Digital Commons Network^™

Immunity From Nk Cell Subsets Is Important For Vaccine-Mediated Protection In Hpv+ Cancers, Madison P O'Hara, Ananta V Yanamandra, K Jagannadha Sastry

Faculty, Staff and Student Publications

High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential. We reported earlier that in a syngeneic immunocompetent preclinical HPV tumor mouse model, intranasal immunization with an HPV peptide therapeutic vaccine containing the combination of aGalCer and CpG-ODN adjuvants (TVAC) promoted clearance of HPV vaginal tumors via induction …

Long Trimer-Immunization Interval And Appropriate Adjuvant Reduce Immune Responses To The Soluble Hiv-1-Envelope Trimer Base, Hongying Duan, Angela R Corrigan, Cheng Cheng, Andrea Biju, Christopher A Gonelli, Adam S Olia, I-Ting Teng, Kai Xu, Sijy O'Dell, Sandeep Narpala, Mike Castro, Leonid Serebryannyy, Jennifer Wang, Danealle K Parchment, Edward K Sarfo, Jelle Van Schooten, John-Paul Todd, Shuishu Wang, Darcy R Harris, Hui Geng, Alexander J Jafari, Vrc Production Program, Ruth A Woodward, Nicole A Doria-Rose, Kathryn E Foulds, Adrian B Mcdermott, Marit J Van Gils, Richard A Koup, Theodore C Pierson, Peter D Kwong, John R Mascola

Faculty, Staff and Student Publications

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth. Here, we demonstrate that long trimer-boosting intervals, but not long FP immunization intervals, reduce the anti-base response. Additionally, we identify that FP priming before trimer immunization enhances antibody avidity to the Env trimer. We also establish that adjuvants Matrix …

A Small Molecule With Big Impact: Mrtx1133 Targets The Krasg12d Mutation In Pancreatic Cancer, Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier

Faculty, Staff and Student Publications

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent …

Sting Licensing Of Type I Dendritic Cells Potentiates Antitumor Immunity, Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is …

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Inter-Individual Variations In Circadian Misalignment-Induced Nafld Pathophysiology In Mice, Nobuya Koike, Yasuhiro Umemura, Hitoshi Inokawa, Isao Tokuda, Yoshiki Tsuchiya, Yuh Sasawaki, Atsushi Umemura, Naoko Masuzawa, Kazuya Yabumoto, Takashi Seya, Akira Sugimoto, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita

Faculty, Staff and Student Publications

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of …

Cyp2a6 Activity And Cigarette Consumption Interact In Smoking-Related Lung Cancer Susceptibility, Mulong Du, Junyi Xin, Rui Zheng, Qianyu Yuan, Zhihui Wang, Hongliang Liu, Hanting Liu, Guoshuai Cai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gad Rennert, Susanne Arnold, Paul Brennan, John K Field, Sanjay S Shete, Loïc Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Matthew B Schabath, Melinda C Aldrich, Meilin Wang, Hongbing Shen, Feng Chen, Zhengdong Zhang, Rayjean J Hung, Christopher I Amos, Qingyi Wei, Philip Lazarus, David C Christiani

Faculty, Staff and Student Publications

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns …

A Mutation In F-Actin Polymerization Factor Suppresses The Distal Arthrogryposis Type 5 Piezo2 Pathogenic Variant In Caenorhabditis Elegans, Xiaofei Bai, Harold E Smith, Luis O Romero, Briar Bell, Valeria Vásquez, Andy Golden

Faculty, Staff and Student Publications

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a …

Frequency Specific Optogenetic Stimulation Of The Locus Coeruleus Induces Task-Relevant Plasticity In The Motor Cortex, Ching-Tzu Tseng, Hailey F Welch, Ashley L Gi, Erica Mina Kang, Tanushree Mamidi, Sahiti Pydimarri, Kritika Ramesh, Alfredo Sandoval, Jonathan E Ploski, Catherine A Thorn

