Digital Commons Network^™

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 …

Mechanisms Of Mcl-1 Protein Stability Induced By Mcl-1 Antagonists In B-Cell Malignancies, Shady I Tantawy, Aloke Sarkar, Stefan Hubner, Zhi Tan, William G Wierda, Abdelraouf Eldeib, Shuxing Zhang, Steven Kornblau, Varsha Gandhi

Faculty, Staff and Student Publications

PURPOSE: Several MCL-1 inhibitors (MCL-1i), including AMG-176 and AZD5991, have shown promise in preclinical studies and are being tested for the treatment of hematologic malignancies. A unique feature of these agents is induction and stability of Mcl-1 protein; however, the precise mechanism is unknown. We aim to study the mechanism of MCL-1i-induced Mcl-1 protein stability.

EXPERIMENTAL DESIGN: Using several B-cell leukemia and lymphoma cell lines and primary chronic lymphocytic leukemia (CLL) lymphocytes, we evaluated molecular events associated with Mcl-1 protein stability including protein half-life, reverse-phase protein array, protein-protein interaction, phosphorylation, ubiquitination, and de-ubiquitination, followed by molecular simulation and modeling.

RESULTS: …

Planarians To Schistosomes: An Overview Of Flatworm Cell-Types And Regulators, J Lee

Faculty, Staff and Student Publications

Schistosomiasis remains a major neglected tropical disease that afflicts over 200 million people globally. Schistosomes, the aetiological agent of schistosomiasis, are parasitic flatworms that propagate between molluscan and mammalian hosts. Inside the mammalian host, schistosomes rapidly grow over 100-fold in size and develop into a sexually mature male or female that thrives in the bloodstream for several decades. Recent work has identified schistosome stem cells as the source that drives parasite transmission, reproduction and longevity. Moreover, studies have begun to uncover molecular programmes deployed by stem cells that are essential for tissue development and maintenance, parasite survival and immune evasion. …

Adar1 Deletion Causes Degeneration Of The Exocrine Pancreas Via Mavs-Dependent Interferon Signaling, Dhwani N Rupani, Fredrik I Thege, Vidhi Chandra, Hajar Rajaei, Robert W Cowan, Sonja M Wörmann, Olivereen Le Roux, Prerna Malaney, Sara L Manning, Jack Hashem, Jennifer Bailey-Lundberg, Andrew D Rhim, Florencia Mcallister

Faculty, Staff and Student Publications

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a …

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.

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 …

A Gain-Of-Function Tpc2 Variant R210c Increases Affinity To Pi(3,5)P2 And Causes Lysosome Acidification And Hypopigmentation, Qiaochu Wang, Zengge Wang, Yizhen Wang, Zhan Qi, Dayong Bai, Chentong Wang, Yuanying Chen, Wenjian Xu, Xili Zhu, Jaepyo Jeon, Jian Xiong, Chanjuan Hao, Michael Xi Zhu, Aihua Wei, Wei Li

Faculty, Staff and Student Publications

Albinism is a group of inherited disorders mainly affecting skin, hair and eyes. Here we identify a de novo point mutation, p.R210C, in the TPCN2 gene which encodes Two Pore Channel 2 (TPC2) from a patient with albinism. TPC2 is an endolysosome and melanosome localized non-selective cation channel involved in regulating pigment production. Through inside-out recording of plasma membrane targeted TPC2 and direct recording of enlarged endolysosomal vacuoles, we reveal that the R210C mutant displays constitutive channel activation and markedly increased affinity to PI(3,5)P2. Mice harboring the homologous mutation, R194C, also exhibit hypopigmentation in the fur and skin, as well …

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, …

Characteristics And Clinical Outcomes Of Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib For ≥5 Years In The Resonate-2 Study, Jennifer A Woyach, Paul M Barr, Thomas J Kipps, Jacqueline C Barrientos, Inhye E Ahn, Paolo Ghia, Vincent Girardi, Emily Hsu, Mandy Jermain, Jan A Burger

Faculty, Staff and Student Publications

Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5−0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n …

