Digital Commons Network^™

Itaconate Confers Tolerance To Late Nlrp3 Inflammasome Activation, Monika Bambouskova, Lucie Potuckova, Tomas Paulenda, Martina Kerndl, Denis A Mogilenko, Amanda Swain, Samantha Burdess, Anwesha Laha, Gaya K Amarasinghe, Michael S Diamond, Maxim N Artyomov, Et Al

Open Access Publications

Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of …

Insulinase-Like Protease 1 Contributes To Macrogamont Formation In Cryptosporidium Parvum, Rui Xu, Yaoyu Feng, Lihua Xiao, L David Sibley

Open Access Publications

The apicomplexan parasite

The Transcription Factor Pdr802 Regulates Titan Cell Formation And Pathogenicity Of Cryptococcus Neoformans, Julia C V Reuwsaat, Daniel P Agustinho, Heryk Motta, Andrew L Chang, Holly Brown, Michael R Brent, Livia Kmetzsch, Tamara L Doering

Open Access Publications

No abstract provided.

Microbiota Functional Activity Biosensors For Characterizing Nutrient Metabolism In Vivo, Darryl A. Wesener, Zachary W. Beller, Samantha L. Peters, Amir Rajabi, Gianluca Dimartino, Richard J. Giannone, Robert L. Hettich, Jeffrey I. Gordon

Open Access Publications

Methods for measuring gut microbiota biochemical activities in vivo are needed to characterize its functional states in health and disease. To illustrate one approach, an arabinan-containing polysaccharide was isolated from pea fiber, its structure defined, and forward genetic and proteomic analyses used to compare its effects, versus unfractionated pea fiber and sugar beet arabinan, on a human gut bacterial strain consortium in gnotobiotic mice. We produced 'Microbiota Functional Activity Biosensors' (MFABs) consisting of glycans covalently linked to the surface of fluorescent paramagnetic microscopic glass beads. Three MFABs, each containing a unique glycan/fluorophore combination, were simultaneously orally gavaged into gnotobiotic mice, …

Complex Consequences Of Cantu Syndrome Sur2 Variant R1154q In Genetically Modified Mice, Haixia Zhang, Alex Hanson, Tobias Scherf De Almeida, Christopher Emfinger, Conor Mcclenaghan, Theresa Harter, Zihan Yan, Paige E Cooper, G Schuyler Brown, Eric C Arakel, Robert P Mecham, Atilla Kovacs, Carmen M Halabi, Blanche Schwappach, Maria S Remedi, Colin G Nichols

Open Access Publications

Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits, the most common mutations being SUR2[R1154Q] and SUR2[R1154W], carried by approximately 30% of patients. We used CRISPR/Cas9 genome engineering to introduce the equivalent of the human SUR2[R1154Q] mutation into the mouse ABCC9 gene. Along with minimal CS disease features, R1154Q cardiomyocytes and vascular smooth muscle showed much lower KATP current density and pinacidil activation than WT cells. Almost complete loss of SUR2-dependent protein and KATP in homozygous R1154Q ventricles revealed underlying diazoxide-sensitive SUR1-dependent KATP channel activity. Surprisingly, sequencing …

Parabrachial Opioidergic Projections To Preoptic Hypothalamus Mediate Behavioral And Physiological Thermal Defenses, Aaron J. Norris, Jordan R. Shaker, Aaron L. Cone, Imeh B. Ndiokho, Michael R. Bruchas

Open Access Publications

Maintaining stable body temperature through environmental thermal stressors requires detection of temperature changes, relay of information, and coordination of physiological and behavioral responses. Studies have implicated areas in the preoptic area of the hypothalamus (POA) and the parabrachial nucleus (PBN) as nodes in the thermosensory neural circuitry and indicate that the opioid system within the POA is vital in regulating body temperature. In the present study we identify neurons projecting to the POA from PBN expressing the opioid peptides dynorphin and enkephalin. Using mouse models, we determine that warm-activated PBN neuronal populations overlap with both prodynorphin (Pdyn) and proenkephalin (Penk) …