Faculty, Staff and Student Publications

The locus ceruleus (LC) is the primary source of neocortical noradrenaline, which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in the sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production. In this study, we test whether optogenetic stimulation of the LC paired with motor performance is sufficient to induce task-relevant plasticity in the somatotopic cortical …

Multifaceted Roles For Stat3 In Gammaherpesvirus Latency Revealed Through In Vivo B Cell Knockout Models, Chad H Hogan, Shana M Owens, Glennys V Reynoso, Yifei Liao, Thomas J Meyer, Monika A Zelazowska, Bin Liu, Xiaofan Li, Anna K Grosskopf, Camille Khairallah, Varvara Kirillov, Nancy C Reich, Brian S Sheridan, Kevin M Mcbride, Benjamin E Gewurz, Heather D Hickman, J Craig Forrest, Laurie T Krug

Faculty, Staff and Student Publications

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). To better understand the role of STAT3 during gammaherpesvirus latency and the B cell response to infection, we used the model pathogen murine gammaherpesvirus 68 (MHV68). Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/f mice reduced peak MHV68 latency approximately sevenfold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to wild-type (WT) littermates. To circumvent the systemic immune alterations observed in …

Sugar-Binding And Split Domain Combinations In Repeats-In-Toxin Adhesins From Vibrio Cholerae And Aeromonas Veronii Mediate Cell-Surface Recognition And Hemolytic Activities, Mustafa Sherik, Robert Eves, Shuaiqi Guo, Cameron J Lloyd, Karl E Klose, Peter L Davies

Faculty, Staff and Student Publications

Many pathogenic Gram-negative bacteria use repeats-in-toxin adhesins for colonization and biofilm formation. In the cholera agent Vibrio cholerae, flagellar-regulated hemagglutinin A (FrhA) enables these functions. Using bioinformatic analysis, a sugar-binding domain was identified in FrhA adjacent to a domain of unknown function. AlphaFold2 indicated the boundaries of both domains to be slightly shorter than previously predicted and assisted in the recognition of the unknown domain as a split immunoglobulin-like fold that can assist in projecting the sugar-binding domain toward its target. The AlphaFold2-predicted structure is in excellent agreement with the molecular envelope obtained from small-angle X-ray scattering analysis of …

The Il6/Jak/Stat3 Signaling Axis Is A Therapeutic Vulnerability In Smarcb1-Deficient Bladder Cancer, Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Yang Yuntao, Yuen San Chan, Danthasinghe Waduge Badrajee Piyarathna, Lacey Elizabeth Dobrolecki, David J H Shih, Zhongcheng Shi, Jun Xu, Shixia Huang, Matthew J Ellis, Andrea B Apolo, Leomar Y Ballester, Jianjun Gao, Donna E Hansel, Yair Lotan, H Courtney Hodges, Seth P Lerner, Chad J Creighton, Arun Sreekumar, W Jim Zheng, Pavlos Msaouel, Shyam M Kavuri, Nagireddy Putluri

Faculty, Staff and Student Publications

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces …

Protecting Human And Animal Health: The Road From Animal Models To New Approach Methods, Barbara L F Kaplan, Alan M Hoberman, William Slikker, Mary Alice Smith, Emanuela Corsini, Thomas B Knudsen, M Sue Marty, Sonya K Sobrian, Suzanne C Fitzpatrick, Marcia H Ratner, Donna L Mendrick

Faculty, Staff and Student Publications

Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used …

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Thsd1 Suppresses Autophagy-Mediated Focal Adhesion Turnover By Modulating The Fak-Beclin 1 Pathway, Zhen Xu, Jiayi Lu, Song Gao, Yan-Ning Rui

Faculty, Staff and Student Publications

Focal adhesions (FAs) play a crucial role in cell spreading and adhesion, and their autophagic degradation is an emerging area of interest. This study investigates the role of Thrombospondin Type 1 Domain-Containing Protein 1 (THSD1) in regulating autophagy and FA stability in brain endothelial cells, shedding light on its potential implications for cerebrovascular diseases. Our research reveals a physical interaction between THSD1 and FAs. Depletion of THSD1 significantly reduces FA numbers, impairing cell spreading and adhesion. The loss of THSD1 also induces autophagy independently of changes in mTOR and AMPK activation, implying that THSD1 primarily governs FA dynamics rather than …

Functional Epas1/ Hif2a Missense Variant Is Associated With Hematocrit In Andean Highlanders, Elijah S Lawrence, Wanjun Gu, Ryan J Bohlender, Cecilia Anza-Ramirez, Amy M Cole, James J Yu, Hao Hu, Erica C Heinrich, Katie A O'Brien, Carlos A Vasquez, Quinn T Cowan, Patrick T Bruck, Kysha Mercader, Mona Alotaibi, Tao Long, James E Hall, Esteban A Moya, Marco A Bauk, Jennifer J Reeves, Mitchell C Kong, Rany M Salem, Gustavo Vizcardo-Galindo, Jose-Luis Macarlupu, Rómulo Figueroa-Mujíca, Daniela Bermudez, Noemi Corante, Eduardo Gaio, Keolu P Fox, Veikko Salomaa, Aki S Havulinna, Andrew J Murray, Atul Malhotra, Frank L Powel, Mohit Jain, Alexis C Komor, Gianpiero L Cavalleri, Chad D Huff, Francisco C Villafuerte, Tatum S Simonson

Faculty, Staff and Student Publications

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations …

Risk Factors For Non-Healing Wounds—A Single-Centre Study, Daniel Wolny, Ladislav Štěpánek, Dagmar Horáková, Janet Thomas, Jana Zapletalová, Mihir Sanjay Patel

Faculty, Staff and Student Publications

Background: Chronic wounds present a significant clinical, social, and economic challenge. This study aimed to objectify the risk factors of healing outcomes and the duration of chronic wounds from various etiologies. Methods: Patients treated for non-healing wounds at the surgical outpatient clinic of the Olomouc Military Hospital were involved. Data from patients treated between 8/2021 and 9/2023 were selected. Patients were mostly treated as outpatients, with microbiological follow-up indicated in cases of advanced signs of inflammation. Results: There were 149 patients who met our selection criteria (the mean age was 64.4 years). Predominant causes of wounds involved diabetes (30.9%), post-trauma …

Prex1 Improves Homeostatic Proliferation To Maintain A Naive Cd4+ T Cell Compartment In Older Age, Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M Weyand, Jӧrg J Goronzy

Faculty, Staff and Student Publications

The human adult immune system maintains normal T cell counts and compensates for T cell loss throughout life, mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naive CD4+ T cell compartment into older age. Here, we describe that naive CD4+ T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 in older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic …

Impact Of An Integrated Health, Nutrition, And Early Child Stimulation And Responsive Care Intervention Package Delivered To Preterm Or Term Small For Gestational Age Babies During Infancy On Growth And Neurodevelopment: Study Protocol Of An Individually Randomized Controlled Trial In India (Small Babies Trial), Ranadip Chowdhury, Rukman Manapurath, Ingvild Fossgard Sandøy, Ravi Prakash Upadhyay, Neeta Dhabhai, Saijuddin Shaikh, Harish Chellani, Tarun Shankar Choudhary, Abhinav Jain, Jose Martines, Nita Bhandari, Tor A Strand, Sunita Taneja

Faculty, Staff and Student Publications

BACKGROUND: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating.

METHODS: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata …

Targeting Dna2 Overcomes Metabolic Reprogramming In Multiple Myeloma, Natthakan Thongon, Feiyang Ma, Natalia Baran, Pamela Lockyer, Jintan Liu, Christopher Jackson, Ashley Rose, Ken Furudate, Bethany Wildeman, Matteo Marchesini, Valentina Marchica, Paola Storti, Giannalisa Todaro, Irene Ganan-Gomez, Vera Adema, Juan Jose Rodriguez-Sevilla, Yun Qing, Min Jin Ha, Rodrigo Fonseca, Caleb Stein, Caleb Class, Lin Tan, Sergio Attanasio, Guillermo Garcia-Manero, Nicola Giuliani, David Berrios Nolasco, Andrea Santoni, Claudio Cerchione, Carlos Bueso-Ramos, Marina Konopleva, Philip Lorenzi, Koichi Takahashi, Elisabet Manasanch, Gabriella Sammarelli, Rashmi Kanagal-Shamanna, Andrea Viale, Marta Chesi, Simona Colla