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 …

Excessive Mechanotransduction In Sensory Neurons Causes Joint Contractures, Shang Ma, Adrienne E Dubin, Luis O Romero, Meaghan Loud, Alexandra Salazar, Sarah Chu, Nikola Klier, Sameer Masri, Yunxiao Zhang, Yu Wang, Alex T Chesler, Katherine A Wilkinson, Valeria Vásquez, Kara L Marshall, Ardem Patapoutian

Faculty, Staff and Student Publications

Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin …

Systematic Design Of Adenosine Analogs As Inhibitors Of A Clostridioides Difficile- Specific Dna Adenine Methyltransferase Required For Normal Sporulation And Persistence, Jujun Zhou, John R Horton, Martina Menna, Francesco Fiorentino, Ren Ren, Dan Yu, Taraneh Hajian, Masoud Vedadi, Giulia Mazzoccanti, Alessia Ciogli, Elmar Weinhold, Michael Hüben, Robert M Blumenthal, Xing Zhang, Antonello Mai, Dante Rotili, Xiaodong Cheng

Faculty, Staff and Student Publications

Antivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of …

Perspectives Of Health Care Staff On Predictors Of Success In A Food Prescription Program: A Qualitative Study, John Wesley Mcwhorter, Jennifer N Aiyer, Nalini Ranjit, Jack Toups, Esther Liew, Jemima C John, Shreela V Sharma

Faculty, Staff and Student Publications

Partnerships between food prescription programs and food banks can address food insecurity and support health; however, few studies have examined the experience and perceptions of health care partners about these programs. Our objective was to analyze secondary qualitative data from clinicians and clinic staff involved in implementing a food prescription program in Houston, Texas. We collected data from 17 health care clinics from May 2018 through March 2021 to learn how implementation of the food prescription program was perceived, and we received 252 responses. Principal themes were the importance of a value-based care strategy, patient and food pantry barriers to …

Cost-Effectiveness Of Sugammadex Versus Neostigmine To Reverse Neuromuscular Blockade In A University Hospital In Taiwan: A Propensity Score-Matched Analysis, Winnie Lan, Ka-Wai Tam, Jui-Tai Chen, Juan P Cata, Yih-Giun Cherng, Yun-Yun Chou, Li-Nien Chien, Chia-Li Chang, Ying-Hsuan Tai, Lu-Min Chu

Faculty, Staff and Student Publications

Sugammadex has several pharmacological advantages over neostigmine, including faster reversal of neuromuscular blockade and fewer adverse effects. However, the economic impact of sugammadex remains controversial due to the considerable heterogeneity of study designs and clinical settings in previous studies. In a post-hoc analysis of a randomized controlled trial, we evaluated patients who underwent elective surgeries and general anesthesia with endotracheal intubation in a medical center in Taiwan between March 2020 and August 2020. Patients were divided into either the sugammadex or neostigmine group based on the neuromuscular blocking drug used. Propensity score matching was used to balance the baseline patient …

Antihuman T Lymphocyte Porcine Immunoglobulin Combined With Cyclosporine As First-Line Immunosuppressive Therapy For Severe Aplastic Anemia In China: A Large Single-Center, 10-Year Retrospective Study, Wenrui Yang, Xu Liu, Xin Zhao, Li Zhang, Guangxin Peng, Lei Ye, Kang Zhou, Yuan Li, Jianping Li, Huihui Fan, Yang Yang, Youzhen Xiong, Liping Jing, Fengkui Zhang

Faculty, Staff and Student Publications

BACKGROUND: Antihuman T lymphocyte porcine immunoglobulin (p-ATG) has been the most common ATG preparation in immunosuppressive therapy (IST) in Chinese patients with severe aplastic anemia (SAA) since 2009.

OBJECTIVES: This study aimed to evaluate the early hematologic response and long-term outcomes of a large cohort of patients with SAA who received p-ATG plus cyclosporine (CsA) as first-line therapy from 2010 to 2019.

DESIGN: This is a single-center retrospective study of medical records.

METHODS: We analyzed the data of 1023 consecutive patients with acquired aplastic anemia (AA) who underwent p-ATG combined with CsA as a first-line IST treatment from 2010 to …

Alk-Positive Large B-Cell Lymphoma, A Rare B-Cell Lymphoma Expressing Alk, Karen A Nahmod, Francisco Vega

Faculty, Staff and Student Publications

No abstract provided.