Coding Of Sexual Assault By Emergency Physicians: A Nationally Representative Study, Vithya Murugan, Katherine J Holzer, Michael G Vaughn, Jason T Carbone, Dylan B Jackson, Cindy C Bitter

Open Access Publications

INTRODUCTION: Sexual assault is a public health problem that affects many Americans and has multiple long-lasting effects on victims. Medical evaluation after sexual assault frequently occurs in the emergency department, and documentation of the visit plays a significant role in decisions regarding prosecution and outcomes of legal cases against perpetrators. The American College of Emergency Physicians recommends coding such visits as sexual assault rather than adding modifiers such as "alleged."

METHODS: This study reviews factors associated with coding of visits as sexual assault compared to suspected sexual assault using the 2016 Nationwide Emergency Department Sample.

RESULTS: Younger age, female gender, …

Uveal Melanoma Cells Use Ameboid And Mesenchymal Mechanisms Of Cell Motility Crossing The Endothelium, Michael D. Onken, Kendall J. Blumer, John A. Cooper

Open Access Publications

Uveal melanomas (UMs) are malignant cancers arising from the pigmented layers of the eye. UM cells spread through the bloodstream, and circulating UM cells are detectable in patients before metastases appear. Extravasation of UM cells is necessary for formation of metastases, and transendothelial migration (TEM) is a key step in extravasation. UM cells execute TEM via a stepwise process involving the actin-based processes of ameboid blebbing and mesenchymal lamellipodial protrusion. UM cancers are driven by oncogenic mutations that activate Gαq/11, and this activates TRIO, a guanine nucleotide exchange factor for RhoA and Rac1. We found that pharmacologic inhibition of Gαq/11 …

The Novel Use Of A Commercially Available Video-Conference Platform To Facilitate Multidisciplinary Target Volume Review And Delineation For Skull-Base Radiation Therapy During The Coronavirus Disease 2019 Pandemic, Amit Roy, Neal Andruska, Hilary L P Orlowski, Patrik Pipkorn, Mackenzie D Daly

Open Access Publications

Multidisciplinary involvement in radiation therapy (RT) treatment planning is currently underused. A radiation oncologist sought input for generating target contours from a neuro-radiologist (NR) and otolaryngologist (OL) for 3 patients requiring skull-base RT during the coronavirus disease 2019 pandemic. A Health Insurance Portability and Accountability Act compliant virtual meeting between the radiation oncologist, NR, and OL was arranged. Involvement of the OL and NR led to significant changes in the clinical target volume for all patients. Our experience highlights the feasibility of using commercially available video-conference platforms for multidisciplinary target volume delineation for complex RT cases. Further applications include interdisciplinary …

Bidirectional Regulation Of Glial Potassium Buffering - Glioprotection Versus Neuroprotection, Hailun Li, Lorenzo Lones, Aaron Diantonio

Open Access Publications

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A salt inducible kinase 3 (SIK3)-regulated gene expression program controls the glial capacity to buffer K

Norovirus Evolution In Immunodeficient Mice Reveals Potentiated Pathogenicity Via A Single Nucleotide Change In The Viral Capsid, Forrest C Walker, Ebrahim Hassan, Stefan T. Peterson, Rachel Rodgers, Lawrence A. Schriefer, Cassandra E. Thompson, Yuhao Li, Gowri Kalugotla, Carla Blum-Johnston, Dylan Lawrence, Broc T. Mccune, Vincent R. Graziano, Larissa Lushniak, Sanghyun Lee, Alexa N. Roth, Stephanie M. Karst, Timothy J. Nice, Jonathan J. Miner, Craig B. Wilen, Megan T. Baldridge

Open Access Publications

Interferons (IFNs) are key controllers of viral replication, with intact IFN responses suppressing virus growth and spread. Using the murine norovirus (MNoV) system, we show that IFNs exert selective pressure to limit the pathogenic evolutionary potential of this enteric virus. In animals lacking type I IFN signaling, the nonlethal MNoV strain CR6 rapidly acquired enhanced virulence via conversion of a single nucleotide. This nucleotide change resulted in amino acid substitution F514I in the viral capsid, which led to >10,000-fold higher replication in systemic organs including the brain. Pathogenicity was mediated by enhanced recruitment and infection of intestinal myeloid cells and …

