Impacts of yeast metabolic network structure on enzyme evolution

Vitkup et al. recently presented an analysis of the influence of yeast metabolic network structure on enzyme evolution; different conclusions are reached when modularity is properly accounted for

Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis

Contribution of the -160C/A polymorphism in the E-cadherin promoter to cancer risk: a meta-analysis of 47 case-control studies.

BACKGROUND: The -160C/A polymorphism (rs16260) of E-cadherin, a tumor repressor gene, has been shown to be a tumor susceptibility allele for various types of cancers. Because the significance of this polymorphism to cancer risk has been recognized, there are increasing studies investigating -160C/A in different types of cancers and ethnic populations. However, there is still uncertainty about the level of risk for a variety of cancers. METHODS: To resolve the controversial question raised by these studies as of March 2012 and provide more statistical power for detecting the significance of -160C/A, we performed a meta-analysis of 47 case-control studies in 16 types of cancers (18,194 cases and 20,207 controls). A meta-regression model and subgroup analysis were employed to identify the source of heterogeneity. Publication bias was evaluated, and sensitivity analysis and cumulative evidence assessment were also performed. RESULTS: Using fixed- and random-effects models, the -160AA homozygote was more susceptible to urothelial cancer compared with the -160CA heterozygote. Additionally, the -160A allele is an ethnicity-dependent risk factor for prostate and colorectal cancers. Carriers of the -160A allele in Asians and Europeans were more susceptible to prostate cancer, whereas their North American counterparts seemed tolerant. The -160AA homozygote plays a protective role for Europeans who develop colorectal cancer. The stability of these observations was confirmed by a one-way sensitivity analysis. However, the cumulative evidence for all cancer types was considered 'weak' using the Venice guidelines. CONCLUSIONS: A meta-analysis indicated that the -160A allele of E-cadherin provides a higher risk for the development of prostate and urothelial cancers and a protective role for colorectal cancer in an ethnicity-dependent manner

Synergetic cooperation of microRNAs with transcription factors in iPS cell generation.

Induced pluripotent stem (iPS) cells were first generated by forced expression of transcription factors (TFs) in fibroblasts. Recently, iPS cells have been generated more rapidly and efficiently using miRNAs with or without other transcription factors. However, the specific and collaborative roles of miRNAs and transcription factors in pluripotency acquisition and maintenance remain to be further investigated. Here, based on the miRNA profiling in mouse embryonic fibroblasts (MEFs), MEFs infected with Oct3/4, Sox2, Klf4 and c-Myc (OSKM) for 1, 2, 4, or 8 day, two iPS cell lines and ES cells, representing iPS activation and maintenance steps, we found that two unique miRNA sets are responsible for different steps of iPS generation, and the miRNA expression profiles of iPS cells are very similar to that of ES cells. Furthermore, we searched for transcription factors binding sites at the promoter regions of up-regulated miRNAs, and found that up-regulated miRNAs such as the miR-429-200 and miR-17 clusters are directly activated by exogenous TFs. The GO and pathway enrichment for candidate target gene sets of miRNAs or OSKM provided a clear picture of division and collaboration between miRNAs and OSKM during completion of the iPS process. Compared with the pathways regulated by OSKM, we found that miRNAs play critical roles in regulating iPS-specific pathways, such as the adherens junction and Wnt signaling pathways. Furthermore, we blocked miRNA expression using Dicer knockdown, and found that the level of miRNAs was decreased following this treatment, and the efficiency of iPS generation was significantly repressed. By combining high-throughput analysis, biostatistical analysis and functional experiments, this study provides new ideas for investigating the important roles of miRNAs, the mechanisms of miRNAs and related signaling pathways, and the potential for many more applications of miRNAs in somatic cell reprogramming

The relationship between thiamin, folic acid and cognitive function in a rat model of uremia

