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Salivary Duct Carcinoma Arising In A Warthin Tumor Of The Parotid Gland: A Rare Case Report With Review Of Literature And Pd-L1 Expression, Kaitlyn J. Nielson, Gamaliel Lorenzo, Shweta Agarwal

Pathology Research and Scholarship

Warthin's tumor is the second most common neoplasm of the parotid gland and consists of 2 components, including lymphoid stroma and glandular epithelium. Malignant transformation in this tumor is mostly seen in the lymphoid component; however, the carcinomatous transformation of the epithelial component is extremely rare. Cases of latter reported in the literature include squamous cell carcinoma, adenocarcinoma, mucoepidermoid carcinoma, oncocytic carcinoma, Merkel cell carcinoma, and undifferentiated carcinoma. We describe an extremely rare case of salivary duct carcinoma arising in a Warthin tumor in a 64-year-old male. Patient presented with an enlarging left parotid mass, biopsy of which showed salivary …

Iron Promotes Glycolysis To Drive Colon Tumorigenesis., Zhaoli Liu, Luke Villareal, Lavanya Goodla, Hyeoncheol Kim, Daniel M. Falcon, Mohammad Haneef, David R. Martin, Li Zhang, Ho-Joon Lee, Daniel Kremer, Costas A. Lyssiotis, Yatrik M. Shah, Henry C. Lin, Hui-Kuan Lin, Xiang Xue

Pathology Research and Scholarship

Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment.

Hospital Adhering To The Ten Steps To Successful Breastfeeding Predicts Exclusive Breastfeeding In Latinx Mothers., Ana Linares, Diana Cartagena, Marialda Moreira Christoffel

Nursing Faculty Publications

Introduction: Assessing how well a hospital adheres to the Ten Steps to Successful Breastfeeding is the key to outlining necessary modifications in mother breastfeeding support. This study aimed to assess Latinx mothers’ perception of how well a hospital adheres to the Ten Steps to Successful Breastfeeding and its influence on exclusive breastfeeding (EBF) rates at hospital discharge.

Methods: Secondary analysis of two longitudinal studies. The combined sample (N = 74) of Latinx pregnant women residing in the US. We modified, translated, and evaluated reliability of the Questionnaire for the Breastfeeding Mother (QBFM), which was applied to evaluate mothers’ …

Characteristics And Outcomes Of Patients With Pregnancy-Related End-Stage Kidney Disease., Lauren Kucirka, Ana Angarita, Tracy Manuck, Kim Boggess, Vimal Derebail, Mollie Wood, Michelle Meyer, Dorry Segev, Monica Reynolds

Department of Obstetrics and Gynecology Faculty Papers

IMPORTANCE: The incidence of pregnancy-related acute kidney injury is increasing and is associated with significant maternal morbidity including progression to end-stage kidney disease (ESKD). Little is known about characteristics and long-term outcomes of patients who develop pregnancy-related ESKD.

OBJECTIVES: To examine the characteristics and clinical outcomes of patients with pregnancy-related ESKD and to investigate associations between pre-ESKD nephrology care and outcomes.

DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study of 183 640 reproductive-aged women with incident ESKD between January 1, 2000, and November 20, 2020, from the US Renal Data System and maternal data from births captured in the …

How Societal Forces Of Change Are Transforming Youth Physical Activity Promotion In North America, Jacob Szeszulski, Jamie M Faro, Rodney P Joseph, Kevin Lanza, Lucie Lévesque, Courtney M Monroe, Elsa A Pérez-Paredes, Erica G Soltero, Rebecca E Lee

Children’s Nutrition Research Center Staff Publications

Background: Climate change, increasing recognition of institutionalized discrimination, and the COVID-19 pandemic are large-scale, societal events (ie, forces of change) that affect the timing, settings, and modes of youth physical activity. Despite the impact that forces of change have on youth physical activity and physical activity environments, few studies consider how they affect physical activity promotion.

Methods: The authors use 2 established frameworks, the ecological model of physical activity and the youth physical activity timing, how, and setting framework, to highlight changes in physical activity patterns of youth in North America that have resulted from contemporary forces of change.