Association Of Early Versus Delayed Normalisation Of Left Ventricular Ejection Fraction With Mortality In Ischemic Cardiomyopathy, Walter B Schiffer, Andrew Perry, Elena Deych, David L Brown, Luigi Adamo

Open Access Publications

OBJECTIVE: In patients with non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (LVEF), normalisation of LVEF is associated with improved outcomes. However, data on patients with ischaemic cardiomyopathy and recovered LVEF are lacking. The goal of this study was to assess the prognostic significance of normalisation of the LVEF in patients with ischaemic cardiomyopathy.

METHODS/RESULTS: We performed a non-prespecified post hoc analysis of the Surgical Treatment for Ischaemic Heart Failure (STICH) trial to determine the association between normalisation of LVEF (>50%) and mortality during follow-up. Of the 1212 patients with LVEF <35% enroled in the STICH trial, 932 underwent assessment of LVEF at 4 months and/or 2 years after enrolment. Among them, 18 patients experienced normalisation in LVEF at 4-month follow-up and 35 patients experienced recovery in LVEF at 2 years. Recovery of LVEF at 4 months and recovery of LVEF at 2 years were not correlated. Recovery of LVEF at 4 months was not associated with reduced all-cause mortality in unadjusted analysis (log-rank test p=0.54) or in Cox proportional hazards analysis (HR: 0.93; 95% CI: 0.48 to 1.80; p=0.82). Ejection fraction recovery at 2 years was associated with a reduction in all-cause mortality, both in unadjusted analysis (log-rank test p=0.004) and in the Cox proportional hazard model (HR: 0.41; 95% CI: 0.21 to 0.80; p=0.009).

CONCLUSIONS: In patients with ischaemic cardiomyopathy, delayed normalisation …

Response-Adapted Therapy With Infusional Epoch Chemotherapy Plus Rituximab In Hiv-Associated, B-Cell Non-Hodgkin's Lymphoma, Joseph A. Sparano, Jeannette Y. Lee, Lawrence D. Kaplan, Juan Carlos Ramos, Richard F. Ambinder, William Wachsman, David Aboulafia, Ariela Noy, David H. Henry, Lee Ratner, Ethel Cesarman, Amy Chadburn, Ronald Mitsuyasu, Aids Malignancy Consortium

Open Access Publications

Four cycles of rituximab plus CHOP chemotherapy is as effective as 6 cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with HIV-associated DLBCL and high-grade lymphoma treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy. 106 evaluable patients with HIV-associated DLBCL or high-grade CD20-positive non-Hodgkin's lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and …

Not All Lymphoid Aggregates In Chronic Lymphocytic Leukemia (Cll) Patients Are Due To Cll!, Lily Mahapatra, Tianjiao Wang, Yi-Shan Lee, John L Frater

Open Access Publications

Infection is a common cause of morbidity and mortality in chronic lymphocytic leukemia and should be considered when examining bone marrow specimens to identify a potentially treatable pathogen.

Clinical Utility Of Anti-Cytosolic 5'-Nucleotidase 1a Antibody In Idiopathic Inflammatory Myopathies, Chiseko Ikenaga, Andrew R Findlay, Namita A Goyal, Sarah Robinson, Jonathan Cauchi, Yessar Hussain, Leo H Wang, Joshua C Kershen, Brent A Beson, Michael Wallendorf, Robert C Bucelli, Tahseen Mozaffar, Alan Pestronk, Conrad C Weihl

Open Access Publications

OBJECTIVE: To define the clinicopathologic features and diagnostic utility associated with anti-cytosolic 5'-nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs).

METHODS: Anti-NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases.

