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    • Avasimibe Thrombosis is a common complication in

    2018-11-13

    Thrombosis is a common complication in colorectal cancer (CRC) patients, but its molecular mechanisms remain elusive (Sorensen et al., 2000). A dynamic balance between pro-thrombotic TXA2 and anti-thrombotic PGI2 production is generally accepted to be a contributor to homeostasis of the Avasimibe (Cheng et al., 2002). Our data strongly suggested that elevated circulating TXA2 levels might be linked with CRC pathophysiology. We also observed that in FAP patients, the levels of circulating TXA2 were increased by 25.6-fold compared to healthy subjects, whereas circulating PGI2 levels did not change significantly. These findings implied that FAP patients might also be more prone to a risk of cardiovascular disease than healthy subjects. Additional clinical studies are needed to examine this possibility. Detection of malignant neoplasms at an early stage offers clinical advantages (Srivastava et al., 2001). However, the disturbing reality is that very few reliable biomarkers are available to predict the risk of CRC, one of the most common and deadly cancers. Considering the compliance issues associated with optical colonoscopy and the fecal occult blood test, a large amount of effort is being invested in developing reliable but minimally invasive methods for CRC risk screening. Blood is easily sampled by relatively non-invasive methods, and thus the introduction of a blood-based test could offer an advantage for enhancing patient compliance compared to other tests (deVos et al., 2009). Our findings suggest that circulating TXA2 levels might have a potential prognostic or predictive value for the early detection of CRC. Currently, a prospective collective of plasma samples from subjects in a CRC screening guideline-eligible population is underway to further confirm the clinical performance of this biomarker. Although our findings are promising for translating circulating TXA2-based biomarkers from basic research into clinic use, several issues still need to be addressed. For example, our sample size is small, and data collection is only limited in CRC. Thus more rigorous experiments should be conducted to determine biomarker cut-off optimization and calculation of ROC curves. Another issue is how to exclude the possibility of plasma TXA2 level confounded by platelet aggregation. To the end, venous blood was carefully collected with anticoagulant in this study. Although, in theory, the possibility that the plasma TXA2 levels are confounded by platelet aggregation is very low, measurement of urinary TXA2 metabolites such as 11-dehydro TXB2 might provide the best estimate of systemic TXA2 biosynthesis in vivo. Thus, we confirmed that urinary 11-dehydro TXB2 levels were significantly increased in CRC patients compared to healthy subjects (0.83±0.29 versus 5.83±4.22ng/mg creatinine, respectively, p<0.01) (Supplementary Fig. 3). In summary, this study established the importance of the TXA2 pathway in CRC pathophysiology, and laid the groundwork for introducing TXA2-targeted strategy to CRC prevention, early detection and even management. The following are the supplementary data related to this article.
    Acknowledgments We acknowledge the support from Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDKP30DK084567). We thank Ms. Cindy Nordyke for the technical assistance in clinical tissue processing and Ms. Nicki Brickman at The Hormel Institute, University of Minnesota for the assistance in submitting our manuscript.
    Introduction The WHO estimates that there were 8.6 million cases of tuberculosis and 1.3 million deaths due to tuberculosis (TB) in 2012 (World Health Organization (WHO): Global Tuberculosis Report (2013)). Infection with Mycobacterium tuberculosis (Mtb) has an unpredictable outcome. The proportion of individuals who truly remain infected after tuberculin skin test (TST) or interferon gamma release assay (IGRA) conversion is unknown (Mack et al., 2009). An estimated 5–10% of infected individuals will develop pulmonary TB, mostly within the first 2years following infection (Comstock et al., 1974; Vynnycky and Fine, 2000). At present it is impossible to predict who will progress to disease and who will remain latently infected.