Results: …

Mortality And Morbidity Among Individuals With Hypertension Receiving A Diuretic, Ace Inhibitor, Or Calcium Channel Blocker: A Secondary Analysis Of A Randomized Clinical Trial, Jose-Miguel Yamal, Journey Martinez, Mikala C Osani, Xianglin L Du, Lara M Simpson, Barry R Davis

Faculty, Staff and Student Publications

IMPORTANCE: The long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood.

OBJECTIVE: to determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, calcium channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor with up to 23 years of follow-up.

DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a multicenter randomized, double-blind, active-controlled clinical trial, followed up with participants aged 55 years or older with a diagnosis of hypertension and at …

A Double-Robust Test For High-Dimensional Gene Coexpression Networks Conditioning On Clinical Information, Maomao Ding, Ruosha Li, Jin Qin, Jing Ning

Faculty, Staff and Student Publications

It has been increasingly appealing to evaluate whether expression levels of two genes in a gene coexpression network are still dependent given samples' clinical information, in which the conditional independence test plays an essential role. For enhanced robustness regarding model assumptions, we propose a class of double-robust tests for evaluating the dependence of bivariate outcomes after controlling for known clinical information. Although the proposed test relies on the marginal density functions of bivariate outcomes given clinical information, the test remains valid as long as one of the density functions is correctly specified. Because of the closed-form variance formula, the proposed …

Shaping Policy And Practice: Analyzing The Reach Of Highly Cited And High Altmetrics Publications For Broader Impact On Physical Activity, Andrea Ramírez Varela, Natalicio Serrano, Juliana Mejía Grueso, Anita Nguyen, Deborah Salvo, Ross C Brownson, Adrian Bauman, Rodrigo Reis, Pedro Hallal, Michael Pratt

Faculty, Staff and Student Publications

BACKGROUND: A significant gap remains between the availability of physical activity (PA) evidence-based interventions and their application in real-world settings in policy and practice areas. This study aims to describe highly cited and high altmetrics publications in PA research and explore their impact on PA policy and practice.

METHODS: Mixed-methods sequential explanatory study including the identification and description of the top highly cited and high altmetrics PA publications from the last 10 years (including study design, population, type of PA study, number of citations, and altmetrics score), and interviews with key informants regarding research dissemination and implications on PA policy …

Endothelial Adam10 Utilization Defines A Molecular Pathway Of Vascular Injury In Mice With Bacterial Sepsis, Danielle N. Alfano, Mark J. Miller, Juliane Bubeck-Wardenburg

2020-Current year OA Pubs

The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial ADAM10 was essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to α-toxin-mediated (Hla-mediated) microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in …

Ezh2 Cooperates With Brd4-Nut To Drive Nut Carcinoma Growth By Silencing Key Tumor Suppressor Genes, Yeying Huang, R Taylor Durall, Nhi M Luong, Hans J Hertzler, Julianna Huang, Prafulla C Gokhale, Brittaney A Leeper, Nicole S Persky, David E Root, Praju V Anekal, Paula D L M Montero Llopis, Clement N David, Jeffery L Kutok, Alejandra Raimondi, Karan Saluja, Jia Luo, Cynthia A Zahnow, Biniam Adane, Kimberly Stegmaier, Catherine E Hawkins, Christopher Ponne, Quan Le, Geoffrey I Shapiro, Madeleine E Lemieux, Kyle P Eagen, Christopher A French

Faculty, Staff and Student Publications

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NC that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy are limited. Here, we demonstrated that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple …

The Application Of Simultaneous Mainstem Bronchus Dilation With Pulmonary Artery Stenting In The Context Of Hypoplastic Left Heart Syndrome, Sylwia Hasterok, Thomas G Scott, Devin G Roller, Adam Spencer, Arun B Dutta, Kizhakke M Sathyan, Daniel E Frigo, Michael J Guertin, Daniel Gioeli

Faculty, Staff and Student Publications

The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes …

Resuscitative Endovascular Balloon Occlusion Of The Aorta And Resuscitative Thoracotomy Are Associated With Similar Outcomes In Traumatic Cardiac Arrest, Ezra Y Koh, Erin E Fox, Charles E Wade, Thomas M Scalea, Charles J Fox, Ernest E Moore, Bryan C Morse, Kenji Inaba, Eileen M Bulger, David E Meyer

Faculty, Staff and Student Publications

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive alternative to resuscitative thoracotomy (RT) for patients with hemorrhagic shock. However, the potential benefits of this approach remain subject of debate. The aim of this study was to compare the outcomes of REBOA and RT for traumatic cardiac arrest.

Methods: A planned secondary analysis of the United States Department of Defense-funded Emergent Truncal Hemorrhage Control study was performed. Between 2017 and 2018, a prospective observational study of noncompressible torso hemorrhage was conducted at six Level I trauma centers. Patients were dichotomized by REBOA or RT, and baseline …

Mediators And Moderators Of Active Music Engagement To Reduce Traumatic Stress Symptoms And Improve Well-Being In Parents Of Young Children With Cancer., Sheri L. Robb, Kristin Stegenga, Susan M. Perkins, Timothy E. Stump, Karen M. Moody, Amanda K. Henley, Jessica Maclean, Seethal A. Jacob, David Delgado, Paul R. Haut

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: This trial examined the effects of proximal/distal mediators and moderators of an Active Music Engagement (AME) intervention on young child/parent distress, quality of life, and family function outcomes.

METHODS: Child/parent dyads (n = 125) were randomized to AME or Audio-storybooks attention control condition. Each group received 3 sessions with a credentialed music therapist for 3 consecutive days with data collection at baseline, post-intervention (T2), and 30-days later (T3). Potential proximal mediators included within session child and parent engagement. Potential distal mediators included changes in perceived family normalcy, parent self-efficacy, and independent use of play materials. Potential moderators included parent/child …

Longitudinal Magnetic Resonance Imaging-Based Superficial Femoral Artery Velocity Measurements In Diabetic And Nondiabetic Patients With Peripheral Artery Disease, Ankita Sinharoy, Neeti Reddy, John Kent Lin, Vijay Nambi, Eric Y Yang, Panagiotis Kougias, Addison A Taylor, Alan B Lumsden, Christie M Ballantyne, Gerd Brunner

Faculty, Staff and Students Publications

Background: Longitudinal associations of noninvasive 2-dimensional phase-contrast magnetic resonance imaging (2D-PC-MRI) velocity markers of the superficial femoral artery (SFA) were analyzed along with the characteristics of peripheral artery disease (PAD). We hypothesized that the 2-year differences in MRI-based measures of SFA velocity were associated with longitudinal changes in markers of PAD.

Methods: A total of 33 (11 diabetic, 22 nondiabetic) patients with PAD with baseline and 2-year follow-up MRI scans were included in this secondary analysis of the Effect of Lipid Modification on Peripheral Artery Disease after Endovascular Intervention Trial (ELIMIT). Electrocardiographically gated 2D-PC-MRI was performed at a proximal and …

Type 2 Diabetes Modifies The Association Of Cad Genomic Risk Variants With Subclinical Atherosclerosis, Natalie R Hasbani, Kenneth E Westerman, Soo Heon Kwak, Han Chen, Xihao Li, Daniel Di Corpo, Jennifer Wessel, Joshua C Bis, Chloè Sarnowski, Peitao Wu, Lawrence F Bielak, Xiuqing Guo, Nancy Heard-Costa, Gregory L Kinney, Michael C Mahaney, May E Montasser, Nicholette D Palmer, Laura M Raffield, James G Terry, Lisa R Yanek, Jessica Bon, Donald W Bowden, Jennifer A Brody, Ravindranath Duggirala, David R Jacobs, Rita R Kalyani, Leslie A Lange, Braxton D Mitchell, Jennifer A Smith, Kent D Taylor, April P Carson, Joanne E Curran, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Richard A Gibbs, Namrata Gupta, Sharon L R Kardia, Brian G Kral, Zeineen Momin, Anne B Newman, Wendy S Post, Karine A Viaud-Martinez, Kendra A Young, Lewis C Becker, Alain G Bertoni, John Blangero, John J Carr, Katherine Pratte, Bruce M Psaty, Stephen S Rich, Joseph C Wu, Rajeev Malhotra, Patricia A Peyser, Alanna C Morrison, Ramachandran S Vasan, Xihong Lin, Jerome I Rotter, James B Meigs, Alisa K Manning, Paul S De Vries

