Browsing by Subject "tissue transglutaminase"

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    Latitude and Celiac Disease Prevalence: A Meta-Analysis and Meta-Regression
    (Elsevier, 2020) Celdir, Melis G.; Jansson-Knodell, Claire L.; Hujoel, Isabel A.; Prokop, Larry J.; Wang, Zhen; Murad, M. Hassan; Murray, Joseph A.; Medicine, School of Medicine
    Background & Aims The latitudinal gradient effect is described for several autoimmune diseases including celiac disease in the United States. However, the association between latitude and global celiac disease prevalence is unknown. We aimed to explore the association between latitude and serology-based celiac disease prevalence through meta-analysis. Methods We searched MEDLINE, Embase, Cochrane, and Scopus databases from their beginning through June 29, 2018, to identify screening studies that targeted a general population sample, used serology-based screening tests, and provided a clear location from which we could assign a latitude. Studies were excluded if sampling was based on symptoms, risk factors, or referral. Study selection and data extraction were performed by independent reviewers. The association measures between latitude and prevalence of serology-based celiac disease were evaluated with random-effects meta-analyses and meta-regression. Results Of the identified 4667 unique citations, 128 studies were included, with 155 prevalence estimates representing 40 countries. Celiac disease was more prevalent at the higher latitudes of 51° to 60° (relative risk [RR], 1.62; 95% CI, 1.09–2.38) and 61° to 70° (RR, 2.30; 95% CI, 1.36–3.89) compared with the 41° to 50° reference level. No statistically significant difference was observed at lower latitudes. When latitude was treated as continuous, we found a statistically significant association between CD prevalence and latitude overall in the world (RR, 1.03, 95% CI, 1.01–1.05) and a subregional analysis of Europe (RR, 1.05; 95% CI, 1.02–1.07) and North America (RR, 1.1; 95% CI, 1.0–1.2). Conclusions In this comprehensive review of screening studies, we found that a higher latitude was associated with greater serology-based celiac disease prevalence.
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    Small Molecules Target the Interaction between Tissue Transglutaminase and Fibronectin
    (American Association for Cancer Research, 2019-06-01) Sima, Livia Elena; Yakubov, Bakhtiyor; Zhang, Sheng; Condello, Salvatore; Grigorescu, Arabela A.; Nwani, Nkechiyere G.; Chen, Lan; Schiltz, Gary E.; Arvanitis, Constandina; Zhang, Zhong-Yin; Matei, Daniela; Medicine, School of Medicine
    Tissue transglutaminase (TG2) is a multi-functional protein, with enzymatic, GTP-ase and scaffold properties. TG2 interacts with fibronectin (FN) through its N-terminus domain, stabilizing integrin complexes, which regulate cell adhesion to the matrix. Through this mechanism, TG2 participates in key steps involved in metastasis in ovarian and other cancers. High throughput screening identified several small molecule inhibitors (SMIs) for the TG2/FN complex. Rational medicinal chemistry optimization of the hit compound (TG53) led to second generation analogues (MT1–6). ELISA demonstrated that these analogues blocked TG2/FN interaction and bio-layer interferometry (BLI) showed that the SMIs bound to TG2. The compounds also potently inhibited cancer cell adhesion to FN and decreased outside-in signaling mediated through the focal adhesion kinase (FAK). Blockade of TG2/FN interaction by the small molecules caused membrane ruffling, delaying the formation of stable focal contacts and mature adhesions points and disrupted organization of the actin cytoskeleton. In an in vivo model measuring intraperitoneal (ip) dissemination, MT4 and MT6 inhibited the adhesion of ovarian cancer (OC) cells to the peritoneum. Pre-treatment with MT4 also sensitized OC cells to paclitaxel. The data support continued optimization of the new class of SMIs that block the TG2/FN complex at the interface between cancer cells and the tumor niche.
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    Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression.
    (AACR, 2015-10-01) Lee, Jiyoon; Condello, Salvatore; Yakubov, Bakhtiyor; Emerson, Robert; Caperell-Grant, Andrea; Hitomi, Kiyotaka; Xie, Jingwu; Matei, Daniela; Department of Biochemistry and Molecular Biology, IU School of Medicine
    Purpose: Aggressive pancreatic cancer is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. The objective of the study was to determine the functions of tissue transglutaminase (TG2), a Ca2+-dependent enzyme which crosslinks proteins through transamidation and is abundantly expressed by pancreatic cancer cells in the pancreatic stroma. Experimental Design: Orthotopic pancreatic xenografts and co-culture systems tested the mechanisms by which the enzyme modulates tumor-stroma interactions. Results: We show that TG2 secreted by cancer cells effectively molds the stroma by crosslinking collagen, which in turn activates fibroblasts and stimulates their proliferation. The stiff fibrotic stromal reaction conveys mechanical cues to cancer cells leading to activation of the YAP/TAZ transcription factors, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells led to decreased size of pancreatic xenografts. Conclusions: Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the crosstalk between cancer cells and stroma fundamentally impacting tumor growth. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression.