BackgroundThe pathogenesis of obesity is reportedly related to variations in the fat mass and an obesity-associated gene (FTO); however, as the number of reports increases, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each ethnic group. In addition, some reports have claimed ethnic-specific associations with alternative SNPs, and to that end there has been a degree of confusion.MethodsWe searched PubMed, MEDLINE, Web of Science, EMBASE, and BIOSIS Preview to identify studies investigating the associations between the five polymorphisms and obesity risk. Individual study odds ratios (OR) and their 95% confidence intervals (CI) were estimated using per-allele comparison. Summary ORs were estimated using a random effects model.ResultsWe identified 59 eligible case-control studies in 27 articles, investigating 41,734 obesity cases and 69,837 healthy controls. Significant associations were detected between obesity risk and the five polymorphisms: rs9939609 (OR: 1.31, 95% CI: 1.26 to 1.36), rs1421085 (OR: 1.43, 95% CI: 1.33 to 1.53), rs8050136 (OR: 1.25, 95% CI: 1.13 to 1.38), rs17817449 (OR: 1.54, 95% CI: 1.41 to 1.68), and rs1121980 (OR: 1.34, 95% CI: 1.10 to 1.62). Begg's and Egger's tests provided no evidence of publication bias for the polymorphisms except rs1121980. There is evidence of higher heterogeneity, with I2 test values ranging from 38.1% to 84.5%.ConclusionsThis meta-analysis suggests that FTO may represent a low-penetrance susceptible gene for obesity risk. Individual studies with large sample size are needed to further evaluate the associations between the polymorphisms and obesity risk in various ethnic populations.

Our purpose was to investigate the role of SOX9, a novel downstream molecule of beta-catenin, in colorectal cancer. Expression of SOX9 and beta-catenin was detected by immunostaining, quantitative real-time reverse transcription-polymerase chain reaction (Q-PCR), and Western blot in colorectal cancer. The correlation between SOX9 or beta-catenin expression and clinicopathologic parameters was also analyzed. Immunostaining, Q-PCR, and Western blot consistently confirmed SOX9 up-regulation in colorectal cancer compared with normal mucosa (P < .05). Immunostaining showed more SOX9+ cells in the lower zone of colonic crypts than in the upper zone (P < .05). Cancers with strong SOX9 immunostaining were significantly associated with a lower 5-year overall survival (40% [17/43] vs low expression, 69% [66/95]; P < .01). The Cox proportional hazards model showed that strong SOX9 expression was an independent adverse prognosticator in colorectal cancer (P < .05). The detection of SOX9 expression might contribute to predicting clinical outcomes for patients with colorectal cancer.

Insulin-like growth factor binding protein-7 (IGFBP7) is a gene identified as being low expressed in colorectal adenocarcinoma (CRC) cell lines. In the current study, we investigated the function of IGFBP7 in CRC by transfection studies. We found that IGFBP7 could inhibit cell growth, decrease soft agar colony formation activity and induce apoptosis in RKO and SW620 cells. Correlation analysis between the expression of IGFBP7 in CRC tissue and the prognosis in 218 patients showed that high expression of IGFBP7 was associated with favorable prognosis. Based on above results, we conclude that IGFBP7 plays a potential tumor suppressor role in colorectal carcinogenesis.

The immune contexture, a composition of the tumor microenvironment, plays multiple important roles in cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT), and hence critically influences tumor initiation, progression and patient outcome. Tumor-associated macrophages (TAMs) are abundant in immune contexture, however their roles in CSC, EMT and prognosis of colorectal cancer (CRC) have not been elucidated. In 419 colorectal carcinomas, immune cell types (CD68 macrophages, CD3, CD4 or CD8 T lymphocytes, CD20 B lymphocytes), EMT markers (E-cadherin and Snail) as well as the stem cell marker (CD44v6) were detected in tumor center (TC) and tumor invasive front (TF) respectively by immunohistochemistry. Tumor buds, that represent EMT phenotype, were also counted. It was found CD68 macrophages were the most infiltrating immune cells in CRC. By correlation analysis, more CD68 macrophages were associated with more CD44v6 expression (p < 0.001), lower Snail expression (p = 0.08) and fewer tumor buds (p < 0.001). More CD68 macrophages were significantly related to more CD3 T lymphocytes (p = 0.002), CD8 T lymphocytes (p < 0.001) and CD20 B lymphocytes counts (p = 0.004). Strong CD68 macrophages infiltration also predicted long term overall survival. CRC patients with more tumor buds had worse survival. However, strong CD68 macrophages infiltration could reverse the unfavorable results since patients with more tumor buds but increasing CD68 macrophages infiltration had the favorable outcome, similar to lower tumor buds groups. This study provided direct morphological evidence that tumor-associated macrophages in the invasive front play critical roles in fighting with the unfavorable results of tumor buds, thus resulting favorable outcomes for CRC patients.

