Digital Commons Network^™

Epigenetic Resetting In The Human Germ Line Entails Histone Modification Remodeling, Wolfram H Gruhn, Walfred W C Tang, Sabine Dietmann, João P Alves-Lopes, Christopher A Penfold, Frederick C K Wong, Navin B Ramakrishna, M Azim Surani

2020-Current year OA Pubs

Epigenetic resetting in the mammalian germ line entails acute DNA demethylation, which lays the foundation for gametogenesis, totipotency, and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genes and transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCs exhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signatures at most genes and TEs and the acquisition of a neutral or paused epigenetic state without transcriptional activation. Efficient maintenance of a heterochromatic state is limited to a subset of genomic …

Differential Effects Of Anti-Cd20 Therapy On Cd4 And Cd8 T Cells And Implication Of Cd20-Expressing Cd8 T Cells In Ms Disease Activity, Koji Shinoda, Anne H Cross, Et Al.

2020-Current year OA Pubs

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20

Examining Stripes On A Herd Of Zebras: Impact Of Genomic Matching For Ultrarare Sarcomas In Phase 1 Clinical Trials (Samba 102), Justin T Moyers, Roberto Carmagnani Pestana, Jason Roszik, David S Hong, Aung Naing, Siqing Fu, Sarina Piha-Paul, Timothy A Yap, Daniel Karp, Jordi Rodon, Andy Livingston, Maria Alejandra Zarzour, Vinod Ravi, Shreyaskumar Patel, Robert S Benjamin, Joseph Ludwig, Cynthia Herzog, Ravin Ratan, Neeta Somaiah, Anthony Conley, Richard Gorlick, Funda Meric-Bernstam, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Recently, the Connective Tissue Oncology Society published consensus guidelines for recognizing ultrarare sarcomas (URS), defined as sarcomas with an incidence ≤1 per 1,000,000. We assessed the outcomes of 56 patients with soft tissue, and 21 with bone sarcomas, enrolled in Phase 1 trials.

Experimental design: In this Sarcoma-Matched Biomarker Analysis (SAMBA-102 study), we reviewed records from patients on Phase 1 trials at the University of Texas MD Anderson Cancer Center between January 2013 and June 2021.

Results: Among 587 sarcomas, 106 (18.1%) were classified as URS. Fifty (47%) were male, and the median age was 44.3 years (range, 19-82). …

Physical Activity, Seasonal Sensitivity And Psychological Well-Being Of People Of Different Age Groups Living In Extreme Environments, Caren Alvarado, Matías Castillo-Aguilar, Valeska Villegas, Claudia Estrada Goic, Katherine Harris, Patricio Barria, Michele M Moraes, Thiago T Mendes, Rosa M E Arantes, Pablo Valdés-Badilla, Cristian Núñez-Espinosa

Faculty, Staff and Student Publications

Physical activity can prevent many organic and mental pathologies. For people living in extreme southern high-latitude environments, weather conditions can affect these activities, altering their psychological well-being and favoring the prevalence of seasonal sensitivity (SS). This study aims to determine the relationships between the practice of physical activity, seasonal sensitivity and well-being in people living in high southern latitudes. A cross-sectional study was conducted, using the Seasonal Pattern Assessment Questionnaire (SPAQ), applying a psychological well-being scale, and determining sports practice according to the recommendations of the World Health Organization (WHO) for the 370 male (n = 209; 55%) and female …

Features Of Tumor-Microenvironment Images Predict Targeted Therapy Survival Benefit In Patients With Egfr-Mutant Lung Cancer, Shidan Wang, Ruichen Rong, Donghan M Yang, Junya Fujimoto, Justin A Bishop, Shirley Yan, Ling Cai, Carmen Behrens, Lynne D Berry, Clare Wilhelm, Dara Aisner, Lynette Sholl, Bruce E Johnson, David J Kwiatkowski, Ignacio I Wistuba, Paul A Bunn, John Minna, Guanghua Xiao, Mark G Kris, Yang Xie

Faculty, Staff and Student Publications

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation …

Posoleucel, An Allogeneic, Off-The-Shelf Multivirus-Specific T-Cell Therapy, For The Treatment Of Refractory Viral Infections In The Post-Hct Setting, Thomas Pfeiffer, Ifigeneia Tzannou, Mengfen Wu, Carlos Ramos, Ghadir Sasa, Caridad Martinez, Premal Lulla, Robert A Krance, Lauren Scherer, Daniel Ruderfer, Swati Naik, Claire Bocchini, Iain P Fraser, Badrish Patel, Dany Ward, Tao Wang, Helen E Heslop, Ann M Leen, Bilal Omer

Faculty, Staff and Students Publications

PURPOSE: Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus.