Faculty, Staff and Student Publications

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein …

Discovery And Clinical Proof-Of-Concept Of Rly-2608, A First-In-Class Mutant-Selective Allosteric Pi3kα Inhibitor That Decouples Antitumor Activity From Hyperinsulinemia, Andreas Varkaris, Ermira Pazolli, Hakan Gunaydin, Qi Wang, Levi Pierce, Alessandro A Boezio, Artemisa Bulku, Lucian Dipietro, Cary Fridrich, Adam Frost, Fabrizio Giordanetto, Erika P Hamilton, Katherine Harris, Michael Holliday, Tamieka L Hunter, Amanda Iskandar, Yongli Ji, Alexandre Larivée, Jonathan R Larochelle, André Lescarbeau, Fabien Llambi, Brenda Lormil, Mary M Mader, Brenton G Mar, Iain Martin, Thomas H Mclean, Klaus Michelsen, Yakov Pechersky, Erika Puente-Poushnejad, Kevin Raynor, Dipali Rogala, Ramin Samadani, Alison M Schram, Kelley Shortsleeves, Sweta Swaminathan, Shahein Tajmir, Gege Tan, Yong Tang, Roberto Valverde, Bryan Wehrenberg, Jeremy Wilbur, Bret R Williams, Hongtao Zeng, Hanmo Zhang, W Patrick Walters, Beni B Wolf, David E Shaw, Donald A Bergstrom, James Watters, James S Fraser, Pascal D Fortin, D Randal Kipp

Faculty, Staff and Student Publications

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor …

[Summary: International Consensus Statement On Nomenclature And Classification Of The Congenital Bicuspid Aortic Valve And Its Aortopathy, For Clinical, Surgical, Interventional And Research Purposes], Hector I Michelena, Alessandro Della Corte, Arturo Evangelista, Joseph J Maleszewski, William D Edwards, Mary J Roman, Richard B Devereux, Borja Fernández, Federico M Asch, Alex J Barker, Lilia M Sierra, Laurent De Kerchove, Susan M Fernandes, Paul W M Fedak, Evaldas Girdauskas, Victoria Delgado, Suhny Abbara, Emmanuel Lansac, Siddharth K Prakash, Malenka M Bissell, Bogdan A Popescu, Michael D Hope, Marta Sitges, Vinod H Thourani, Phillippe Pibarot, Krishnaswamy Chandrasekaran, Patrizio Lancellotti, Michael A Borger, John K Forrest, John Webb, Dianna M Milewicz, Raj Makkar, Martin B Leon, Stephen P Sanders, Michael Markl, Victor A Ferrari, William C Roberts, Jae-Kwan Song, Philipp Blanke, Charles S White, Samuel Siu, Lars G Svensson, Alan C Braverman, Joseph Bavaria, Thoralf M Sundt, Gebrine El Khoury, Ruggero De Paulis, Maurice Enriquez-Sarano, Jeroen J Bax, Catherine M Otto, Hans-Joachim Schäfers

Faculty, Staff and Student Publications

This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Examining Associations Between School-Level Determinants And The Implementation Of Physical Activity Opportunities, Derek W Craig, Timothy J Walker, Shreela V Sharma, Paula Cuccaro, Natalia I Heredia, Andjelka Pavlovic, Laura F Defina, Harold W Kohl, Maria E Fernandez

Faculty, Staff and Student Publications

School-based physical activity (PA) opportunities can help students engage in greater amounts of daily PA, meet PA guidelines, and lead to improved health and educational outcomes. However, we do not completely understand the organizational challenges to implementing these opportunities successfully. This exploratory study examined associations between school-level determinants and the implementation of school-based PA opportunities. We analyzed cross-sectional survey data from schools (n = 46) participating in the Healthy Zone School Program (HZSP) (Dallas, Texas, USA) during 2019-2020. Respondents completed an electronic survey that included measures of school-level determinants (e.g. culture, leadership, priority) and the implementation of school-based PA opportunities. …