RESULTS: Of 593 patients, anti-NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases …

Increased Functional Coupling Between Vta And Hippocampus During Rest In First-Episode Psychosis, David F Gregory, Jane M Rothrock, Maria Jalbrzikowski, William Foran, David F Montez, Beatriz Luna, Vishnu P Murty

Open Access Publications

Animal models suggest that interactions between the hippocampus and ventral tegmental area (VTA) underlie the onset and etiology of psychosis. While a large body of research has separately characterized alterations in hippocampal and VTA function in psychosis, alterations across the VTA and hippocampus have not been characterized in first-episode psychosis (FEP). As the phase of psychosis most proximal to conversion, studies specifically focused on FEP are valuable to psychosis research. Here, we characterize alterations in VTA-hippocampal interactions across male and female human participants experiencing their first episode of psychosis using resting state functional magnetic resonance imaging (rsfMRI). In comparison to …

The Swell1-Lrrc8 Complex Regulates Endothelial Akt-Enos Signaling And Vascular Function, Ahmad F. Alghanem, Javier Abello, Joshua M. Maurer, Ashutosh Kumar, Chau My Ta, Susheel K. Gunasekar, Chen Kang, Litao Xie, Amber N. Stratman, Rajan Sah, Et Al

Open Access Publications

The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure, and blood flow. The endothelial volume-regulated anion channel (VRAC) has been proposed to be mechanosensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the leucine-rich repeat-containing protein 8a, LRRC8A (SWELL1), is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-endothelial nitric oxide synthase (eNOS) signaling under basal, stretch, and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted

A Non-Stop Identity Complex (Nic) Supervises Enterocyte Identity And Protects From Premature Aging, Neta Erez, Lena Israitel, Eliya Bitman-Lotan, Wing H. Wong, Gal Raz, Dayanne V. Cornelio-Parra, Salwa Danial, Na'ama Flint Brodsly, Elena Belova, Oksana Maksimenko, Pavel Georgiev, Todd Druley, Ryan D. Mohan, Amir Orian

Open Access Publications

A hallmark of aging is loss of differentiated cell identity. Aged

Association Of Opioid Use Disorder Treatment With Alcohol-Related Acute Events, Kevin Y. Xu, Ned Presnall, Carrie M. Mintz, Jacob T. Borodovsky, Nisha R. Bhat, Laura J. Bierut, Richard A. Grucza

Open Access Publications

Importance: Persons with opioid use disorder (OUD) and co-occurring alcohol use disorder (AUD) are understudied and undertreated. It is unknown whether the use of medications to treat OUD is associated with reduced risk of alcohol-related morbidity.

Objective: To determine whether the use of OUD medications is associated with decreased risk for alcohol-related falls, injuries, and poisonings in persons with OUD with and without co-occurring AUD.

Design, Setting, and Participants: This recurrent-event, case-control, cohort study used prescription claims from IBM MarketScan insurance databases from January 1, 2006, to December 31, 2016. The sample included persons aged 12 to 64 years in …

Defining Phenotypic And Functional Heterogeneity Of Glioblastoma Stem Cells By Mass Cytometry, Luciano Galdieri, Arijita Jash, Olga Malkova, Diane D Mao, Patrick Desouza, Yunli E Chu, Amber Salter, Jian L Campian, Kristen M Naegle, Cameron W Brennan, Hiroaki Wakimoto, Stephen T Oh, Albert H Kim, Milan G Chheda

Open Access Publications

Most patients with glioblastoma (GBM) die within 2 years. A major therapeutic goal is to target GBM stem cells (GSCs), a subpopulation of cells that contribute to treatment resistance and recurrence. Since their discovery in 2003, GSCs have been isolated using single-surface markers, such as CD15, CD44, CD133, and α6 integrin. It remains unknown how these single-surface marker-defined GSC populations compare with each other in terms of signaling and function and whether expression of different combinations of these markers is associated with different functional capacity. Using mass cytometry and fresh operating room specimens, we found 15 distinct GSC subpopulations in …