PATIENTS AND METHODS: We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either …

Mechanism Of Ca2+ Transport By Ferroportin, Jiemin Shen, Azaan Saalim Wilbon, Ming Zhou, Yaping Pan

Faculty, Staff and Students Publications

Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe2+) from cells and is important for homeostasis of iron in circulation. Export of one Fe2+ by Fpn is coupled to import of two H+ to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca2+ transport. We determine the structure of Ca2+-bound HsFpn and identify a single Ca2+ binding site distinct from the Fe2+ binding sites. Further studies validate the Ca2+ binding site and show that Ca2+ transport is not coupled to transport of another ion. In addition, Ca2+ transport is significantly inhibited in the …

Automating The High-Throughput Screening Of Protein-Based Optical Indicators And Actuators, Jihwan Lee, Beatriz Campillo, Shaminta Hamidian, Zhuohe Liu, Matthew Shorey, François St-Pierre

Faculty, Staff and Students Publications

Over the last 25 years, protein engineers have developed an impressive collection of optical tools to interface with biological systems: indicators to eavesdrop on cellular activity and actuators to poke and prod native processes. To reach the performance level required for their downstream applications, protein-based tools are usually sculpted by iterative rounds of mutagenesis. In each round, libraries of variants are made and evaluated, and the most promising hits are then retrieved, sequenced, and further characterized. Early efforts to engineer protein-based optical tools were largely manual, suffering from low throughput, human error, and tedium. Here, we describe approaches to automating …

Posoleucel, An Allogeneic, Off-The-Shelf Multivirus-Specific T-Cell Therapy, For The Treatment Of Refractory Viral Infections In The Post-Hct Setting, Thomas Pfeiffer, Et Al.

2020-Current year OA Pubs

PURPOSE: Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus.

PATIENTS AND METHODS: We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either …

Entry Receptors - The Gateway To Alphavirus Infection, Ofer Zimmerman, Autumn C. Holmes, Natasha M. Kafai, Lucas J. Adams, Michael S. Diamond

2020-Current year OA Pubs

Alphaviruses are enveloped, insect-transmitted, positive-sense RNA viruses that infect humans and other animals and cause a range of clinical manifestations, including arthritis, musculoskeletal disease, meningitis, encephalitis, and death. Over the past four years, aided by CRISPR/Cas9-based genetic screening approaches, intensive research efforts have focused on identifying entry receptors for alphaviruses to better understand the basis for cellular and species tropism. Herein, we review approaches to alphavirus receptor identification and how these were used for discovery. The identification of new receptors advances our understanding of viral pathogenesis, tropism, and evolution and is expected to contribute to the development of novel strategies …

Dysregulation Of The Prune2/Pca3 Genetic Axis In Human Prostate Cancer: From Experimental Discovery To Validation In Two Independent Patient Cohorts, Richard C. Lauer, Marc Barry, Tracey L. Smith, Andrew Maltez Thomas, Jin Wu, Ruofei Du, Ji-Hyun Lee, Arpit Rao, Andrey S. Dobroff, Marco A. Arap, Diana N. Nunes, Israel T. Silva, Emmanuel Dias-Neto, Isan Chen, Dennis J. Mccance, Webster K. Cavenee, Renata Pasqualini, Wadih Arap

