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Background: The published literature contains conflicting results regarding the impact of the glutathione S-transferase T1 (GSTT1) null genotype on the susceptibility to inflammatory bowel disease. Therefore, we conducted a meta-analysis of observational studies to assess the association. Methods: We searched four online databases for eligible studies. The odds ratio (OR) with 95% CI was used to assess the gene-disease association. We also performed subgroup analyses by type of inflammatory bowel disease and ethnicity. Results: There were 16 individual studies from 11 publications included in the analysis. There were 3366 cases with inflammatory bowel disease and 6013 controls. The meta-analysis of all 16 studies showed the GSTT1 null genotype was associated with increased susceptibility to inflammatory bowel disease (OR = 1.98, 95%CI 1.39-2.84, P < 0.001). The subgroup analysis by ethnicity further identified an association between the GSTT1 null genotype and inflammatory bowel disease in Caucasians, Asians, and Africans. The GSTT1 null genotype was associated with both ulcerative colitis (OR = 1.96, P = 0.004) and Crohn's disease (OR = 2.01, P = 0.022). The GSTT1 null genotype was still significantly associated with ulcerative colitis (OR = 1.63, P < 0.0001) and Crohn's disease (OR = 1.40, P = 0.023) after adjusting for study heterogeneity. Conclusion: The GSTT1 null genotype is significantly associated with an increased susceptibility to inflammatory bowel disease and is a risk factor for both ulcerative colitis and Crohn's disease. [ABSTRACT FROM AUTHOR]

Background: The published literature contains conflicting results regarding the impact of the glutathione S-transferase T1 (GSTT1) null genotype on the susceptibility to inflammatory bowel disease. Therefore, we conducted a meta-analysis of observational studies to assess the association. Methods: We searched four online databases for eligible studies. The odds ratio (OR) with 95% CI was used to assess the gene-disease association. We also performed subgroup analyses by type of inflammatory bowel disease and ethnicity. Results: There were 16 individual studies from 11 publications included in the analysis. There were 3366 cases with inflammatory bowel disease and 6013 controls. The meta-analysis of all 16 studies showed the GSTT1 null genotype was associated with increased susceptibility to inflammatory bowel disease (OR = 1.98, 95%CI 1.39-2.84, P < 0.001). The subgroup analysis by ethnicity further identified an association between the GSTT1 null genotype and inflammatory bowel disease in Caucasians, Asians, and Africans. The GSTT1 null genotype was associated with both ulcerative colitis (OR = 1.96, P = 0.004) and Crohn's disease (OR = 2.01, P = 0.022). The GSTT1 null genotype was still significantly associated with ulcerative colitis (OR = 1.63, P < 0.0001) and Crohn's disease (OR = 1.40, P = 0.023) after adjusting for study heterogeneity. Conclusion: The GSTT1 null genotype is significantly associated with an increased susceptibility to inflammatory bowel disease and is a risk factor for both ulcerative colitis and Crohn's disease. [ABSTRACT FROM AUTHOR]

BRAFV600E-mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis. The combination of anti-BRAF/anti-EGFR (encorafenib/cetuximab) treatment for patients with BRAFV600E-mutant mCRC improves clinical benefits; unfortunately, inevitable acquired resistance limits the treatment outcome, and the mechanism has not been validated. Here, we discovered that monoacylglycerol O-acyltransferase 3--mediated (MOGAT3-mediated) diacylglycerol (DAG) accumulation contributed to acquired resistance to encorafenib/cetuximab by dissecting a BRAFV600E-mutant mCRC patient--derived xenograft (PDX) model exposed to encorafenib/cetuximab administration. Mechanistically, the upregulated MOGAT3 promoted DAG synthesis and reduced fatty acid oxidation--promoting DAG accumulation and activated PKCα/CRAF/MEK/ERK signaling, driving acquired resistance. Resistance-induced hypoxia promoted MOGAT3 transcriptional elevation; simultaneously, MOGAT3-mediated DAG accumulation increased HIF1A expression at the translation level through PKCα/CRAF/eIF4E activation, strengthening the resistance status. Intriguingly, reducing intratumoral DAG with fenofibrate or PF-06471553 restored the antitumor efficacy of encorafenib/cetuximab in resistant BRAFV600E-mutant mCRC, which interrupted PKCα/CRAF/MEK/ERK signaling. These findings reveal the critical role of the metabolite DAG as a modulator of encorafenib/cetuximab efficacy in BRAFV600E-mutant mCRC, suggesting that fenofibrate might prove beneficial for resistant BRAFV600E-mutant mCRC patients. [ABSTRACT FROM AUTHOR]

