Medical Specialties Commons^™

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.

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 …

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 …

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 …

3q262/Mecom Rearrangements By Pericentric Inv(3): Diagnostic Challenges And Clinicopathologic Features, Zhenya Tang, Wei Wang, Su Yang, Hanadi El Achi, Hong Fang, Karen Amelia Nahmod, Gokce A Toruner, Jie Xu, Beenu Thakral, Edward Ayoub, Ghayas C Issa, C Cameron Yin, M James You, Roberto N Miranda, Joseph D Khoury, L Jeffrey Medeiros, Guilin Tang

Faculty, Staff and Student Publications

MECOM rearrangement (MECOM-R) resulting from 3q26.2 aberrations is often associated with myeloid neoplasms and inferior prognosis in affected patients. Uncommonly, certain 3q26.2/MECOM-R can be subtle/cryptic and consequently overlooked by karyotyping. We identified 17 acute myeloid leukemia (AML) patients (male/female: 13/4 with a median age of 67 years, range 42 to 85 years) with a pericentric inv(3) leading to MECOM-R, with breakpoints at 3p23 (n = 11), 3p25 (n = 3), 3p21 (n = 2) and 3p13 (n = 1) on 3p and 3q26.2 on 3q. These pericentric inv(3)s were overlooked by karyotyping initially in 16 of 17 …

Antibody-Drug Conjugates In Lung Cancer: Dawn Of A New Era?, Niamh Coleman, Timothy A Yap, John V Heymach, Funda Meric-Bernstam, Xiuning Le

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, …

Reconstructing Mutational Lineages In Breast Cancer By Multi-Patient-Targeted Single-Cell Dna Sequencing, Jake Leighton, Min Hu, Emi Sei, Funda Meric-Bernstam, Nicholas E Navin

Faculty, Staff and Student Publications

Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells; however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were …

Sgc-Camkk2-1: A Chemical Probe For Camkk2, Carrow Wells, Yi Liang, Thomas L Pulliam, Chenchu Lin, Dominik Awad, Benjamin Eduful, Sean O'Byrne, Mohammad Anwar Hossain, Carolina Moura Costa Catta-Preta, Priscila Zonzini Ramos, Opher Gileadi, Carina Gileadi, Rafael M Couñago, Brittany Stork, Christopher G Langendorf, Kevin Nay, Jonathan S Oakhill, Debarati Mukherjee, Luigi Racioppi, Anthony R Means, Brian York, Donald P Mcdonnell, John W Scott, Daniel E Frigo, David H Drewry

Faculty, Staff and Student Publications

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

Predictors Of Success In Establishing Orthotopic Patient-Derived Xenograft Models Of Triple Negative Breast Cancer, Gloria V Echeverria, Shirong Cai, Yizheng Tu, Jiansu Shao, Emily Powell, Abena B Redwood, Yan Jiang, Aaron Mccoy, Amanda L Rinkenbaugh, Rosanna Lau, Alexander J Trevarton, Chunxiao Fu, Rebekah Gould, Elizabeth E Ravenberg, Lei Huo, Rosalind Candelaria, Lumarie Santiago, Beatriz E Adrada, Deanna L Lane, Gaiane M Rauch, Wei T Yang, Jason B White, Jeffrey T Chang, Stacy L Moulder, W Fraser Symmans, Susan G Hilsenbeck, Helen Piwnica-Worms

Faculty, Staff and Student Publications

Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. We established orthotopic PDX models of triple negative breast cancer (TNBC) from the primary breast tumors of patients prior to and following neoadjuvant chemotherapy (NACT) while they were enrolled in the ARTEMIS trial (NCT02276443). Serial biopsies were obtained from patients prior to treatment (pre-NACT), from poorly responsive disease after four cycles of Adriamycin and cyclophosphamide (AC, mid-NACT), and in cases of AC-resistance, after a 3-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a …

Efficacy Of Eltrombopag With Immunosuppressive Therapy For Children With Acquired Aplastic Anemia, Yufei Zhao, Wenrui Yang, Xin Zhao, Xiangrong Hu, Jing Hu, Xu Liu, Jianping Li, Lei Ye, Youzhen Xiong, Yang Yang, Baohang Zhang, Xiaoxia Li, Xiawan Yang, Yimeng Shi, Guangxin Peng, Yuan Li, Huihui Fan, Kang Zhou, Liping Jing, Li Zhang, Fengkui Zhang

Faculty, Staff and Student Publications

BACKGROUND: Eltrombopag (EPAG), an oral thrombopoietin receptor agonist (TPO-RA), has been proven to improve the hematologic response without increasing toxic effects as a first-line therapy combined with standard immunosuppressive treatment (IST) in adults with severe aplastic anemia (SAA). Nevertheless, the clinical evidence on the efficacy of EPAG in children with acquired aplastic anemia is limited and controversial.