Pathology Research and Scholarship

BACKGROUND: We have previously shown that the long non-coding (lnc)RNA

METHODS: The reciprocal

RESULTS: We consistently observed increased expression of

CONCLUSIONS: We concluded that upregulation of the lncRNA

FUNDING: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological …

A Pleiotropic Variant In Dnajb4 Is Associated With Multiple Myeloma Risk, Marco Dicanio, Matteo Giaccherini, Alyssa Clay-Gilmour, Angelica Macauda, Juan Sainz, Mitchell J Machiela, Malwina Rybicka-Ramos, Aaron D Norman, Agata Tyczyńska, Stephen J Chanock, Torben Barington, Shaji K Kumar, Parveen Bhatti, Wendy Cozen, Elizabeth E Brown, Anna Suska, Eva K Haastrup, Robert Z Orlowski, Marek Dudziński, Ramon Garcia-Sanz, Marcin Kruszewski, Joaquin Martinez-Lopez, Katia Beider, Elżbieta Iskierka-Jazdzewska, Matteo Pelosini, Sonja I Berndt, Małgorzata Raźny, Krzysztof Jamroziak, S Vincent Rajkumar, Artur Jurczyszyn, Annette Juul Vangsted, Pilar Garrido Collado, Ulla Vogel, Jonathan N Hofmann, Mario Petrini, Aleksandra Butrym, Susan L Slager, Elad Ziv, Edyta Subocz, Graham G Giles, Niels Frost Andersen, Grzegorz Mazur, Marzena Watek, Fabienne Lesueur, Michelle A T Hildebrandt, Daria Zawirska, Lene Hyldahl Ebbesen, Herlander Marques, Federica Gemignani, Charles Dumontet, Judit Várkonyi, Gabriele Buda, Arnon Nagler, Agnieszka Druzd-Sitek, Xifeng Wu, Katalin Kadar, Nicola J Camp, Norbert Grzasko, Rosalie G Waller, Celine Vachon, Federico Canzian, Daniele Campa

Faculty, Staff and Student Publications

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Wearable Sensing System For Noninvasive Monitoring Of Intracranial Biofluid Shifts In Aerospace Applications., Jacob L Griffith, Kim Cluff, Grant M Downes, Brandon Eckerman, Subash Bhandari, Benjamin E Loflin, Ryan Becker, Fayez Alruwaili, Noor Mohammed

Henry M. Rowan College of Engineering Departmental Research

The alteration of the hydrostatic pressure gradient in the human body has been associated with changes in human physiology, including abnormal blood flow, syncope, and visual impairment. The focus of this study was to evaluate changes in the resonant frequency of a wearable electromagnetic resonant skin patch sensor during simulated physiological changes observed in aerospace applications. Simulated microgravity was induced in eight healthy human participants (n = 8), and the implementation of lower body negative pressure (LBNP) countermeasures was induced in four healthy human participants (n = 4). The average shift in resonant frequency was -13.76 ± 6.49 MHz for …

A Novel Human Tau Knock-In Mouse Model Reveals Interaction Of Abeta And Human Tau Under Progressing Cerebral Amyloidosis In 5xfad Mice., Susan Barendrecht, An Schreurs, Stefanie Geissler, Victor Sabanov, Victoria Ilse, Vera Rieckmann, Rico Eichentopf, Anja Künemund, Benjamin Hietel, Sebastian Wussow, Katrin Hoffmann, Kerstin Körber-Ferl, Ravi S Pandey, Gregory W. Carter, Hans-Ulrich Demuth, Max Holzer, Steffen Roßner, Stephan Schilling, Christoph Preuss, Detlef Balschun, Holger Cynis

Faculty Research 2023

BACKGROUND: Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer's disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay.

METHODS: We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer's-like …

Sorting Through Life: Evaluating Patient-Important Measures Of Success In A Medication For Opioid Use Disorder (Moud) Treatment Program, Megan K Reed, Kelsey R Smith, Francesca Ciocco, Richard W. Hass, Avery Lin Cox, Erin L Kelly, Lara Weinstein

Department of Emergency Medicine Faculty Papers

Background: Medication for opioid use disorder (MOUD) is the gold standard treatment for opioid use disorder. Traditionally, "success" in MOUD treatment is measured in terms of program retention, adherence to MOUD, and abstinence from opioid and other drug use. While clinically meaningful, these metrics may overlook other aspects of the lives of people with opioid use disorder (OUD) and surprisingly do not reflect the diagnostic criteria for OUD.