Faculty, Staff and Student Publications

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 …

The Brd4-Nut Fusion Alone Drives Malignant Transformation Of Nut Carcinoma, R Taylor Durall, Julianna Huang, Luke Wojenski, Yeying Huang, Prafulla C Gokhale, Brittaney A Leeper, Joshua O Nash, Pedro L Ballester, Scott Davidson, Adam Shlien, Emmanuel Sotirakis, Fabien Bertaux, Vincent Dubus, Jia Luo, Catherine J Wu, Derin B Keskin, Kyle P Eagen, Geoffrey I Shapiro, Christopher A French

Faculty, Staff and Students Publications

NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4-NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous …

Microbial Stimulation Of Oxytocin Release From The Intestinal Epithelium Via Secretin Signaling, Heather A Danhof, Jihwan Lee, Aanchal Thapa, Robert A Britton, Sara C Di Rienzi

Faculty, Staff and Students Publications

Intestinal microbes impact the health of the intestine and organs distal to the gut. Limosilactobacillus reuteri is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for L. reuteri-mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, …

Case Sampling Vs Universal Review For Evaluating Hospital Postoperative Mortality In Us Surgical Quality Improvement Programs, Vivi W Chen, Alexis P Chidi, Tracey Rosen, Yongquan Dong, Peter A Richardson, Jennifer Kramer, David A Axelrod, Laura A Petersen, Nader N Massarweh

Faculty, Staff and Students Publications

IMPORTANCE: Representative surgical case sampling, rather than universal review, is used by US Department of Veterans Affairs (VA) and private-sector national surgical quality improvement (QI) programs to assess program performance and to inform local QI and performance improvement efforts. However, it is unclear whether case sampling is robust for identifying hospitals with safety or quality concerns.

OBJECTIVE: To evaluate whether the sampling strategy used by several national surgical QI programs provides hospitals with data that are representative of their overall quality and safety, as measured by 30-day mortality.

DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study was a national, hospital-level …

The 2023 Model Core Content Of Disaster Medicine, Bryan J Wexler, Carl Schultz, Paul D Biddinger, Gregory Ciottone, Angela Cornelius, Robert Fuller, Roxanna Lefort, Andrew Milsten, James Phillips, Ira Nemeth

Faculty, Staff and Students Publications

Introduction: Disaster Medicine (DM) is the clinical specialty whose expertise includes the care and management of patients and populations outside conventional care protocols. While traditional standards of care assume the availability of adequate resources, DM practitioners operate in situations where resources are not adequate, necessitating a modification in practice. While prior academic efforts have succeeded in developing a list of core disaster competencies for emergency medicine residency programs, international fellowships, and affiliated health care providers, no official standardized curriculum or consensus has yet been published to date for DM fellowship programs based in the United States.

Study objective: The objective …

Idiographic Coping Outcomes In Youth With Autism Spectrum Disorder And Co-Occurring Anxiety: Results From The Taasd Study, Lesley A Norris, Jonathan C Rabner, Eric A Storch, Jeffrey J Wood, Connor Kerns, Adam B Lewin, Brent J Small, Philip C Kendall

Center for Medical Ethics and Health Policy Staff Publications

Versions of cognitive behavioral therapy (Coping Cat, CC; Behavioral Interventions for Anxiety in Children with Autism, BIACA) have shown efficacy in treating anxiety among youth with autism spectrum disorder. Measures of efficacy have been primarily nomothetic symptom severity assessments. The current study examined idiographic coping outcomes in the Treatment of Anxiety in Autism Spectrum Disorder study (N = 167). Longitudinal changes in coping with situations individualized to youth fears (Coping Questionnaire) were examined across CC, BIACA and treatment as usual (TAU) in a series of multilevel models. CC and BIACA produced significantly greater improvements than TAU in caregiver-reported coping. Youth …