Aspscr1-Tfe3 Reprograms Transcription By Organizing Enhancer Loops Around Hexameric Vcp/P97, Amir Pozner, Li Li, Shiv Prakash Verma, Shuxin Wang, Jared J Barrott, Mary L Nelson, Jamie S E Yu, Gian Luca Negri, Shane Colborne, Christopher S Hughes, Ju-Fen Zhu, Sydney L Lambert, Lara S Carroll, Kyllie Smith-Fry, Michael G Stewart, Sarmishta Kannan, Bodrie Jensen, Cini M John, Saif Sikdar, Hongrui Liu, Ngoc Ha Dang, Jennifer Bourdage, Jinxiu Li, Jeffery M Vahrenkamp, Katelyn L Mortenson, John S Groundland, Rosanna Wustrack, Donna L Senger, Franz J Zemp, Douglas J Mahoney, Jason Gertz, Xiaoyang Zhang, Alexander J Lazar, Martin Hirst, Gregg B Morin, Torsten O Nielsen, Peter S Shen, Kevin B Jones

Faculty, Staff and Student Publications

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its …

Shewanella Phage Encoding A Putative Anti-Crispr-Like Gene Represents A Novel Potential Viral Family, Hongmin Wang, Kaiyang Zheng, Min Wang, Keran Ma, Linyi Ren, Ruizhe Guo, Lina Ma, Hong Zhang, Yundan Liu, Yao Xiong, Miaolan Wu, Hongbing Shao, Yeong Yik Sung, Wen Jye Mok, Li Lian Wong, Andrew Mcminn, Yantao Liang

Faculty, Staff and Student Publications

Shewanella is a prevalent bacterial genus in deep-sea environments including marine sediments, exhibiting diverse metabolic capabilities that indicate its significant contributions to the marine biogeochemical cycles. However, only a few Shewanella phages were isolated and deposited in the NCBI database. In this study, we report the isolation and characterization of a novel Shewanella phage, vB_SbaS_Y11, that infects Shewanella KR11 and was isolated from the sewage in Qingdao, China. Transmission electron microscopy revealed that vB_SbaS_Y11 has an icosahedral head and a long tail. The genome of vB_SbaS_Y11 is a linear, double-stranded DNA with a length of 62,799 bp and a G+C …

Fluvoxamine Inhibits Th1 And Th17 Polarization And Function By Repressing Glycolysis To Attenuate Autoimmune Progression In Type 1 Diabetes, Yuan Zou, Jing Zhang, Fei Sun, Qianqian Xu, Longmin Chen, Xi Luo, Ting Wang, Qing Zhou, Shu Zhang, Fei Xiong, Wen Kong, Ping Yang, Qilin Yu, Shiwei Liu, Cong-Yi Wang

Faculty, Staff and Student Publications

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed.

METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune …

Efficacy Of Novel Agents Against Cellular Models Of Familial Platelet Disorder With Myeloid Malignancy (Fpd-Mm), Christopher P Mill, Warren C Fiskus, Courtney D Dinardo, Patrick Reville, John A Davis, Christine E Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and …

Aneuploid Embryonic Stem Cells Drive Teratoma Metastasis, Rong Xiao, Deshu Xu, Meili Zhang, Zhanghua Chen, Li Cheng, Songjie Du, Mingfei Lu, Tonghai Zhou, Ruoyan Li, Fan Bai, Yue Huang

Faculty, Staff and Student Publications

Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities …

The Novel Phosphatase Nudt5 Is A Critical Regulator Of Triple-Negative Breast Cancer Growth, Jing Qian, Yanxia Ma, William M Tahaney, Cassandra L Moyer, Amanda Lanier, Jamal Hill, Darian Coleman, Negar Koupaei, Susan G Hilsenbeck, Michelle I Savage, Brent D G Page, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target …