Epithelial Il-33 Appropriates Exosome Trafficking For Secretion In Chronic Airway Disease, Ella Katz-Kiriakos, Deborah F Steinberg, Colin E Kluender, Omar A Osorio, Catie Newsom-Stewart, Arjun Baronia, Derek E Byers, Michael J Holtzman, Dawn Katafiasz, Kristina L Bailey, Steven L Brody, Mark J Miller, Jennifer Alexander-Brett

Open Access Publications

IL-33 is a key mediator of chronic airway disease driven by type 2 immune pathways, yet the nonclassical secretory mechanism for this cytokine remains undefined. We performed a comprehensive analysis in human airway epithelial cells, which revealed that tonic IL-33 secretion is dependent on the ceramide biosynthetic enzyme neutral sphingomyelinase 2 (nSMase2). IL-33 is cosecreted with exosomes by the nSMase2-regulated multivesicular endosome (MVE) pathway as surface-bound cargo. In support of these findings, human chronic obstructive pulmonary disease (COPD) specimens exhibited increased epithelial expression of the abundantly secreted IL33Δ34 isoform and augmented nSMase2 expression compared with non-COPD specimens. Using an Alternaria-induced …

Circulating Mitochondrial Dna Is An Early Indicator Of Severe Illness And Mortality From Covid-19, Davide Scozzi, Marlene Cano, Lina Ma, Dequan Zhou, Ji Hong Zhu, Jane A. O'Halloran, Charles Goss, Adriana M. Rauseo, Zhiyi Liu, Sanjaya K. Sahu, Mohsen Ibrahim, Ramsey Hachem, Daniel Kreisel, Philip A. Mudd, Hrishikesh S. Kulkarni, Andrew E. Gelman, Et Al

Open Access Publications

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with …

Use Of Mechanical Circulatory Support Devices Among Patients With Acute Myocardial Infarction Complicated By Cardiogenic Shock, Sanket S. Dhruva, Joseph S. Ross, Bobak J. Mortazavi, Nathan C. Hurley, Harlan M. Krumholz, Jeptha P. Curtis, Alyssa P. Berkowitz, Frederick A. Masoudi, John C. Messenger, Craig S. Parzynski, Che G. Ngufor, Saket Girotra, Amit P. Amin, Nilay D. Shah, Nihar R. Desai

Open Access Publications

Importance: Mechanical circulatory support (MCS) devices, including intravascular microaxial left ventricular assist devices (LVADs) and intra-aortic balloon pumps (IABPs), are used in patients who undergo percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) complicated by cardiogenic shock despite limited evidence of their clinical benefit.

Objective: To examine trends in the use of MCS devices among patients who underwent PCI for AMI with cardiogenic shock, hospital-level use variation, and factors associated with use.

Design, Setting, and Participants: This cross-sectional study used the CathPCI and Chest Pain-MI Registries of the American College of Cardiology National Cardiovascular Data Registry. Patients who underwent …

Evaluation Of Optimal Blood Culture Incubation Time To Maximize Clinically Relevant Results From A Contemporary Blood Culture Instrument And Media System, Eric M Ransom, Zahra Alipour, Meghan A Wallace, Carey-Ann D. Burnham

Open Access Publications

Timely diagnosis of microorganisms in blood cultures is necessary to optimize therapy. Although blood culture media and systems have evolved for decades, the standard interval for incubation prior to being discarded as negative has remained 5 days. Here, we evaluated the optimal incubation time for the BacT/Alert Virtuo blood culture detection system (bioMérieux) using FA Plus (aerobic) and FN Plus (anaerobic) resin culture bottles in routine clinical use. Following institutional review board (IRB) approval, a retrospective review evaluated the outcomes of 158,710 bottles collected between November 2018 and October 2019. The number of positive blood bottles was 13,592 (8.6%); 99% …

Racial Residential Segregation And Colorectal Cancer Mortality In The Mississippi Delta Region, Aaron J Kruse-Diehr, Justin T Mcdaniel, Marquita W Lewis-Thames, Aimee S James, Musa Yahaya

Open Access Publications

INTRODUCTION: Few studies have examined the effects of racial segregation on colorectal cancer (CRC) outcomes, and none has determined whether rurality moderates the effect of racial segregation on CRC mortality. We examined whether the effect of segregation on CRC mortality varied by rurality in the Mississippi Delta Region, an economically distressed and historically segregated region of the United States.