Trogocytosis Of Neurons And Glial Cells By Microglia In A Healthy Adult Macaque Retina, Megan Goyal, Andrea S Bordt, Jay Neitz, David W Marshak

Faculty, Staff and Student Publications

Microglial cells are the primary resident immune cells in the retina. In healthy adults, they are ramified; that is, they have extensive processes that move continually. In adult retinas, microglia maintain the normal structure and function of neurons and other glial cells, but the mechanism underlying this process is not well-understood. In the mouse hippocampus, microglia engulf small pieces of axons and presynaptic terminals via a process called trogocytosis. Here we report that microglia in the adult macaque retina also engulf pieces of neurons and glial cells, but not at sites of synapses. We analyzed microglia in a volume of …

Feasibility Of A Meditation Intervention For Stroke Survivors And Informal Caregivers: A Randomized Controlled Trial, Jennifer E S Beauchamp, Anjail Sharrief, Alejandro Chaoul, Tahani Casameni Montiel, Mary F Love, Stanley Cron, Alan Prossin, Sudhakar Selvaraj, Deniz Dishman, Sean I Savitz

Faculty, Staff and Student Publications

BACKGROUND: Depressive symptoms are a significant psychological complication of stroke, impacting both survivors and informal caregivers of survivors. Randomized controlled trials are needed to determine optimal non-pharmacological strategies to prevent or ameliorate depressive symptoms in stroke survivors and their informal caregivers.

METHODS: A prospective, randomized, parallel-group, single-center, feasibility study. Participants were assigned to a 4-week meditation intervention or expressive writing control group. The intervention comprised four facilitator-led group meditation sessions, one session per week and building upon prior session(s). Descriptive statistics were used to examine the proportion of eligible individuals who enrolled, retention and adherence rates, and the proportion of …

Accelerating Catalytic Oxyanion Reduction With Inert Metal Hydroxides, Jinyu Gao, Qiang Zhao, Cheng Tan, Shaohua Xie, Yadong Yin, Fudong Liu, Haizhou Liu, Baoliang Chen, Jinyong Liu

Faculty, Staff and Student Publications

Adding CrIII or AlIII salts into the water suspension of platinum group metal (PGM) catalysts accelerated oxyanion pollutant reduction by up to 600%. Our initial attempts of adding K2CrVIO4, K2CrVI2O7, or KCrIII(SO4)2 into Pd/C enhanced BrO3– reduction with 1 atm H2 by 6-fold. Instrument characterizations and kinetic explorations collectively confirmed the immobilization of reduced CrVI as CrIII(OH)3 on the catalyst surface. This process altered the ζ-potentials from negative to positive, thus substantially enhancing the Langmuir–Hinshelwood adsorption equilibrium constant for BrO3– onto Pd/C by 37-fold. Adding AlIII(OH)3 from alum at pH 7 achieved similar enhancements. The Cr–Pd/C and Al–Pd/C showed top-tier …

Enasidenib Vs Conventional Care In Older Patients With Late-Stage Mutant-Idh2 Relapsed/Refractory Aml: A Randomized Phase 3 Trial, Stéphane De Botton, Pau Montesinos, Andre C Schuh, Cristina Papayannidis, Paresh Vyas, Andrew H Wei, Hans Ommen, Sergey Semochkin, Hee-Je Kim, Richard A Larson, Jaime Koprivnikar, Olga Frankfurt, Felicitas Thol, Jörg Chromik, Jenny Byrne, Arnaud Pigneux, Xavier Thomas, Olga Salamero, Maria Belen Vidriales, Vadim Doronin, Hartmut Döhner, Amir T Fathi, Eric Laille, Xin Yu, Maroof Hasan, Patricia Martin-Regueira, Courtney D Dinardo

Faculty, Staff and Student Publications

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). …

Tlr5 Agonists Enhance Anti-Tumor Immunity And Overcome Resistance To Immune Checkpoint Therapy, Caleb Gonzalez, Sarah Williamson, Seth T Gammon, Sarah Glazer, Joon Haeng Rhee, David Piwnica-Worms

Faculty, Staff and Student Publications

Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive immunity. Low serum levels of G-CSF …

Microrna-Mrna Networks Are Dysregulated In Opioid Use Disorder Postmortem Brain: Further Evidence For Opioid-Induced Neurovascular Alterations, Sandra L Grimm, Emily F Mendez, Laura Stertz, Thomas D Meyer, Gabriel R Fries, Tanmay Gandhi, Rupa Kanchi, Sudhakar Selvaraj, Antonio L Teixeira, Thomas R Kosten, Preethi Gunaratne, Cristian Coarfa, Consuelo Walss-Bass

Faculty, Staff and Student Publications

INTRODUCTION: To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function.

