Medicine and Health Sciences Commons^™

Braf D594a Mutation Defines A Unique Biological And Immuno-Modulatory Subgroup Associated With Functional Cd8+ T Cell Infiltration In Colorectal Cancer, Wenjing Li, Chenyi Zhao, Wenhui Li, Yang Gong, Kaili Ma, Yujie Lu, Xiaowei Liu, Lianjun Zhang, Feng Guo

Faculty, Staff and Student Publications

BACKGROUND: BRAF non-V600 mutation occupies a relatively small but critical subset in colorectal cancer (CRC). However, little is known about the biological functions and impacts of BRAF class III mutation in CRC. Here, we aim to explore how D594A mutation impacts on biological behaviors and immune related signatures in murine CRC cells.

METHODS: BRAF V600E (class I), G469V (class II) and D594A (class III) mutant cell lines were established based on MC38 cells. The biological behaviors of cells were evaluated in respect of cell growth, cell proliferation, cell apoptosis, cell migration and invasion by the methods of colony-forming assay, CCK-8 …

Long-Term Evaluation Of Clinical Success And Safety Of Omadacycline In Nontuberculous Mycobacteria Infections: A Retrospective, Multicenter Cohort Of Real-World Health Outcomes, Amer El Ghali, Taylor Morrisette, Sara Alosaimy, Kristen Lucas, Maria G Tupayachi-Ortiz, Raaga Vemula, Carly Wadle, Julie V Philley, Carlos Mejia-Chew, Yasir Hamad, Ryan W Stevens, John D Zeuli, Andrew J Webb, Christina T Fiske, Anahit Simonyan, Christo L Cimino, Mehriban Mammadova, Virginia E Umana, Rodrigo Hasbun, Saira Butt, Kyle C Molina, Michael Thomas, Emily A Kaip, Jeannette Bouchard, Tristan W Gore, Catessa Howard, M Gabriela Cabanilla, Dana J Holger, Jeremy J Frens, Melissa Barger, Aaron Ong, Keira A Cohen, Michael J Rybak

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Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, …

Helping Frontline Workers In Texas-A Framework For Resource Development, Karima Lalani, Meredith O'Neal, Simone Lee Joannou, Bhanumathi Gopal, Tiffany Champagne-Langabeer

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First responders disproportionately experience occupational stress when compared to the general population, and COVID-19 has exacerbated this stress. The nature of their duties as law enforcement officers, firefighters, and medics exposes them to repeated trauma, increasing their risk of developing a broad array of mental health issues, including post-traumatic stress disorder (PTSD), substance use disorder (SUD), and compassion fatigue. This paper describes the need for resources for frontline workers and provides a framework for creating and implementing resources. A team of interdisciplinary subject matter experts developed two major resources. The first resource was a 24/7 helpline to support first responders …

Helping Frontline Workers In Texas-A Framework For Resource Development, Karima Lalani, Meredith O'Neal, Simone Lee Joannou, Bhanumathi Gopal, Tiffany Champagne-Langabeer

Faculty, Staff and Student Publications

First responders disproportionately experience occupational stress when compared to the general population, and COVID-19 has exacerbated this stress. The nature of their duties as law enforcement officers, firefighters, and medics exposes them to repeated trauma, increasing their risk of developing a broad array of mental health issues, including post-traumatic stress disorder (PTSD), substance use disorder (SUD), and compassion fatigue. This paper describes the need for resources for frontline workers and provides a framework for creating and implementing resources. A team of interdisciplinary subject matter experts developed two major resources. The first resource was a 24/7 helpline to support first responders …

Endogenous Renal Adiponectin Drives Gluconeogenesis Through Enhancing Pyruvate And Fatty Acid Utilization, Toshiharu Onodera, May-Yun Wang, Joseph M Rutkowski, Stanislaw Deja, Shiuhwei Chen, Michael S Balzer, Dae-Seok Kim, Xuenan Sun, Yu A An, Bianca C Field, Charlotte Lee, Ei-Ichi Matsuo, Monika Mizerska, Ina Sanjana, Naoto Fujiwara, Christine M Kusminski, Ruth Gordillo, Laurent Gautron, Denise K Marciano, Ming Chang Hu, Shawn C Burgess, Katalin Susztak, Orson W Moe, Philipp E Scherer