METHODS: We used data from the US Census Bureau and the 1999-2018 Surveillance, Epidemiology, and End Results (SEER) program to estimate mixed linear regression models in which CRC mortality rates among Black and White residents in Delta Region counties (N = …

Pharmacokinetic And Pharmacodynamic Profiling Of Minocycline For Injection Following A Single Infusion In Critically Ill Adults In A Phase Iv Open-Label Multicenter Study (Acumin), Thomas P Lodise, Yasir Hamad, Et Al

Open Access Publications

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR)

Cancer-Associated Exportin-6 Upregulation Inhibits The Transcriptionally Repressive And Anticancer Effects Of Nuclear Profilin-1, Cuige Zhu, Sun-Joong Kim, Arshag Mooradian, Faliang Wang, Ziqian Li, Sean Holohan, Patrick L Collins, Keren Wang, Zhanfang Guo, Jeremy Hoog, Cynthia X Ma, Eugene M Oltz, Jason M Held, Jieya Shao

Open Access Publications

Aberrant expression of nuclear transporters and deregulated subcellular localization of their cargo proteins are emerging as drivers and therapeutic targets of cancer. Here, we present evidence that the nuclear exporter exportin-6 and its cargo profilin-1 constitute a functionally important and frequently deregulated axis in cancer. Exportin-6 upregulation occurs in numerous cancer types and is associated with poor patient survival. Reducing exportin-6 level in breast cancer cells triggers antitumor effects by accumulating nuclear profilin-1. Mechanistically, nuclear profilin-1 interacts with eleven-nineteen-leukemia protein (ENL) within the super elongation complex (SEC) and inhibits the ability of the SEC to drive transcription of numerous pro-cancer …

Kmt2c Mutations Enhance Hsc Self-Renewal Capacity And Convey A Selective Advantage After Chemotherapy, Ran Chen, Theresa Okeyo-Owuor, Riddhi M Patel, Emily B Casey, Andrew S Cluster, Wei Yang, Jeffrey A Magee

Open Access Publications

The myeloid tumor suppressor KMT2C is recurrently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that KMT2C deletions convey a selective advantage to hematopoietic stem cells (HSCs) after chemotherapy treatment that may precipitate t-MDS/t-AML. Kmt2c deletions markedly enhance murine HSC self-renewal capacity without altering proliferation rates. Haploid Kmt2c deletions convey a selective advantage only when HSCs are driven into cycle by a strong proliferative stimulus, such as chemotherapy. Cycling Kmt2c-deficient HSCs fail to differentiate appropriately, particularly in response to interleukin-1. Kmt2c deletions mitigate histone …

Transcriptomic And Functional Analyses Of Mitochondrial Dysfunction In Pressure Overload-Induced Right Ventricular Failure, Hyuntae V Hwang, Nefthi Sandeep, Ramesh V Nair, Dong-Qing Hu, Mingming Zhao, Ingrid S Lan, Giovanni Fajardo, Scot J Matkovich, Daniel Bernstein, Sushma Reddy

Open Access Publications

Background In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods and Results We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. RV failure …

Reg4 And Its Downstream Transcriptional Activator Cd44icd In Stage Ii And Iii Colorectal Cancer, Jared A. Sninsky, Kumar S. Bishnupuri, Iván González, Nikolaos A. Trikalinos, Ling Chen, Brian K. Dieckgraefe

Open Access Publications

Reg4 is highly expressed in gastrointestinal malignancies and acts as a mitogenic and pro-invasive factor. Our recent works suggest that Reg4 binds with CD44 and induces its proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study is to demonstrate clinical significance of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with clinical parameters of aggression. We constructed a tissue microarray (TMA) of 93 stage II/III matched colon adenocarcinoma patients, 23 with recurrent disease. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins and analyzed to identify associations with tumor characteristics, …