Droid: Dose-Ranging Approach To Optimizing Dose In Oncology Drug Development, Beibei Guo, Ying Yuan

Faculty, Staff and Student Publications

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to …

Inhibition Of The Proline Metabolism Rate-Limiting Enzyme P5cs Allows Proliferation Of Glutamine-Restricted Cancer Cells, Samantha J Linder, Tiziano Bernasocchi, Bárbara Martínez-Pastor, Kelly D Sullivan, Matthew D Galbraith, Caroline A Lewis, Christina M Ferrer, Ruben Boon, Giorgia G Silveira, Hyo Min Cho, Charles Vidoudez, Stuti Shroff, Joao P Oliveira-Costa, Kenneth N Ross, Rami Massri, Yusuke Matoba, Eugene Kim, Bo R Rueda, Shannon L Stott, Eyal Gottlieb, Joaquin M Espinosa, Raul Mostoslavsky

Faculty, Staff and Student Publications

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized …

An "Off-The-Shelf" Cd2 Universal Car-T Therapy For T-Cell Malignancies, Jingyu Xiang, Jessica M Devenport, Alun J Carter, Karl W Staser, Miriam Y Kim, Julie O' Neal, Julie K Ritchey, Michael P Rettig, Feng Gao, Garrett Rettig, Rolf Turk, Byung Ha Lee, Matthew L Cooper, John F Dipersio

2020-Current year OA Pubs

T-cell malignancies are associated with frequent relapse and high morbidity, which is partly due to the lack of effective or targeted treatment options. To broaden the use of CAR-T cells in pan T-cell malignancies, we developed an allogeneic "universal" CD2-targeting CAR-T cell (UCART2), in which the CD2 antigen is deleted to prevent fratricide, and the T-cell receptor is removed to prevent GvHD. UCART2 demonstrated efficacy against T-ALL and CTCL and prolonged the survival of tumor-engrafted NSG mice in vivo. To evaluate the impact of CD2 on CAR-T function, we generated CD19 CAR-T cells (UCART19) with or without CD2 deletion, single-cell …

Neurofibromin 1 Mutations Impair The Function Of Human Induced Pluripotent Stem Cell-Derived Microglia, Leonard D Kuhrt, Edyta Motta, Nirmeen Elmadany, Hannah Weidling, Raphaela Fritsche-Guenther, Ibrahim E Efe, Olivia Cobb, Jit Chatterjee, Lucy G Boggs, Marina Schnauß, Sebastian Diecke, Marcus Semtner, Corina Anastasaki, David H Gutmann, Helmut Kettenmann

2020-Current year OA Pubs

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human …

Programmable And Reversible Integrin-Mediated Cell Adhesion Reveals Hysteresis In Actin Kinetics That Alters Subsequent Mechanotransduction, Zheng Zhang, Guy M Genin, Et Al.

2020-Current year OA Pubs

Dynamically evolving adhesions between cells and extracellular matrix (ECM) transmit time-varying signals that control cytoskeletal dynamics and cell fate. Dynamic cell adhesion and ECM stiffness regulate cellular mechanosensing cooperatively, but it has not previously been possible to characterize their individual effects because of challenges with controlling these factors independently. Therefore, a DNA-driven molecular system is developed wherein the integrin-binding ligand RGD can be reversibly presented and removed to achieve cyclic cell attachment/detachment on substrates of defined stiffness. Using this culture system, it is discovered that cyclic adhesion accelerates F-actin kinetics and nuclear mechanosensing in human mesenchymal stem cells (hMSCs), with …

Competing Engagement Of Β-Arrestin Isoforms Balances Igf1r/P53 Signaling And Controls Melanoma Cell Chemotherapeutic Responsiveness, Sonia Cismas, Sylvya Pasca, Caitrin Crudden, Iara Trocoli Drakensjo, Naida Suleymanova, Simin Zhang, Benjamin Gebhard, Dawei Song, Shiyong Neo, Takashi Shibano, Terry J Smith, George A Calin, Ada Girnita, Leonard Girnita