Faculty, Staff and Student Publications

Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction …

Adapting An Evidence-Based Mindfulness-Based Intervention For Sheltered Youth Experiencing Homelessness, Diane Santa Maria, Paula Cuccaro, Kimberly Bender, Erica Sibinga, Natalie Guerrero, Najiba Keshwani, Jennifer Jones, Micki Fine

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Objectives: Youth experiencing homelessness (YEH) face challenges that impact their physical, mental, and social wellbeing, emotion regulation, and coping. Mindfulness reduces stress and improves resilience, emotion regulation, and executive functioning. Mindfulness-based interventions (MBI) teach the practice of mindfulness to foster present-moment attention without judgement and enhance self-observation and self-regulation, resulting in greater awareness of thoughts and emotions and improved interpersonal relationships. One such intervention, .b, has been shown to lower stress among youth. While a pilot study of .b among sheltered youth found the intervention to be feasible, the need for modifications was identified to improve its relevance, accessibility, and …

Editorial: Implementation Mapping For Selecting, Adapting And Developing Implementation Strategies, Maria E Fernandez, Byron J Powell, Gill A Ten Hoor

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No abstract provided.

Impairment Of Serine Transport Across The Blood-Brain Barrier By Deletion Of Slc38a5 Causes Developmental Delay And Motor Dysfunction, Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker

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Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. …

Oncolytic Virus M1 Functions As A Bifunctional Checkpoint Inhibitor To Enhance The Antitumor Activity Of Dc Vaccine, Jia Dan, Jing Cai, Yingqian Zhong, Chaoqun Wang, Shanyu Huang, Ying Zeng, Zhen Fan, Cuiying Xu, Linyi Hu, Jiayu Zhang, Jun Hu, Ying Liu, Xingwen Su, Wenbo Zhu, Guangmei Yan, Jiankai Liang, Yuan Lin

Faculty, Staff and Student Publications

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can …

Author Correction: Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

No abstract provided.

Neuroprotective Activity Of Enantiomers Of Salsolinol And N-Methyl-(R)-Salsolinol: In Vitro And In Silico Studies, Magdalena Kurnik-Łucka, Gniewomir Latacz, Adam Bucki, Mario Rivera-Meza, Nadia Khan, Jahnobi Konwar, Kamil Skowron, Marcin Kołaczkowski, Krzysztof Gil

Faculty, Staff and Student Publications

Salsolinol (1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol) is a close structural analogue of dopamine with an asymmetric center at the C1 position, and its presence in vivo, both in humans and rodents, has already been proven. Yet, given the fact that salsolinol colocalizes with dopamine-rich regions and was first detected in the urine of Parkinson's disease patients, its direct role in the process of neurodegeneration has been proposed. Here, we report that

Association Between Whole Blood-Derived Mitochondrial Dna Copy Number, Low-Density Lipoprotein Cholesterol, And Cardiovascular Disease Risk, Xue Liu, Xianbang Sun, Yuankai Zhang, Wenqing Jiang, Meng Lai, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Wei Zhao, Achilleas Pitsillides, Jeffrey Haessler, Yinan Zheng, Thomas W Blackwell, Jie Yao, Xiuqing Guo, Yong Qian, Bharat Thyagarajan, Nathan Pankratz, Stephen S Rich, Kent D Taylor, Patricia A Peyser, Susan R Heckbert, Sudha Seshadri, Eric Boerwinkle, Megan L Grove, Nicholas B Larson, Jennifer A Smith, Ramachandran S Vasan, Annette L Fitzpatrick, Myriam Fornage, Jun Ding, April P Carson, Goncalo Abecasis, Josée Dupuis, Alexander Reiner, Charles Kooperberg, Lifang Hou, Bruce M Psaty, James G Wilson, Daniel Levy, Jerome I Rotter, Joshua C Bis, Claudia L Satizabal, Dan E Arking, Chunyu Liu

Faculty, Staff and Student Publications

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia).

Isospectral Intermediates In The Photochemical Reaction Cycle Of Anion Channelrhodopsin Gtacr1, Pamela Schleissner, Istvan Szundi, Eefei Chen, Hai Li, John L Spudich, David S Kliger

Faculty, Staff and Student Publications

The most effective tested optogenetic tools available for neuronal silencing are the light-gated anion channel proteins found in the cryptophyte alga Guillardia theta (GtACRs). Molecular mechanisms of GtACRs, including the photointermediates responsible for the open channel state, are of great interest for understanding their exceptional conductance. In this study, the photoreactions of GtACR1 and its D234N, A75E, and S97E mutants were investigated using multichannel time-resolved absorption spectroscopy. For each of the proteins, the analysis showed two early microsecond transitions between K-like and L-like forms and two late millisecond recovery steps. Spectral forms associated with potential molecular intermediates of the proteins …

