Digital Commons Network^™

Non-Canonical Metabolic Pathways In The Malaria Parasite Detected By Isotope-Tracing Metabolomics, Simon A Cobbold, Madel V Tutor, Philip Frasse, Emma Mchugh, Markus Karnthaler, Darren J Creek, Audrey Odom John, Leann Tilley, Stuart A Ralph, Malcolm J Mcconville

Open Access Publications

The malaria parasite, Plasmodium falciparum, proliferates rapidly in human erythrocytes by actively scavenging multiple carbon sources and essential nutrients from its host cell. However, a global overview of the metabolic capacity of intraerythrocytic stages is missing. Using multiplex

Ambient Fine Particulate Matter Air Pollution And Risk Of Weight Gain And Obesity In United States Veterans: An Observational Cohort Study, Benjamin Bowe, Andrew K. Gibson, Yan Xie, Yan Yan, Aaron Van Donkelaar, Randall V. Martin, Ziyad Al-Aly

Open Access Publications

BACKGROUND: Experimental evidence and studies of children and adolescents suggest that ambient fine particulate matter [particulate matter

OBJECTIVES: Our goal was to characterize the association between

METHODS: We followed 3,902,440 U.S. Veterans from 2010 to 2018 (median 8.1 y, interquartile range: 7.3-8.4) and assigned time-updated

RESULTS: A

DISCUSSION:

Multimodal Examination Of Emotion Processing Systems Associated With Negative Affectivity Across Early Childhood, M Catalina Camacho, Elizabeth M Williams, Keya Ding, Susan B Perlman

Open Access Publications

High Temperamental Negative Affectivity in early childhood has been found to predict later emotion dysregulation. While much work has been conducted to separately probe bio-behavioral systems associated with Negative Affectivity, very little work has examined the relations among multiple systems across age. In this study, we use multi-modal methods to index neurobiological systems associated with Negative Affectivity in 53 4-7-year-old children. Prefrontal activation during emotion regulation was measured using functional near-infrared spectroscopy over the lateral prefrontal cortex (PFC) while children played a game designed to elicit frustration in Social (Happy and Angry faces) and Nonsocial contexts. Gaze behaviors while free-viewing …

A Clinician’S Guide For Navigating The World Of Attention Deficit Hyperactivity Disorder Medications, Gregory W. Mattingly, Joel Young

Open Access Publications

No abstract provided.

Endogenous And Combination Retinoids Are Active In Myelomonocytic Leukemias, Orsola Di Martino, Haixia Niu, Gayla Hadwiger, Heikki Kuusanmaki, Margaret A. Ferris, Anh Vu, Jeremy Beales, Carl Wagner, María P. Menéndez-Gutiérrez, Mercedes Ricote, Caroline Heckman, John S. Welch

Open Access Publications

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation …

The Epidemiology And Biology Of Pulmonary Metastases, William D Gerull, Varun Puri, Benjamin D Kozower

Open Access Publications

Our goal in this chapter is to explore the complex processes of metastasis and why there is a predisposition for this to occur in the lung. In addition, we aim to describe the incidence of pulmonary metastases in various contexts and based on the origin of the primary tumor. There are unique characteristics of the pulmonary system that make metastases more likely to occur in the lung than anywhere else in the body. Some of these characteristics include receiving the entire cardiac output every minute, having the densest capillary bed in the body, and being the first reservoir of most …

An Open-Source Device For Measuring Food Intake And Operant Behavior In Rodent Home-Cages, Bridget A. Matikainen-Ankney, Thomas Earnest, Eric Casey, Justin G. Wang, Alex A. Legaria, Kia M. Barclay, Makenzie R. Norris, Yu-Hsuan Chang, Eric Lin, Sineadh M. Conway, Ream Al-Hasani, Jordan G. Mccall, Meaghan C. Creed, Alexxai V. Kravitz, Et Al

Open Access Publications

Feeding is critical for survival, and disruption in the mechanisms that govern food intake underlies disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation in rodent home-cages: the Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of …

Crosstalk Between Nonclassical Monocytes And Alveolar Macrophages Mediates Transplant Ischemia-Reperfusion Injury Through Classical Monocyte Recruitment, Chitaru Kurihara, Wenjun Li, Daniel Kreisel, Et Al

Open Access Publications

Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that …

Laminin Β2 Variants Associated With Isolated Nephropathy That Impact Matrix Regulation, Yamato Kikkawa, Helen Liapis, Jeffrey H. Miner, Et Al.

Open Access Publications

Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β2 secretion, the …

Cryo-Em Structure Of The Rous Sarcoma Virus Octameric Cleaved Synaptic Complex Intasome, Krishan K Pandey, Sibes Bera, Ke Shi, Michael J Rau, Amarachi V Oleru, James A J Fitzpatrick, Alan N Engelman, Hideki Aihara, Duane P Grandgenett

Open Access Publications

Despite conserved catalytic integration mechanisms, retroviral intasomes composed of integrase (IN) and viral DNA possess diverse structures with variable numbers of IN subunits. To investigate intasome assembly mechanisms, we employed the Rous sarcoma virus (RSV) IN dimer that assembles a precursor tetrameric structure in transit to the mature octameric intasome. We determined the structure of RSV octameric intasome stabilized by a HIV-1 IN strand transfer inhibitor using single particle cryo-electron microscopy. The structure revealed significant flexibility of the two non-catalytic distal IN dimers along with previously unrecognized movement of the conserved intasome core, suggesting ordered conformational transitions between intermediates that …

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) …

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 …

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 …

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

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 …

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% …

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)

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, …