University of Medicine and Dentistry of New Jersey

About: University of Medicine and Dentistry of New Jersey is a based out in . It is known for research contribution in the topics: Population & Pregnancy. The organization has 14634 authors who have published 19610 publications receiving 1041794 citations.

Cytokine gene polymorphism in human disease: on-line databases, supplement 2.

Abstract: N Haukim1, JL Bidwell1, AJP Smith1, LJ Keen1, G Gallagher2, R Kimberly3, T Huizinga4, MF McDermott5, J Oksenberg6, J McNicholl7, F Pociot8, C Hardt9 and S D’Alfonso10 1Department of Pathology and Microbiology, University of Bristol, Homoeopathic Hospital Site, Cotham, Bristol BS6 6JU, UK; Dental Research Centre, UMDNJ, NJ, USA; Division of Clinical Immunology and Rheumatology, Tinsley Harrison Tower, Room 429, University of Alabama at Birmingham, 1900 University Boulevard, Birmingham, AL 35294–0006, USA; Leiden University Medical Center, Department of Rheumatology, C4-R, PO Box 9600, 2300 RC Leiden, The Netherlands; 5Medical Unit, St Bartholemew’s and the Royal London Hospital School of Medicine and Dentistry, Whitechapel, London E1 1BB, UK; Department of Neurology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143–0435, USA; Immunology, DASTLR, NCID, CDC MS A25, 1600 Clifton Road NE, Atlanta, GA 30333, USA; 8Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark; Institut für Humangenetik, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany; Dipartimento Scienze Mediche, Via Solaroli 17, 28100 Novara, Italy

Formation of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury in rats

Abstract: In the present study, the contribution of nitric oxide (NO), superoxide, and peroxynitrite to the inflammatory response induced by myocardial ischemia-reperfusion (MI/R) was investigated. Male Sprague-Dawley rats were anesthetized, and the left main coronary artery was ligated for 20 min and reperfused for 5 h. MI/R induced severe arrhythmias, indicated by a significantly elevated arrhythmia score in the MI/R group compared with that in the sham control group. Creatine kinase activity in the left ventricular free wall of the MI/R group was significantly reduced by 38%. In contrast, myeloperoxidase activity in the left ventricular free wall of the MI/R group was increased by 140%. Similarly, superoxide and tissue NO levels in the ischemic region of the heurt were increased by 140 and 90%, respectively. Superoxide and NO values in the nonischemic regions were similar to the sham control group. Total NO synthase (NOS) activity was elevated by 212%; moreover, inducible NOS (iNOS) activity increased 6.7-fold in the ischemic vs. nonischemic regions. MI/R also induced both systemic and remote organ (lung) inflammatory responses. Circulating neutrophils and plasma NO levels were increased by 163 and 138%, respectively, in MI/R rats compared with sham control animals. NO levels and superoxide generation were increased by 90 and 176%, respectively, in the lung tissues. The expression of iNOS and peroxynitrite generation were demonstrated by immunohistochemical staining with polyclonal anti-iNOS and monoclonal anti-nitrotyrosine antibodies, respectively. Sections of both the ischemic area of the ventricular wall and the lung tissue of MI/R animals exhibited a marked immunoreactivity with anti-iNOS and anti-nitrotyrosine antibodies, indicating the presence of iNOS and nitrotyrosine. Our data indicate that NO, superoxide, and peroxynitrite formation are elevated after reperfusion of the ischemic heart, suggesting that these inflammatory mediators may be involved in MI/R injury.

HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis

Abstract: The ten–eleven translocation (TET) family of methylcytosine dioxygenases initiates demethylation of DNA and is associated with tumorigenesis in many cancers; however, the mechanism is mostly unknown. Here we identify upstream activators and downstream effectors of TET1 in breast cancer using human breast cancer cells and a genetically engineered mouse model. We show that depleting the architectural transcription factor high mobility group AT-hook 2 ( HMGA2 ) induces TET1 . TET1 binds and demethylates its own promoter and the promoter of homeobox A ( HOXA ) genes, enhancing its own expression and stimulating expression of HOXA genes including HOXA7 and HOXA9 . Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts. The genes comprising the HMGA2–TET1–HOXA9 pathway are coordinately regulated in breast cancer and together encompass a prognostic signature for patient survival. These results implicate the HMGA2–TET1–HOX signaling pathway in the epigenetic regulation of human breast cancer and highlight the importance of targeting methylation in specific subpopulations as a potential therapeutic strategy.

Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties.

Abstract: Abnormalities in cellular differentiation are frequent occurrences in human cancers. Treatment of human melanoma cells with recombinant fibroblast interferon (IFN-β) and the protein kinase C activator mezerein (MEZ) results in an irreversible loss in growth potential, suppression of tumorigenic properties and induction of terminal cell differentiation. Subtraction hybridization identified melanoma differentiation associated gene-7 (mda-7), as a gene induced during these physiological changes in human melanoma cells. Ectopic expression of mda-7 by means of a replication defective adenovirus results in growth suppression and induction of apoptosis in a broad spectrum of additional cancers, including melanoma, glioblastoma multiforme, osteosarcoma and carcinomas of the breast, cervix, colon, lung, nasopharynx and prostate. In contrast, no apparent harmful effects occur when mda-7 is expressed in normal epithelial or fibroblast cells. Human clones of mda-7 were isolated and its organization resolved in terms of intron/exon structure and chromosomal localization. Hu-mda-7 encompasses seven exons and six introns and encodes a protein with a predicted size of 23.8 kDa, consisting of 206 amino acids. Hu-mda-7 mRNA is stably expressed in the thymus, spleen and peripheral blood leukocytes. De novo mda-7 mRNA expression is also detected in human melanocytes and expression is inducible in cells of melanocyte/melanoma lineage and in certain normal and cancer cell types following treatment with a combination of IFN-β plus MEZ. Mda-7 expression is also induced during megakaryocyte differentiation induced in human hematopoietic cells by treatment with TPA (12-O-tetradecanoyl phorbol-13-acetate). In contrast, de novo expression of mda-7 is not detected nor is it inducible by IFN-β+MEZ in a spectrum of additional normal and cancer cells. No correlation was observed between induction of mda-7 mRNA expression and growth suppression following treatment with IFN-β+MEZ and induction of endogenous mda-7 mRNA by combination treatment did not result in significant intracellular MDA-7 protein. Radiation hybrid mapping assigned the mda-7 gene to human chromosome 1q, at 1q 32.2 to 1q41, an area containing a cluster of genes associated with the IL-10 family of cytokines. Mda-7 represents a differentiation, growth and apoptosis associated gene with potential utility for the gene-based therapy of diverse human cancers.

Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR.

Abstract: Myotonic dystrophy is caused by an expanded CTG repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The expanded repeat triggers the nuclear retention of mutant DMPK transcripts, but the resulting underexpression of DMPK probably does not fully account for the severe phenotype. One proposed disease mechanism is that nuclear accumulation of expanded CUG repeats may interfere with nuclear function. Here we show by thermal melting and nuclease digestion studies that CUG repeats form highly stable hairpins. Furthermore, CUG repeats bind to the dsRNA-binding domain of PKR, the dsRNA-activated protein kinase. The threshold for binding to PKR is approximately 15 CUG repeats, and the affinity increases with longer repeat lengths. Finally, CUG repeats that are pathologically expanded can activate PKR in vitro. These results raise the possibility that the disease mechanism could be, in part, a gain of function by mutant DMPK transcripts that involves sequestration or activation of dsRNA binding proteins.