METHODS: We performed a single-center, retrospective study to analyze the clinical outcomes of fifteen patients aged ≤18 years with newly diagnosed acquired SAA who received first-line IST and EPAG (EPAG group) compared with those of forty-five patients who received IST alone (IST group) …

Diverticular Disease And Cancer Risk: More Than A Gut Feeling, Veronika Fedirko, Scott Kopetz, Carrie R Daniel

Faculty, Staff and Student Publications

No abstract provided.

Disabling Uncompetitive Inhibition Of Oncogenic Idh Mutations Drives Acquired Resistance, Junhua Lyu, Yuxuan Liu, Lihu Gong, Mingyi Chen, Yazan F Madanat, Yuannyu Zhang, Feng Cai, Zhimin Gu, Hui Cao, Pranita Kaphle, Yoon Jung Kim, Fatma N Kalkan, Helen Stephens, Kathryn E Dickerson, Min Ni, Weina Chen, Prapti Patel, Alice S Mims, Uma Borate, Amy Burd, Sheng F Cai, C Cameron Yin, M James You, Stephen S Chung, Robert H Collins, Ralph J Deberardinis, Xin Liu, Jian Xu

Faculty, Staff and Student Publications

Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. Allosteric inhibition of mutant IDH suppresses R-2HG production in a subset of patients with AML; however, acquired resistance emerges as a new challenge, and the underlying mechanisms remain incompletely understood. Here we establish isogenic leukemia cells containing common IDH oncogenic mutations by CRISPR base editing. By mutational scanning of IDH single amino acid variants in base-edited cells, we describe a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH …

A Molecular Switch Between Mammalian Mll Complexes Dictates Response To Menin-Mll Inhibition, Yadira M Soto-Feliciano, Francisco J Sánchez-Rivera, Florian Perner, Douglas W Barrows, Edward R Kastenhuber, Yu-Jui Ho, Thomas Carroll, Yijun Xiong, Disha Anand, Alexey A Soshnev, Leah Gates, Mary Clare Beytagh, David Cheon, Shengqing Gu, X Shirley Liu, Andrei V Krivtsov, Maximiliano Meneses, Elisa De Stanchina, Richard M Stone, Scott A Armstrong, Scott W Lowe, C David Allis

Faculty, Staff and Student Publications

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin-modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors …

The Axillary View Typically Does Not Contribute To Decision Making In Care For Proximal Humeral Fractures, Alfadl A Abdulfattah, Hanan A Jawkhab, Altaf A Alhazmi, Nada A Alfaifi, Maryam A Sultan, Rajaa A Alnami, Nada Y Kenani, Shorooq A Hamzi, Shahd M Abu Sharha, Ibrahim M Dighriri

Faculty, Staff and Student Publications

Background: Helicobacter pylori (H. pylori) is a severe infection responsible for upper gastrointestinal symptoms (UGISs). Several causes of H. pylori infection include food ingestion and person-to-person transmission. Many lifestyle variables can affect the occurrence of UGISs such as coffee consumption and smoking.

Objective: To assess the association between smoking and coffee consumption and the occurrence of UGISs in patients with active H. pylori infection in Jazan city in Saudi Arabia.

Methodology: A descriptive cross-sectional research design was used to conduct the study between July 2022 and August 2022 in Jazan, southern Saudi Arabia. Male and female Saudis or …

Many People With Chronic Lymphocytic Leukemia Or Small Lymphocytic Lymphoma Benefit From Ibrutinib Treatment Up To 8 Years: A Plain Language Summary, Paul M Barr, Carolyn Owen, Tadeusz Robak, Alessandra Tedeschi, Osnat Bairey, Jan A Burger, Peter Hillmen, Claire Dearden, Sebastian Grosicki, Helen Mccarthy, Jian Yong Li, Fritz Offner, Carol Moreno, Mandy Jermain, Cathy Zhou, Emily Hsu, Anita Szoke, Thomas J Kipps, Paolo Ghia

Faculty, Staff and Student Publications

What is this summary about?: This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022.

What were the results?: Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated …

Multicenter International Study Of The Consensus Immunoscore For The Prediction Of Relapse And Survival In Early-Stage Colon Cancer, Bernhard Mlecnik, Alessandro Lugli, Gabriela Bindea, Florence Marliot, Carlo Bifulco, Jiun-Kae Jack Lee, Inti Zlobec, Tilman T Rau, Martin D Berger, Iris D Nagtegaal, Elisa Vink-Börger, Arndt Hartmann, Carol I Geppert, Julie Kolwelter, Susanne Merkel, Robert Grützmann, Marc Van Den Eynde, Anne Jouret-Mourin, Alex Kartheuser, Daniel Léonard, Christophe Remue, Julia Wang, Prashant Bavi, Michael H A Roehrl, Pamela S Ohashi, Linh T Nguyen, Seongjun Han, Heather L Macgregor, Sara Hafezi-Bakhtiari, Bradly G Wouters, Giuseppe V Masucci, Emilia K Andersson, Eva Zavadova, Michal Vocka, Jan Spacek, Lubos Petruzelka, Bohuslav Konopasek, Pavel Dundr, Helena Skalova, Kristyna Nemejcova, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Gennaro Ciliberto, Michele Maio, Luigi Laghi, Fabio Grizzi, Tessa Fredriksen, Bénédicte Buttard, Lucie Lafontaine, Pauline Maby, Amine Majdi, Assia Hijazi, Carine El Sissy, Amos Kirilovsky, Anne Berger, Christine Lagorce, Christopher Paustian, Carmen Ballesteros-Merino, Jeroen Dijkstra, Carlijn Van De Water, Shannon Van Lent-Van Vliet, Nikki Knijn, Ana-Maria Mușină, Dragos-Viorel Scripcariu, Boryana Popivanova, Mingli Xu, Tomonobu Fujita, Shoichi Hazama, Nobuaki Suzuki, Hiroaki Nagano, Kiyotaka Okuno, Toshihiko Torigoe, Noriyuki Sato, Tomohisa Furuhata, Ichiro Takemasa, Prabhu Patel, Hemangini H Vora, Birva Shah, Jayendrakumar B Patel, Kruti N Rajvik, Shashank J Pandya, Shilin N Shukla, Yili Wang, Guanjun Zhang, Yutaka Kawakami, Francesco M Marincola, Paolo A Ascierto, Bernard A Fox, Franck Pagès, Jérôme Galon

Faculty, Staff and Student Publications

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival …

Benchmarking Outcomes For Molecularly Characterized Synchronous Oligo Metastatic Non-Small-Cell Lung Cancer Reveals Egfr Mutations To Be Associated With Longer Overall Survival, Brian De, Ahsan S Farooqi, Kyle G Mitchell, Ethan B Ludmir, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J Jack Lee, Stephen G Swisher, Don L Gibbons, Jianjun Zhang, Xiuning Le, Yasir Y Elamin, Daniel R Gomez, Matthew S Ning, Steven H Lin, Zhongxing Liao, Joe Y Chang, Ara A Vaporciyan, John V Heymach, Mara B Antonoff, Saumil J Gandhi

Faculty, Staff and Student Publications

PURPOSE: Local consolidative therapy (LCT) for patients with synchronous oligometastatic non-small-cell lung cancer is an evolving treatment strategy, but outcomes following LCT stratified by genetic mutations have not been reported. We sought to identify genomic associations with overall survival (OS) and progression-free survival (PFS) for these patients.

METHODS: We identified all patients presenting between 2000 and 2017 with stage IV non-small-cell lung cancer and ≤ 3 synchronous metastatic sites. Patients were grouped according to mutational statuses. Primary outcomes included OS and PFS following initial diagnosis.

RESULTS: Of 194 included patients, 121 received comprehensive LCT to all sites of disease with …

Predicting The Risk Of A Clinical Event Using Longitudinal Data: The Generalized Landmark Analysis, Yi Yao, Liang Li, Brad Astor, Wei Yang, Tom Greene

Faculty, Staff and Student Publications

Background: In the development of prediction models for a clinical event, it is common to use the static prediction modeling (SPM), a regression model that relates baseline predictors to the time to event. In many situations, the data used in training and validation are from longitudinal studies, where predictor variables are time-varying and measured at clinical visits. But these data are not used in SPM. The landmark analysis (LA), previously proposed for dynamic prediction with longitudinal data, has interpretational difficulty when the baseline is not a risk-changing clinical milestone, as is often the case in observational studies of chronic disease …