The intestinal microbiota regulates mammalian lipid absorption, metabolism, and storage. We report that the microbiota reprograms intestinal lipid metabolism in mice by repressing the expression of long noncoding RNA (lncRNA) Snhg9 (small nucleolar RNA host gene 9) in small intestinal epithelial cells. Snhg9 suppressed the activity of peroxisome proliferator–activated receptor γ (PPARγ)—a central regulator of lipid metabolism—by dissociating the PPARγ inhibitor sirtuin 1 from cell cycle and apoptosis protein 2 (CCAR2). Forced expression of Snhg9 in the intestinal epithelium of conventional mice impaired lipid absorption, reduced body fat, and protected against diet-induced obesity. The microbiota repressed Snhg9 expression through an immune relay encompassing myeloid cells and group 3 innate lymphoid cells. Our findings thus identify an unanticipated role for a lncRNA in microbial control of host metabolism. [ABSTRACT FROM AUTHOR]

Aging is a complex process that has been shown to be linked to accumulation of DNA damage. Telomere shortening represents a cell-intrinsic mechanism leading to DNA damage accumulation and activation of DNA damage checkpoints in aging cells. Activation of DNA damage checkpoints in response to telomere dysfunction results in induction of cellular senescence—a permanent cell cycle arrest. Senescence represents a tumor suppressor mechanism protecting cells from evolution of genomic instability and transformation. As a drawback, telomere shortening may also limit tissue renewal and regenerative capacity of tissues in response to aging and chronic disease. In aged organs, telomere shortening may also increase the cancer risk by initiation of chromosomal instability, loss of proliferative competition of aging stem cells, and selection of aberrant growing clones. Consequently, aged individuals are more susceptible and vulnerable to various diseases and show an increased cancer risk. Recently, proteins were discovered, which are induced by telomere dysfunction and DNA damage. It was shown that these proteins represent new biomarkers of human aging and disease. Here, we review the scientific background and experimental data on these newly discovered biomarkers. [ABSTRACT FROM AUTHOR]

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1α, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc-/-). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc-/-mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to γ-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease. [ABSTRACT FROM AUTHOR]

Purpose 5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer, but many patients still suffer from treatment failure due to 5-Fu resistance. Emerging observations revealed the important role of chemokine (C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer. This study is designed to reveal the important role of CXCL-13 in causing colorectal cancer resistance to 5-Fu. Materials and Methods CXCL-13 levels of patient's serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell Counting Kit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells. Results In this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and nonresistant cells. Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu--resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome. The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibody overcame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance, which can be saved by added recombination CXCL-13. Conclusion These results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu--resistant colorectal cancer in prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Recent studies have identified a set of serological markers for telomere dysfunction and DNA damage. The relevance of these serological markers in type 2 diabetes remains elusive. We investigated the association of serological markers (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase) with leukocyte telomere length, a functional variant of uncoupling protein-2 (UCP2), and susceptibility of type 2 diabetes. RESEARCH DESIGN AND METHODS--A total of 930 patients and 867 control subjects were recruited to examine the association between leukocyte telomere length, UCP2 variant (-886G>A), recently identified serological markers, and type 2 diabetes. Telomere length was determined by a quantitative real-time PCR-based assay. EF-1α, stathmin, and C-reactive proteins were measured by enzyme-linked immunosorbent assays. N-acetyl-glucosaminidase was measured by an enzyme activity assay. The VCP2 variant was determined by PCR and restriction enzyme digestion. RESULTS--The average telomere length of type 2 diabetic patients was significantly shorter than that of control subjects. Serological N-acetyl-glucosaminidase correlates with both age and telomere length and was significantly higher in patients than in control subjects. Neither EF-1α nor stathmin showed significant difference between patients and control subjects. The UCP2-886G>A variant correlated with type 2 diabetes status but did not correlate with telomere length or the serological markers. Multivariate analysis showed that higher serological N-acetyl-glucosaminidase, shorter telomeres, and the UCP2-886G>A variant are independent risk factors for type 2 diabetes. CONCLUSIONS--Serological N-acetyl-glucosaminidase, telomere length, and the UCP2-886G>A variant are independent risk factors for type 2 diabetes. Serological N-acetyl-glucosaminidase correlates with telomere length but not with the UCP2-886G>A variant. [ABSTRACT FROM AUTHOR]

The article presents information about the solitary extramedullary plasmacytoma (SEP) of anorectum. It is distinguished by monoclonal proliferation of the plasma cell and occurs from the region of head and neck, especially in the submucosal tissue of the upper respiratory tract. The most common therapeutic means for SEP are operation and radiation, which are usually different in other diseases.