Emotional Barriers And Facilitators Of Deprescribing For Older Adults With Cancer And Polypharmacy: A Qualitative Study, Erika Ramsdale, Arul Malhotra, Holly M Holmes, Lisa Zubkoff, Jinjiao Wang, Supriya Mohile, Sally A Norton, Paul R Duberstein

Faculty, Staff and Student Publications

Purpose: To describe emotional barriers and facilitators to deprescribing (the planned reduction or discontinuation of medications) in older adults with cancer and polypharmacy.

Methods: Virtual focus groups were conducted over Zoom with 5 key informant groups: oncologists, oncology nurses, primary care physicians, pharmacists, and patients. All groups were video- and audio-recorded and transcribed verbatim. Focus group transcripts were analyzed using inductive content analysis, and open coding was performed by two coders. A codebook was generated based on the initial round of open coding and updated throughout the analytic process. Codes and themes were discussed for each transcript until consensus was …

Priorities And Progress In Gram-Positive Bacterial Infection Research By The Antibacterial Resistance Leadership Group: A Narrative Review, Sarah B Doernberg, Cesar A Arias, Deena R Altman, Ahmed Babiker, Helen W Boucher, C Buddy Creech, Sara E Cosgrove, Scott R Evans, Vance G Fowler, Stephanie A Fritz, Toshimitsu Hamasaki, Brendan J Kelly, Sixto M Leal, Catherine Liu, Thomas P Lodise, Loren G Miller, Jose M Munita, Barbara E Murray, Melinda M Pettigrew, Felicia Ruffin, Marc H Scheetz, Bo Shopsin, Truc T Tran, Nicholas A Turner, Derek J Williams, Smitha Zaharoff, Thomas L Holland

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The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, …

Sptan1/Numb Axis Senses Cell Density To Restrain Cell Growth And Oncogenesis Through Hippo Signaling, Dongxue Su, Yuxi Li, Weiji Zhang, Huan Gao, Yao Cheng, Yongqiang Hou, Junhong Li, Yi Ye, Zhangjian Lai, Zhe Li, Haitao Huang, Jiaxin Li, Jinhuan Li, Mengyu Cheng, Cheng Nian, Na Wu, Zhien Zhou, Yunzhi Xing, Yu Zhao, He Liu, Jiayu Tang, Qinghua Chen, Lixin Hong, Wengang Li, Zhihai Peng, Bin Zhao, Randy L Johnson, Pingguo Liu, Wanjin Hong, Lanfen Chen, Dawang Zhou

Faculty, Staff and Student Publications

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and …

Genome-Wide Analysis Of The Interplay Between Chromatin-Associated Rna And 3d Genome Organization In Human Cells, Riccardo Calandrelli, Xingzhao Wen, John Lalith Charles Richard, Zhifei Luo, Tri C Nguyen, Chien-Ju Chen, Zhijie Qi, Shuanghong Xue, Weizhong Chen, Zhangming Yan, Weixin Wu, Kathia Zaleta-Rivera, Rong Hu, Miao Yu, Yuchuan Wang, Wenbo Li, Jian Ma, Bing Ren, Sheng Zhong

Faculty, Staff and Student Publications

The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA …

Investigating Associations Of Omega-3 Fatty Acids, Lung Function Decline, And Airway Obstruction, Bonnie K Patchen, Pallavi Balte, Traci M Bartz, R Graham Barr, Myriam Fornage, Mariaelisa Graff, David R Jacobs, Ravi Kalhan, Rozenn N Lemaitre, George O'Connor, Bruce Psaty, Jungkyun Seo, Michael Y Tsai, Alexis C Wood, Hanfei Xu, Jingwen Zhang, Sina A Gharib, Ani Manichaikul, Kari North, Lyn M Steffen, Josée Dupuis, Elizabeth Oelsner, Dana B Hancock, Patricia A Cassano

Faculty, Staff and Student Publications

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health.

Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts.

Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters.