Methods: Authors identified items for a pilesorting task to identify participant-driven measures of MOUD treatment success through semi-structured interviews. Interviews were transcribed verbatim and coded in Nvivo using directed and conventional content …

Modernization, Collectivism, And Gender Equality Predict Love Experiences In 45 Countries, Piotr Sorokowski, Marta Kowal, Robert J Sternberg, Toivo Aavik, Grace Akello, Mohammad Madallh Alhabahba, Charlotte Alm, Naumana Amjad, Afifa Anjum, Kelly Asao, Chiemezie S Atama, Derya Atamtürk Duyar, Richard Ayebare, Daniel Conroy-Beam, Mons Bendixen, Aicha Bensafia, Boris Bizumic, Mahmoud Boussena, David M Buss, Marina Butovskaya, Seda Can, Antonin Carrier, Hakan Cetinkaya, Ilona Croy, Rosa María Cueto, Marcin Czub, Daria Dronova, Seda Dural, Izzet Duyar, Berna Ertugrul, Agustín Espinosa, Ignacio Estevan, Carla Sofia Esteves, Tomasz Frackowiak, Jorge Contreras Garduño, Karina Ugalde González, Farida Guemaz, Mária Halamová, Iskra Herak, Marina Horvat, Ivana Hromatko, Chin-Ming Hui, Jas Laile Jaafar, Feng Jiang, Konstantinos Kafetsios, Tina Kavčič, Leif Edward Ottesen Kennair, Nicolas Kervyn, Truong Thi Khanh Ha, Imran Ahmed Khilji, Nils C Köbis, Aleksandra Kostic, Hoang Moc Lan, András Láng, Georgina R Lennard, Ernesto León, Torun Lindholm, Trinh Thi Linh, Giulia Lopez, Nguyen Van Luot, Alvaro Mailhos, Zoi Manesi, Rocio Martinez, Sarah L Mckerchar, Norbert Meskó, Marija Pejičić, Girishwar Misra, Conal Monaghan, Emanuel C Mora, Alba Moya-Garófano, Bojan Musil, Jean Carlos Natividade, George Nizharadze, Elisabeth Oberzaucher, Anna Oleszkiewicz, Mohd Sofian Omar-Fauzee, Ike E Onyishi, Baris Özener, Ariela Francesca Pagani, Vilmante Pakalniskiene, Miriam Parise, Farid Pazhoohi, Annette Pisanski, Katarzyna Pisanski, Edna Ponciano, Camelia Popa, Pavol Prokop, Muhammad Rizwan, Mario Sainz, Svjetlana Salkičević, Ruta Sargautyte, Ivan Sarmány-Schuller, Susanne Schmehl, Anam Shahid, Shivantika Sharad, Razi Sultan Siddiqui, Franco Simonetti, Meri Tadinac, Christin-Melanie Vauclair, Luis Diego Vega, Kathryn V Walter, Dwi Ajeng Widarini, Gyesook Yoo, Marta Zaťková, Maja Zupančič, Agnieszka Sorokowska

Faculty, Staff and Student Publications

Recent cross-cultural and neuro-hormonal investigations have suggested that love is a near universal phenomenon that has a biological background. Therefore, the remaining important question is not whether love exists worldwide but which cultural, social, or environmental factors influence experiences and expressions of love. In the present study, we explored whether countries' modernization indexes are related to love experiences measured by three subscales (passion, intimacy, commitment) of the Triangular Love Scale. Analyzing data from 9474 individuals from 45 countries, we tested for relationships with country-level predictors, namely, modernization proxies (i.e., Human Development Index, World Modernization Index, Gender Inequality Index), collectivism, and …

Modus Operandi Of Clc-K2 Cl- Channel In The Collecting Duct Intercalated Cells, Anna Stavniichuk, Kyrylo Pyrshev, Viktor N Tomilin, Mariya Kordysh, Oleg Zaika, Oleh Pochynyuk

Faculty, Staff and Student Publications

The renal collecting duct is known to play a critical role in many physiological processes, including systemic water-electrolyte homeostasis, acid-base balance, and the salt sensitivity of blood pressure. ClC-K2 (ClC-Kb in humans) is a Cl--permeable channel expressed on the basolateral membrane of several segments of the renal tubule, including the collecting duct intercalated cells. ClC-Kb mutations are causative for Bartters' syndrome type 3 manifested as hypotension, urinary salt wasting, and metabolic alkalosis. However, little is known about the significance of the channel in the collecting duct with respect to the normal physiology and pathology of Bartters' syndrome. In this review, …

Radiation-Induced Senescence: Therapeutic Opportunities, Jae Ho Kim, Stephen L. Brown, Marcia N. Gordon

Radiation Oncology Articles

The limitation of cancer radiotherapy does not derive from an inability to ablate tumor, but rather to do so without excessively damaging critical tissues and organs and adversely affecting patient's quality of life. Although cellular senescence is a normal consequence of aging, there is increasing evidence showing that the radiation-induced senescence in both tumor and adjacent normal tissues contributes to tumor recurrence, metastasis, and resistance to therapy, while chronic senescent cells in the normal tissue and organ are a source of many late damaging effects. In this review, we discuss how to identify cellular senescence using various bio-markers and the …