METHODS: Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues.

RESULTS: miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood …

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 …

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. …

Global Biobank Analyses Provide Lessons For Developing Polygenic Risk Scores Across Diverse Cohorts, Ying Wang, Shinichi Namba, Esteban Lopera, Sini Kerminen, Kristin Tsuo, Kristi Läll, Masahiro Kanai, Wei Zhou, Kuan-Han Wu, Marie-Julie Favé, Laxmi Bhatta, Philip Awadalla, Ben Brumpton, Patrick Deelen, Kristian Hveem, Valeria Lo Faro, Reedik Mägi, Yoshinori Murakami, Serena Sanna, Jordan W Smoller, Jasmina Uzunovic, Brooke N Wolford, Global Biobank Meta-Analysis Initiative, Cristen Willer, Eric R Gamazon, Nancy J Cox, Ida Surakka, Yukinori Okada, Alicia R Martin, Jibril Hirbo

Faculty, Staff and Student Publications

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially …

Individual And Neighborhood Socioeconomic Status And Long-Term Individual Trajectories Of Sleep Duration Among Black And White Adults: The Southern Community Cohort Study, Samuel H Nyarko, Liying Luo, David G Schlundt, Qian Xiao

Faculty, Staff and Student Publications

STUDY OBJECTIVES: Sleep duration can change over the life course; however, previous studies rarely investigated the association between socioeconomic status (SES) and individual sleep trajectories over time. We examined the association between baseline socioeconomic characteristics and long-term sleep trajectories among Black and White adults.

METHODS: This study used data from the Southern Community Cohort Study (N = 45 035). Diverse trajectories of sleep duration were constructed using self-reported sleep duration at baseline and after ~10 years of follow-up. The associations between baseline socioeconomic characteristics and sleep trajectories were examined using multinomial logistic regression.

RESULTS: Both Black and White participants experienced …

Class 1 And 2 Integrons In Escherichia Coli Strains Isolated From Diarrhea And Bacteremia In Children Less Than 2 Years Of Age From Peru, Maribel Riveros, Maria J Pons, David Durand, Theresa J Ochoa, Joaquim Ruiz

Faculty, Staff and Student Publications

Class 1 and Class 2 integrons are mobilizable elements able to carry a variety of antibiotic resistance determinants. In the present study, Class 1 and 2 integrons present in 355 pathogenic Escherichia coli (285 diarrheagenic, of these 129 were enteropathogenic, 90 enteroaggregative, 66 enterotoxigenic, and 70 bacteremic) isolated from healthy and ill children under age 5 from periurban areas of Lima, Peru, were characterized. The presence of integrase 1 and 2 was established by polymerase chain reaction (PCR), and variable regions were grouped by PCR-restriction fragment length polymorphism and subsequent sequencing. Antimicrobial resistance was established by disk diffusion. Ninety-seven isolates …

Prevalence And Geographic Distribution Of Self-Reported Chronic Kidney Disease And Potential Risk Factors In Central America, Erika Figueroa-Solis, David Gimeno Ruiz De Porras, Marianela Rojas-Garbanzo, Lawrence Whitehead, Kai Zhang, George L Delclos

Faculty, Staff and Student Publications

BACKGROUND: Cases for chronic kidney disease of unknown etiology (CKDu) are increasing in specific disease hotspots located in rural agricultural communities over Central America. The goal of the study was to estimate the prevalence and geographic distribution of self-reported work-related CKD and associated risk factors for CKDu by industry sector in Central America.

METHODS: We calculated the prevalence and distribution of self-reported CKD, work-related CKD, and suspected CKDu risk factors among the 9032 workers in the Second Central American Survey of Working Conditions and Health (II ECCTS, 2018). We mapped the distribution of suspected CKDu risk factors to work-related CKDu …

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 …