Martin Domin, Felix Von Podewills, Soenke Langner, Christian Rummel, Roland Wiest, Pascal Martin, Raviteja Kotikalapudi, Terence J. O'Brien, Benjamin Sinclair, Lucy Vivash, Patricia M. Desmond, Elaine Lui, Anna Elisabetta Vaudano, Stefano Meletti, Manuela Tondelli, Saud Alhusaini, Colin P. Doherty, Gianpiero L. Cavalleri, Norman Delanty, Reetta Kälviäinen, Graeme D. Jackson, Magdalena Kowalczyk, Mario Mascalchi, Mira Semmelroch, Rhys H. Thomas, Hamid Soltanian-Zadeh, Esmaeil Davoodi-Bojd, Junsong Zhang, Gavin P. Winston, Aoife Griffin, Aditi Singh, Vijay K. Tiwari, Barbara A. K Kreilkamp, Matteo Lenge, Renzo Guerrini, Khalid Hamandi, Sonya Foley, Theodor Rüber, Bernd Weber, Chantal Depondt, Julie Absil, Sarah J. A Carr, Eugenio Abela, Mark P. Richardson, Orrin Devinsky, Mariasavina Severino, Pasquale Striano, Domenico Tortora, Erik Kaestner, Sean N. Hatton, Sjoerd B. Vos, Lorenzo Caciagli, John S. Duncan, Christopher D. Whelan, Paul M. Thompson, Sanjay M. Sisodiya, Andrea Bernasconi, Angelo Labate, Carrie R. Mcdonald, Neda Bernasconi, Boris C. Bernhardt

Neurology Articles

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE …

Genome-Wide Association Study Identifies Sjögren's Risk Loci With Functional Implications In Immune And Glandular Cells, Bhuwan Khatri, Kandice L. Tessneer, Astrid Rasmussen, Farhang Aghakhanian, Tove R. Reksten, Adam Adler, Ilias Alevizos, Juan-Manuel Anaya, Lara A. Aqrawi, Eva Baecklund, Johan G. Brun, Sara M. Bucher, Maija-Leena Eloranta, Fiona Engelke, Helena Forsblad-D'Elia, Stuart B. Glenn, Daniel Hammenfors, Juliana Imgenberg-Kreuz, Janicke Liaaen Jensen, Svein J. A. Johnsen, Malin V. Jonsson, Marika Kvarnström, Jennifer A. Kelly, He Li, Thomas Mandl, Javier Martín, Gaétane Nocturne, Katrine B. Norheim, Øyvind Palm, Kathrine Skarstein, Anna M. Stolarczyk, Kimberly E. Taylor, Maria Teruel, Elke Theander, Swamy Venuturupalli, Daniel J. Wallace, Kiely M. Grundahl, Kimberly S. Hefner, Lida Radfar, David M. Lewis, Donald U. Stone, C. Erick Kaufman, Michael T. Brennan, Joel M. Guthridge, Judith A. James, R. Hal Scofield, Patrick M. Gaffney, Lindsey A. Criswell, Roland Jonsson, Per Eriksson, Simon J. Bowman, Roald Omdal, Lars Rönnblom, Blake Warner, Maureen Rischmueller, Torsten Witte, A. Darise Farris, Xavier Mariette, Marta E. Alarcon-Riquelme, Caroline H. Shiboski, Marie Wahren-Herlenius, Wan-Fai Ng, Kathy L. Sivils, Indra Adrianto, Gunnel Nordmark, Christopher J. Lessard

Public Health Sciences Articles

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target …

Targeting De Novo Lipogenesis And The Lands Cycle Induces Ferroptosis In Kras-Mutant Lung Cancer, Caterina Bartolacci, Cristina Andreani, Gonçalo Vale, Stefano Berto, Margherita Melegari, Anna Colleen Crouch, Dodge L Baluya, George Kemble, Kurt Hodges, Jacqueline Starrett, Katerina Politi, Sandra L Starnes, Daniele Lorenzini, Maria Gabriela Raso, Luisa M Solis Soto, Carmen Behrens, Humam Kadara, Boning Gao, Ignacio I Wistuba, John D Minna, Jeffrey G Mcdonald, Pier Paolo Scaglioni

Faculty, Staff and Student Publications

Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, …

Real-World Use Of Tisagenlecleucel In Infant Acute Lymphoblastic Leukemia., Amy Moskop, Lauren Pommert, Christina Baggott, Snehit Prabhu, Holly L. Pacenta, Christine L. Phillips, Jenna Rossoff, Heather E. Stefanski, Julie-An Talano, Steve P. Margossian, Michael R. Verneris, Douglas Myers, Nicole A. Karras, Patrick A. Brown, Muna Qayed, Michelle L. Hermiston, Prakash Satwani, Christa Krupski, Amy K. Keating, Rachel Wilcox, Cara A. Rabik, Vanessa A. Fabrizio, Vasant Chinnabhandar, A Yasemin Goksenin, Kevin J. Curran, Crystal L. Mackall, Theodore W. Laetsch, Erin M. Guest, Erin H. Breese, Liora M. Schultz