Chiatac Is An Efficient Strategy For Multi-Omics Mapping Of 3d Epigenomes From Low-Cell Inputs., Haoxi Chai, Harianto Tjong, Peng Li, Wei Liao, Ping Wang, Chee-Hong Wong, Chew Yee Ngan, Warren J Leonard, Chia-Lin Wei, Yijun Ruan

Faculty Research 2023

Connecting genes to their cis-regulatory elements has been enabled by genome-wide mapping of chromatin interactions using proximity ligation in ChIA-PET, Hi-C, and their derivatives. However, these methods require millions of input cells for high-quality data and thus are unsuitable for many studies when only limited cells are available. Conversely, epigenomic profiling via transposase digestion in ATAC-seq requires only hundreds to thousands of cells to robustly map open chromatin associated with transcription activity, but it cannot directly connect active genes to their distal enhancers. Here, we combine proximity ligation in ChIA-PET and transposase accessibility in ATAC-seq into ChIATAC to efficiently map …

Mendelian Randomization Analysis Reveals A Complex Genetic Interplay Among Atopic Dermatitis, Asthma, And Gastroesophageal Reflux Disease, Kwangmi Ahn, Raymond B. Penn, Satish Rattan, Reynold A. Panettieri, Benjamin F. Voight, Steven S. An

Division of Gastroenterology and Hepatology Faculty Papers

RATIONALE: Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear.

OBJECTIVES: We applied Mendelian randomization (MR) analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis).

METHODS: We conducted two-sample bidirectional MR to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies (GWAS) conducted on asthma (N_cases=56,167) and GERD (N_cases=71,522). Additionally, we generated instrumental variables (IVs) for atopic dermatitis (AD) from the latest population-level GWAS meta-analysis (N_cases=22,474) and …

Associations Between The Dietary Inflammatory Index And Sleep Metrics In The Energy Balance Study (Ebs)., Emily T. Farrell, Michael D. Wirth, Alexander C. Mclain, Thomas G. Hurley, Robin P. Shook, Gregory A. Hand, James R. Hébert, Steven N. Blair

Manuscripts, Articles, Book Chapters and Other Papers

(1) Background: Sleep, a physiological necessity, has strong inflammatory underpinnings. Diet is a strong moderator of systemic inflammation. This study explored the associations between the Dietary Inflammatory Index (DII®) and sleep duration, timing, and quality from the Energy Balance Study (EBS). (2) Methods: The EBS (n = 427) prospectively explored energy intake, expenditure, and body composition. Sleep was measured using BodyMedia's SenseWear® armband. DII scores were calculated from three unannounced dietary recalls (baseline, 1-, 2-, and 3-years). The DII was analyzed continuously and categorically (very anti-, moderately anti-, neutral, and pro-inflammatory). Linear mixed-effects models estimated the DII score impact …

Clonal Hematopoiesis And Risk Of Prostate Cancer In Large Samples Of European Ancestry Men, Anqi Wang, Yili Xu, Yao Yu, Kevin T Nead, Taebeom Kim, Keren Xu, Tokhir Dadaev, Ed Saunders, Xin Sheng, Peggy Wan, Loreall Pooler, Lucy Y Xia, Stephen Chanock, Sonja I Berndt, Susan M Gapstur, Victoria Stevens, Demetrius Albanes, Stephanie J Weinstein, Vincent Gnanapragasam, Graham G Giles, Tu Nguyen-Dumont, Roger L Milne, Mark M Pomerantz, Julie A Schmidt, Konrad H Stopsack, Lorelei A Mucci, William J Catalona, Kurt N Hetrick, Kimberly F Doheny, Robert J Macinnis, Melissa C Southey, Rosalind A Eeles, Fredrik Wiklund, Zsofia Kote-Jarai, Adam J De Smith, David V Conti, Chad Huff, Christopher A Haiman, Burcu F Darst

Faculty, Staff and Student Publications

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not …

Transmission Of Carbapenem-Resistant Klebsiella Pneumoniae In Us Hospitals, Courtney L Luterbach, Liang Chen, Lauren Komarow, Belinda Ostrowsky, Keith S Kaye, Blake Hanson, Cesar A Arias, Samit Desai, Jason C Gallagher, Elizabeth Novick, Stephen Pagkalinawan, Ebbing Lautenbach, Glenn Wortmann, Robert C Kalayjian, Brandon Eilertson, John J Farrell, Todd Mccarty, Carol Hill, Vance G Fowler, Barry N Kreiswirth, Robert A Bonomo, David Van Duin

Faculty, Staff and Student Publications

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated CRKp clustering in patients in US hospitals.