Measurements and Main Results: The …

Possible Delayed Foreign Body Reactions Against Titanium Clips And Coating Materials After Unruptured Cerebral Aneurysm Surgery, Ryota Tatezawa, Taku Sugiyama, Shuho Gotoh, Takafumi Shindo, Hiroshi Ikeda, Masaaki Hokari, Katsumi Takizawa, Naoki Nakayama, Miki Fujimura

Faculty, Staff and Student Publications

Delayed foreign body reactions to either or both clipping and coating materials have been reported in several small series; however, studies in the titanium clip era are scarce. This study aims to survey the contemporary status of such reactions to titanium clips and coating materials. Among patients who received a total of 2327 unruptured cerebral aneurysmal surgeries, 12 developed delayed intraparenchymal reactions during outpatient magnetic resonance imaging (MRI) follow-up. A retrospective investigation was conducted. The patients' average age was 58.6 (45-73) years, and 11 were women. The aneurysms were located in the middle cerebral artery (n = 7), internal carotid …

Stroke Recovery Is A Journey: Prediction And Potentials Of Motor Recovery After A Stroke From A Practical Perspective, Sheng Li

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Stroke recovery is a journey. Stroke survivors can face many consequences that may last the rest of their lives. Assessment of initial impairments allows reasonable prediction of biological spontaneous recovery at 3 to 6 months for a majority of survivors. In real-world clinical practice, stroke survivors continue to improve their motor function beyond the spontaneous recovery period, but management plans for maximal recovery are not well understood. A model within the international classification of functioning (ICF) theoretical framework is proposed to systematically identify opportunities and potential barriers to maximize and realize the potentials of functional recovery from the acute to …

Us Adolescent Rest-Activity Patterns: Insights From Functional Principal Component Analysis (Nhanes 2011-2014), Chris Ho Ching Yeung, Jiachen Lu, Erica G Soltero, Cici Bauer, Qian Xiao

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BACKGROUND: Suboptimal rest-activity patterns in adolescence are associated with worse health outcomes in adulthood. Understanding sociodemographic factors associated with rest-activity rhythms may help identify subgroups who may benefit from interventions. This study aimed to investigate the association of rest-activity rhythm with demographic and socioeconomic characteristics in adolescents.

METHODS: Using cross-sectional data from the nationally representative National Health and Nutrition Examination Survey (NHANES) 2011-2014 adolescents (N = 1814), this study derived rest-activity profiles from 7-day 24-hour accelerometer data using functional principal component analysis. Multiple linear regression was used to assess the association between participant characteristics and rest-activity profiles. Weekday and weekend …

Tuberculosis Presentation And Outcomes In Older Hispanic Adults From Tamaulipas, Mexico, Belinda A Medrano, Miryoung Lee, Gretchen Gemeinhardt, Javier E Rodríguez-Herrera, Moncerrato García-Viveros, Blanca I Restrepo

Faculty, Staff and Student Publications

Older people are at high risk of developing and dying from pulmonary infections like tuberculosis (TB), but there are few studies among them, particularly in Hispanics. To address these gaps, we sought to identify host factors associated with TB and adverse treatment outcomes in older Hispanics by conducting a cross-sectional study of TB surveillance data from Tamaulipas, Mexico (2006-2013; n = 8381). Multivariable logistic regressions were assessed for older adults (OA ≥65 years) when compared to young (YA, 18-39 years) and middle-aged adults (40-64 years). We found that the OA had features associated with a less complicated TB (e.g., lower …

Effect Of Abutment Tooth Location On The Accuracy Of Digital Impressions Obtained Using An Intraoral Scanner For Removable Partial Dentures, Kazuki Sakamoto, Junichiro Wada, Yuki Arai, Hironari Hayama, Yurika Ishioka, Eung-Yeol Kim, Ryunosuke Kazama, Yusuke Toyoshima, Noriyuki Wakabayashi

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Purpose: To verify the effect of abutment tooth location on the accuracy of digital impressions obtained using an intraoral scanner (IOS) for removable partial dentures (RPDs).

Methods: The target abutment teeth included the left first premolar (#34), second molar (#37), and right second premolar (#45) in a mandibular Kennedy class II model and the left and right second molars (#37, #47) in a class III model. Only #37 was isolated from the remaining teeth by the mucosal area in both models. Digital impressions were obtained using a desktop scanner (reference data) and an IOS (IOS data; scanning origin #37; n=10). …

Guide-Specific Loss Of Efficiency And Off-Target Reduction With Cas9 Variants, Liang Zhang, Wei He, Rongjie Fu, Shuyue Wang, Yiwen Chen, Han Xu