Recently, many new loci associated with type 2 diabetes have been uncovered by genetic association studies and genome-wide association studies. As more reports are made, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each major racial group. In addition, some reports have claimed ethnic-specific associations with alternative single-nucleotide polymorphisms (SNPs), and to that end there has been a degree of confusion. We conducted a meta-analysis using an additive genetic model. Eight polymorphisms in 155 studies with 121174 subjects (53385 cases and 67789 controls) were addressed in this meta-analysis. Significant associations were found between type 2 diabetes and rs7903146, rs12255372, rs11196205, rs7901695, rs7895340 and rs4506565, with summary odds ratios (ORs) (95% confidence interval) of 1.39 (1.34-1.45), 1.33 (1.27-1.40), 1.20 (1.14-1.26), 1.32 (1.25-1.39), 1.21 (1.13-1.29) and 1.39 (1.29-1.49), respectively. In addition, no significant associations were found between the two polymorphisms (rs290487 and rs11196218) and type 2 diabetes. The summary ORs for the six statistically significant associations (P < 0.05) were further evaluated by estimating the false-positive report probability, with results indicating that all of the six significant associations were considered noteworthy, and may plausibly be true associations. Significant associations were found between the six polymorphisms (rs7903146, rs12255372, rs11196205, rs7901695, rs7895340 and rs4506565) in the TCF7L2 gene and type 2 diabetes risk, and the other two polymorphisms (rs11196218 and rs290487) were not found to be significantly associated with type 2 diabetes. Subgroups analyses show that significant associations are not found between the six SNPs (rs7903146, rs12255372, rs11196205, rs7901695, rs7895340, and rs4506565) and the type 2 diabetes in some ethnic populations.

Colorectal carcinoma with a micropapillary component (MP) is an exceptionally aggressive variant, but has never been investigated in terms of survival analysis. Thirty colorectal carcinomas with a MP were identified from a series of 221 colorectal carcinomas. Carcinomas with and without a MP were compared in terms of histologic and immunohistochemical markers. Colorectal carcinoma with a MP seemed to have a lower differentiation status, increased tumor budding, more frequent lymphovascular and perineural invasion, more frequent lymph node metastasis, higher tumor node metastasis (TNM) stage, and less nuclear beta-catenin staining (P<0.05). Further analysis revealed that the presence of a MP predicted more frequent lymph node metastasis in T1 and T2 stages but not in T3 and T4 stages. Five-year survival rates for patients with a MP and those without were 50% and 73%, respectively. Furthermore, in TNM stages I and II, but not in TNM stages III and IV, a MP was an unfavorable prognostic variable. A MP was demonstrated to be an independent unfavorable prognostic indicator in TNM stages I and II by the multivariate Cox proportional hazard model. Colorectal carcinoma with a MP should be distinguished from colorectal carcinoma of conventional histologic type.

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.

NAD(P)H dehydrogenase-like (NDH) complex NDH-1L of cyanobacteria plays a crucial role in cyclic electron flow (CEF) around photosystem I and respiration processes. NDH-1L couples the electron transport from ferredoxin (Fd) to plastoquinone (PQ) and proton pumping from cytoplasm to the lumen that drives the ATP production. NDH-1L-dependent CEF increases the ATP/NADPH ratio, and is therefore pivotal for oxygenic phototrophs to function under stress. Here we report two structures of NDH-1L from Thermosynechococcus elongatus BP-1, in complex with one Fd and an endogenous PQ, respectively. Our structures represent the complete model of cyanobacterial NDH-1L, revealing the binding manner of NDH-1L with Fd and PQ, as well as the structural elements crucial for proper functioning of the NDH-1L complex. Together, our data provides deep insights into the electron transport from Fd to PQ, and its coupling with proton translocation in NDH-1L.