METHODS: From April 2016 to August 2017, 350 patients with clonal group 258 CRKp were enrolled in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae, a prospective, multicenter, cohort study. A maximum likelihood tree was constructed using RAxML. Static clusters shared ≤21 single-nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster.

RESULTS: Most patients …

Oxphos Defects Cause Hypermetabolism And Reduce Lifespan In Cells And In Patients With Mitochondrial Diseases, Gabriel Sturm, Kalpita R Karan, Anna S Monzel, Balaji Santhanam, Tanja Taivassalo, Céline Bris, Sarah A Ware, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J Mcmanus, Andres Cardenas, Jue Lin, Elissa S Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G Haller, Guy Lenaers, Douglas C Wallace, Marie-Pierre St-Onge, Saeed Tavazoie, Vincent Procaccio, Brett A Kaufman, Erin L. Seifert, Michio Hirano, Martin Picard

Department of Pediatrics Faculty Papers

Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated …

Systemic Interindividual Epigenetic Variation In Humans Is Associated With Transposable Elements And Under Strong Genetic Control, Chathura J Gunasekara, Harry Mackay, C Anthony Scott, Shaobo Li, Eleonora Laritsky, Maria S Baker, Sandra L Grimm, Goo Jun, Yumei Li, Rui Chen, Joseph L Wiemels, Cristian Coarfa, Robert A Waterland

Faculty, Staff and Student Publications

BACKGROUND: Genetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example at methylation quantitative trait loci (mQTL). We present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation, which we call correlated regions of systemic interindividual variation (CoRSIVs). These can be assayed in blood DNA and do not reflect interindividual variation in cellular composition.

RESULTS: We use target-capture bisulfite sequencing to assess DNA methylation at 4086 CoRSIVs in multiple tissues from each of 188 donors in the NIH Gene-Tissue Expression (GTEx) program. At CoRSIVs, DNA methylation in peripheral blood correlates with …

Endogenous Retrovirus Rna Expression Differences Between Race, Stage And Hpv Status Offer Improved Prognostication Among Women With Cervical Cancer, Jill Alldredge, Vinay Kumar, James Nguyen, Brooke E Sanders, Karina Gomez, Kay Jayachandran, Jin Zhang, Julie Schwarz, Farah Rahmatpanah

2020-Current year OA Pubs

Endogenous human retroviruses (ERVs) are remnants of exogenous retroviruses that have integrated into the human genome. Using publicly available RNA-seq data from 63 cervical cancer patients, we investigated the expression of ERVs in cervical cancers. Four aspects of cervical cancer were investigated: patient ancestral background, tumor HPV type, tumor stage and patient survival. Between the racial subgroups, 74 ERVs were significantly differentially expressed, with Black Americans having 30 upregulated and 44 downregulated (including MER21C, HERV9-int, and HERVH-int) ERVs when compared to White Americans. We found that 3313 ERVs were differentially expressed between HPV subgroups, including MER41A, HERVH-int and HERVK9. There …

A Clustering Of Heterozygous Missense Variants In The Crucial Chromatin Modifier Wdr5 Defines A New Neurodevelopmental Disorder, Lot Snijders Blok, Jolijn Verseput, Dmitrijs Rots, Hanka Venselaar, A Micheil Innes, Connie Stumpel, Katrin Õunap, Karit Reinson, Eleanor G Seaby, Shane Mckee, Barbara Burton, Katherine Kim, Johanna M Van Hagen, Quinten Waisfisz, Pascal Joset, Katharina Steindl, Anita Rauch, Dong Li, Elaine H Zackai, Sarah E Sheppard, Beth Keena, Hakon Hakonarson, Andreas Roos, Nicolai Kohlschmidt, Anna Cereda, Maria Iascone, Erika Rebessi, Kristin D Kernohan, Philippe M Campeau, Francisca Millan, Jesse A Taylor, Hanns Lochmüller, Martin R Higgs, Amalia Goula, Birgitta Bernhard, Danita J Velasco, Andrew A Schmanski, Zornitza Stark, Lyndon Gallacher, Lynn Pais, Paul C Marcogliese, Shinya Yamamoto, Nicholas Raun, Taryn E Jakub, Jamie M Kramer, Joery Den Hoed, Simon E Fisher, Han G Brunner, Tjitske Kleefstra

Faculty, Staff and Students Publications

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features …

Enhanced Neutralization Resistance Of Sars-Cov-2 Omicron Subvariants Bq1, Bq11, Ba46, Bf7, And Ba2752, Panke Qu, John P Evans, Julia N Faraone, Yi-Min Zheng, Claire Carlin, Mirela Anghelina, Patrick Stevens, Soledad Fernandez, Daniel Jones, Gerard Lozanski, Ashish Panchal, Linda J Saif, Eugene M Oltz, Kai Xu, Richard J Gumina, Shan-Lu Liu

Faculty, Staff and Student Publications

The continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. Here, we examine the neutralization resistance of these subvariants against sera from 3-dose vaccinated healthcare workers, hospitalized BA.1-wave patients, and BA.4/5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially in the BQ.1 and BQ.1.1 subvariants driven by N460K and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation. All Omicron subvariants maintained their weakened infectivity in Calu-3 cells, with the F486S mutation driving further diminished titer for the BA.2.75.2 subvariant. …

Antibody Duration After Infection From Sars-Cov-2 In The Texas Coronavirus Antibody Response Survey, Michael D Swartz, Stacia M Desantis, Ashraf Yaseen, Frances A Brito, Melissa A Valerio-Shewmaker, Sarah E Messiah, Luis G Leon-Novelo, Harold W Kohl, Cesar L Pinzon-Gomez, Tianyao Hao, Shiming Zhang, Yashar Talebi, Joy Yoo, Jessica R Ross, Michael O Gonzalez, Leqing Wu, Steven H Kelder, Mark Silberman, Samantha Tuzo, Stephen J Pont, Jennifer A Shuford, David Lakey, Eric Boerwinkle

Faculty, Staff and Student Publications

Understanding the duration of antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that causes COVID-19 is important to controlling the current pandemic. Participants from the Texas Coronavirus Antibody Response Survey (Texas CARES) with at least 1 nucleocapsid protein antibody test were selected for a longitudinal analysis of antibody duration. A linear mixed model was fit to data from participants (n = 4553) with 1 to 3 antibody tests over 11 months (1 October 2020 to 16 September 2021), and models fit showed that expected antibody response after COVID-19 infection robustly increases for 100 days postinfection, and predicts …

Childhood Adversities And Risk Of Posttraumatic Stress Disorder And Major Depression Following A Motor Vehicle Collision In Adulthood, H N Ziobrowski, B Holt-Gosselin, M V Petukhova, A J King, S Lee, S L House, F L Beaudoin, X An, J S Stevens, D Zeng, T C Neylan, G D Clifford, S D Linnstaedt, L T Germine, K A Bollen, S L Rauch, J P Haran, A B Storrow, Christopher A. Lewandowski, P I Musey, P L Hendry, S Sheikh, C W Jones, B E Punches, M C Kurz, R A Swor, L A Hudak, J L Pascual, M J Seamon, E Harris, C Pearson, R C Merchant, R M Domeier, N K Rathlev, B J O'Neil, P Sergot, L D Sanchez, S E Bruce, M W Miller, R H Pietrzak, J Joormann, D M Barch, D A Pizzagalli, S E Harte, J M Elliott, K J Ressler, S A Mclean, K C Koenen, R C Kessler

Emergency Medicine Articles

AIMS: Childhood adversities (CAs) predict heightened risks of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) among people exposed to adult traumatic events. Identifying which CAs put individuals at greatest risk for these adverse posttraumatic neuropsychiatric sequelae (APNS) is important for targeting prevention interventions.

METHODS: Data came from n = 999 patients ages 18-75 presenting to 29 U.S. emergency departments after a motor vehicle collision (MVC) and followed for 3 months, the amount of time traditionally used to define chronic PTSD, in the Advancing Understanding of Recovery After Trauma (AURORA) study. Six CA types were self-reported at baseline: physical …