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High-fidelity clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) variants have been developed to reduce the off-target effects of CRISPR systems at a cost of efficiency loss. To systematically evaluate the efficiency and off-target tolerance of Cas9 variants in complex with different single guide RNAs (sgRNAs), we applied high-throughput viability screens and a synthetic paired sgRNA-target system to assess thousands of sgRNAs in combination with two high-fidelity Cas9 variants HiFi and LZ3. Comparing these variants against wild-type SpCas9, we found that ∼20% of sgRNAs are associated with a significant loss of efficiency when complexed with either HiFi or LZ3. …

Novobiocin Blocks Nucleic Acid Binding To Polθ And Inhibits Stimulation Of Its Atpase Activity, Aleem Syed, Frantisek Filandr, Jeffrey Patterson-Fortin, Albino Bacolla, Ramya Ravindranathan, Jia Zhou, Drew T Mcdonald, Mohammed E Albuhluli, Amy Verway-Cohen, Joseph A Newman, Miaw-Sheue Tsai, Darin E Jones, David C Schriemer, Alan D D'Andrea, John A Tainer

Faculty, Staff and Student Publications

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB …

Reap-2: An Interactive Quantitative Tool For Robust And Efficient Dose-Response Curve Estimation, Xinying Fang, Xinyi Liu, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee, Shouhao Zhou

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REAP-2 is an interactive dose-response curve estimation tool for Robust and Efficient Assessment of drug Potency. It provides user-friendly dose-response curve estimation for in vitro studies and conducts statistical testing for model comparisons with a redesigned user interface. We also make a major update of the underlying estimation method with penalized beta regression, which demonstrates great reliability and accuracy in dose estimation and uncertainty quantification. In this note, we describe the method and implementation of REAP-2 with a highlight on potency estimation and drug comparison.

Bacterial And Fungal Characterization Of Pancreatic Adenocarcinoma From Endoscopic Ultrasound-Guided Biopsies, Robin D Wright, Thais F Bartelli, Seyda Baydogan, James Robert White, Michael P Kim, Manoop S Bhutani, Florencia Mcallister

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INTRODUCTION: The tumor microbiome (TM) has been linked to pancreatic cancer prognosis. Specific microbes can confer tumor resistance to therapies. Early knowledge of the TM at time of diagnosis would be clinically relevant for precision therapy based on microbial composition. However, it is difficult to define the TM prior to surgical resection.

METHODS: In this pilot feasibility study, patients underwent Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) biopsy of pancreatic adenocarcinoma. These samples were analyzed using 16S rRNA and internal transcribed spacer (ITS) sequencing for characterization of the tumor bacteria and fungi.

RESULT: After in silico decontamination and comparison to non-matched tumor, …

Efficacy And Safety Of Mas825 (Anti-Il-1Β/Il-18) In Covid-19 Patients With Pneumonia And Impaired Respiratory Function, Alex D Hakim, Mustafa Awili, Hollis R O'Neal, Omar Siddiqi, Naseem Jaffrani, Richard Lee, Jeffrey S Overcash, Ann Chauffe, Terese C Hammond, Bela Patel, Michael Waters, Gerard J Criner, Alok Pachori, Guido Junge, Rafael Levitch, Jen Watts, Philip Koo, Tirtha Sengupta, Lili Yu, Michael Kiffe, Anne Pinck, Richard R Stein, Jamie Bendrick-Peart, Janet Jenkins, Marianna Rowlands, Frank Waldron-Lynch, Jesse Matthews

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MAS825, a bispecific IL-1β/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 …

Immune-Depleted Tumor Microenvironment Is Associated With Poor Outcomes And Btk Inhibitor Resistance In Mantle Cell Lymphoma, Preetesh Jain, Krystle Nomie, Nikita Kotlov, Vitaiy Segodin, Holly Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal-Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R Flowers, Michael Wang

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Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [1]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [2]. A few reports have also demonstrated that a decrease in T cell numbers [3, 4] or a downregulation of effector/cytotoxic …

Next-Generation Crispr Gene-Drive Systems Using Cas12a Nuclease, Sara Sanz Juste, Emily M Okamoto, Christina Nguyen, Xuechun Feng, Víctor López Del Amo

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One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate desired genetic traits into a target population. However, all current gene drives employ a Cas9 nuclease that is constitutively active, impeding our control over their propagation abilities and limiting the generation of alternative gene drive arrangements. Yet, other nucleases such as the temperature sensitive Cas12a have not been explored for gene drive designs in insects. to address this, we herein present a proof-of-concept gene-drive system driven by Cas12a that can be regulated …