End-stage renal disease is a worldwide health burden, but the pathogenesis of uremia-associated cognitive impairment (CI) is poorly recognized. We hypothesized that uremia brings about deficiency of thiamin and folic acid and causes CI by inducing oxidative stress. Therefore, 24 Sprague-Dawley rats were randomly divided into two groups: a 5/6 nephrectomy group (n = 12) and a sham-operated group (n = 12). The Morris water maze was used to assess the cognitive function eight weeks post-surgery, and serum levels of thiamin, folic acid and homocysteine were detected subsequently. Brain and kidney tissues were collected for pathological examination and 8-Hydroxy-2’-deoxyguanosine (8-OHdG) immunochemistry staining. Results showed that the escape latency on training days 1-2 was longer, and the time in quadrant IV on experimental day 6 was significantly shorter in 5/6 nephrectomy group. Meanwhile, the uremic rats showed decreased thiamin, folic acid and increased homocysteine. We also found the time in quadrant IV was positively correlated with thiamin and folic acid level, while negatively correlated with the blood urea nitrogen and 8-OHdG positive cell proportion. Furthermore, in 5/6 nephrectomy group, the hippocampal neuron count was significantly reduced, and a greater proportion of 8-OHdG positive cells were detected. Pretreating LPS-stimulated rat microglial cells with thiamin or folic acid in vitro alleviated the inflammatory impairment in terms of cell viability and oxidative stress. In summary, we applied a uremic rat model and proved that uremia causes serum thiamin and folic acid deficiency, homocysteine elevation, along with neuron reduction and severe oxidative stress in hippocampus, finally leading to CI

Heterogeneity test for studies of each genotype in different cancer types (as of March 2012) with Cochrane’s <i>Q</i>-test and the quantity <i>I²</i>.

#<p>Stratified by ethnicity, including Asian, European, and others (North American and African).</p><p>⋇20;Stratified by controls, including benign prostatic hyperplasia (BPH), BPH or visitors or requesting vasectomy (BPH and others), benign urological patients matched, chronic atrophic gastritis (CAG), free of colorectal cancer (free of CRC), free of cancer, healthy, healthy and BPH, healthy and free of cancer, healthy matched, kindreds, and normal peritumoral tissues.</p

Harbord test of each genotype in different cancer types (as of March 2012) with coefficient and standard error.

<p>Harbord test of each genotype in different cancer types (as of March 2012) with coefficient and standard error.</p

Estimates of odds ratios and the corresponding 95% confidence intervals for <i>AA</i> and <i>CA</i> genotype and <i>A</i> allele carriers versus the <i>CC</i> genotype for 16 types of cancers analyzed by fixed- or random- effects models divided by cancer type and ethnicity as of March 2012.

<p>Statistically significant, with <i>P</i><0.05 and a 95% confidence interval (CI) that does not include 1.0.</p>†<p>OR, odds ratio.</p>#<p>Stratified by ethnicity, including Asian, European, and others (North American and African).</p><p>⋇20;Stratified by controls, including benign prostatic hyperplasia (BPH), BPH or visitors or requesting vasectomy (BPH and others), benign urological patients matched, chronic atrophic gastritis (CAG), free of colorectal cancer (free of CRC), free of cancer, healthy, healthy and BPH, healthy and free of cancer, healthy matched, and normal peritumoral tissues.</p

One-way sensitivity analysis for the stability of observations in the meta-analysis.

<p>The pooled odds ratios (ORs) and 95% confidence intervals (CIs) of the <i>-160A</i> allele carriers are evaluated by comparing to the <i>CC</i> genotype, omitting each dataset in each type of cancer (as of March 2012). The pooled ORs are calculated with a random-effects model. The numbers on the <i>x-</i>axis refer to the studies extracted. 22a, Sweden; 22b, Czech Republic; 24a, Familial; 24b, Sporadic; 26a, Phase 1; 26b, Phase 2; 41a, Beijing; 41b, Linqu; 51a, Canada; 51b, Germany; 51c, Portugal; total, no dataset omitted.</p