Manuscripts, Articles, Book Chapters and Other Papers

Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes because of chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is US Food and Drug Administration approved for relapsed or refractory B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown because children(n = 14). Sixty-four percent of patients (n = 9) achieved minimal residual disease-negative remission after CART and 50% of patients remain in remission at last follow-up. All patients with high disease burden at time of CART infusion (>M1 marrow) …

Persistent Ethnicity-Associated Disparity In Anti-Tumor Effectiveness Of Immune Checkpoint Inhibitors Despite Equal Access, Marcus A Florez, Jan O Kemnade, Nan Chen, Wendy Du, Anita L Sabichi, Daniel Y Wang, Quillan Huang, Courtney N Miller-Chism, Aparna Jotwani, Albert C Chen, David Hernandez, Vlad C Sandulache

Faculty, Staff and Students Publications

We reviewed response to immune checkpoint inhibitors (ICI) of 207 patients with diagnoses of lung or head and neck cancer treated with chemotherapy/ICI combination therapy and ICI monotherapy between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine. Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority populations and provide equal access to care regardless of means. 174 patients had a diagnosis of lung cancer (non-small cell or small cell) and 33 had a diagnosis of …

Effect Of High- Vs Low-Dose Tranexamic Acid Infusion On Need For Red Blood Cell Transfusion And Adverse Events In Patients Undergoing Cardiac Surgery: The Optimal Randomized Clinical Trial, Jia Shi, Chenghui Zhou, Wei Pan, Hansong Sun, Sheng Liu, Wei Feng, Weijian Wang, Zhaoyun Cheng, Yang Wang, Zhe Zheng, Optimal Study Group

Faculty, Staff and Students Publications

IMPORTANCE: Tranexamic acid is recommended for reducing blood loss and transfusion in cardiac surgery. However, it remains unknown whether a high dose of tranexamic acid provides better blood-sparing effect than a low dose without increasing the risk of thrombotic complications or seizures in cardiac surgery.

OBJECTIVE: To compare the efficacy and adverse events of high-dose vs low-dose tranexamic acid in patients undergoing cardiac surgery with cardiopulmonary bypass.

DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, randomized clinical trial among adult patients undergoing cardiac surgery with cardiopulmonary bypass. The study enrolled 3079 patients at 4 hospitals in China from December 26, 2018, to …

An Integrated Proteomic And Glycoproteomic Investigation Reveals Alterations In The N-Glycoproteomic Network Induced By 2-Deoxy-D-Glucose In Colorectal Cancer Cells, Cheng Ma, Hong-Yuan Tsai, Qi Zhang, Lakmini Senavirathna, Lian Li, Lih-Shen Chin, Ru Chen, Sheng Pan

Faculty, Staff and Students Publications

As a well-known glycolysis inhibitor for anticancer treatment, 2-Deoxy-D-glucose (2DG) inhibits the growth and survival of cancer cells by interfering with the ATP produced by the metabolism of D-glucose. In addition, 2DG inhibits protein glycosylation in vivo by competing with D-mannose, leading to endoplasmic reticulum (ER) stress and unfolded protein responses in cancer cells. However, the molecular details underlying the impact of 2DG on protein glycosylation remain largely elusive. With an integrated approach to glycoproteomics and proteomics, we characterized the 2DG-induced alterations in N-glycosylation, as well as the cascading impacts on the whole proteome using the HT29 colorectal cancer …

Kstar: An Algorithm To Predict Patient-Specific Kinase Activities From Phosphoproteomic Data, Sam Crowl, Ben T Jordan, Hamza Ahmed, Cynthia X Ma, Kristen M Naegle

2020-Current year OA Pubs

Kinase inhibitors as targeted therapies have played an important role in improving cancer outcomes. However, there are still considerable challenges, such as resistance, non-response, patient stratification, polypharmacology, and identifying combination therapy where understanding a tumor kinase activity profile could be transformative. Here, we develop a graph- and statistics-based algorithm, called KSTAR, to convert phosphoproteomic measurements of cells and tissues into a kinase activity score that is generalizable and useful for clinical pipelines, requiring no quantification of the phosphorylation sites. In this work, we demonstrate that KSTAR reliably captures expected kinase activity differences across different tissues and stimulation contexts, allows for …