Faculty, Staff and Student Publications

Constraints on the p53 tumor suppressor pathway have long been associated with the progression, therapeutic resistance, and poor prognosis of melanoma, the most aggressive form of skin cancer. Likewise, the insulin-like growth factor type 1 receptor (IGF1R) is recognized as an essential coordinator of transformation, proliferation, survival, and migration of melanoma cells. Given that β-arrestin (β-arr) system critically governs the anti/pro-tumorigenic p53/IGF1R signaling pathways through their common E3 ubiquitin-protein ligase MDM2, we explore whether unbalancing this system downstream of IGF1R can enhance the response of melanoma cells to chemotherapy. Altering β-arr expression demonstrated that both β-arr1-silencing and β-arr2-overexpression (-β-arr1/+β-arr2) facilitated …

Primary Results Of The Saval Randomized Trial Of A Paclitaxel-Eluting Nitinol Stent Versus Percutaneous Transluminal Angioplasty In Infrapopliteal Arteries, Hans Van Overhagen, Patrick J Geraghty, Et Al.

2020-Current year OA Pubs

BACKGROUND: Effective and durable options for infrapopliteal artery revascularization for patients with chronic limb-threatening ischemia (CLTI) are limited.

METHODS: The SAVAL trial is a prospective, multicenter, randomized trial of patients with CLTI and infrapopliteal artery lesions with total lesion length ⩽ 140 mm, stenosis ⩾ 70%, and Rutherford category 4-5 assigned 2:1 to treatment with the SAVAL self-expandable paclitaxel drug-eluting stent (DES) or percutaneous transluminal angioplasty (PTA) with an uncoated balloon. The primary effectiveness endpoint was primary vessel patency (i.e., core lab-adjudicated duplex ultrasound-based flow at 12 months in the absence of clinically driven target lesion revascularization or surgical bypass …

In Severe Alcohol-Related Hepatitis, Acute Kidney Injury Is Prevalent, Associated With Mortality Independent Of Liver Disease Severity, And Can Be Predicted Using Il-8 And Micro-Rnas, Luke D Tyson, Stephen Atkinson, Robert W Hunter, Michael Allison, Andrew Austin, James W Dear, Ewan Forrest, Tong Liu, Emma Lord, Steven Masson, Joao Nunes, Paul Richardson, Stephen D Ryder, Mark Wright, Mark Thursz, Nikhil Vergis

Faculty, Staff and Student Publications

BACKGROUND: The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) is uncertain.

AIMS: We aimed to determine AKI incidence; association with mortality; evaluate serum biomarkers and the modifying effects of prednisolone and pentoxifylline in the largest AH cohort to date.

METHODS: Participants in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial with day zero (D0) creatinine available were included. AKI was defined by modified International Club of Ascites criteria; incident AKI as day 7 (D7) AKI without D0-AKI. Survival was compared by Kaplan-Meier; mortality associations by Cox regression; associations with AKI by binary logistic regression; …

Atm Mutations Associate With Distinct Co-Mutational Patterns And Therapeutic Vulnerabilities In Nsclc, Natalie I Vokes, Ana Galan Cobo, Margarita Fernandez-Chas, David Molkentine, Santiago Treviño, Vitaly Druker, Yu Qian, Sonia Patel, Stephanie Schmidt, Lingzhi Hong, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J Jack Lee, Marcelo V Negrao, Don L Gibbons, Ara Vaporciyan, Xiuning Le, Jia Wu, Jianjun Zhang, Una Rigney, Sonia Iyer, Emma Dean, John V Heymach

Faculty, Staff and Student Publications

PURPOSE: Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non-small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.

EXPERIMENTAL DESIGN: Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of …

Improving Radiotherapy In Immunosuppressive Microenvironments By Targeting Complement Receptor C5ar1, Callum Beach, David Maclean, Dominika Majorova, Stavros Melemenidis, Dhanya K Nambiar, Ryan K Kim, Gabriel N Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily Vs Hillson, Ashley K Mcculloch, Ross K Mcmahon, Kathryn Pennel, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, Albert C Koong, Trent M Woodruff, Edward E Graves, Tim Maughan, Simon Ja Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J Leedham, Amato J Giaccia, Monica M Olcina

Faculty, Staff and Student Publications

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased …