We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totalling 21,096 cases and 19,555 controls. We identified three novel CRC risk loci at 6p21 (rs1321311, near CDKN1A; P=1.14×10−10), 11q13.4 (rs3824999, intronic to POLD3; P=3.65×10−10) and Xp22.2 (rs5934683, near SHROOM2; P=7.30×10−10) This brings to 20 the number of independent loci associated with CRC risk, and provides further insight into the genetic architecture of inherited susceptibility to CRC.

Mesenchymal stem cells (MSCs) represent an attractive source for stem cell-based regenerative therapy, but they are vulnerable to oxidative stress-induced premature senescence in pathological conditions. We previously reported antioxidant and antiarthritic effects of melatonin on MSCs against proinflammatory cytokines. In this study, we hypothesized that melatonin could protect MSCs from premature senescence induced by hydrogen peroxide (H2O2) via the silent information regulator type 1 (SIRT1)-dependent pathway. In response to H2O2 at a sublethal concentration of 200 μM, human bone marrow-derived MSCs (BM-MSCs) underwent growth arrest and cellular senescence. Treatment with melatonin before H2O2 exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H2O2 exposure successfully reversed the senescent phenotypes of BM-MSCs in a dose-dependent manner. This result was made evident by improved cell proliferation, decreased senescence-associated β-galactosidase activity, and the improved entry of proliferating cells into the S phase. In addition, treatment with 100 μM melatonin restored the osteogenic differentiation potential of BM-MSCs that was inhibited by H2O2-induced premature senescence. We also found that melatonin attenuated H2O2-stimulated phosphorylation of p38 mitogen-activated protein kinase, decreased expression of the senescence-associated protein p16INK4α, and increased SIRT1. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked melatonin-mediated anti-senescence effects. Inhibition of SIRT1 by sirtinol counteracted the protective effects of melatonin, suggesting that melatonin reversed senescence in cells through the SIRT1-dependent pathway. Together, these findings lay new ground for understanding oxidative stress-induced premature senescence and open perspectives for therapeutic applications of melatonin in stem cell-based regenerative medicine.

BackgroundAlthough several previous studies have assessed the association of fine particulate matter (PM2.5) exposure during pregnancy with preterm birth, the results have been inconsistent and remain controversial. This meta-analysis aims to quantitatively summarize the association between maternal PM2.5 exposure and preterm birth and to further explore the sources of heterogeneity in findings on this association.MethodsWe searched for all studies published before December 2014 on the association between PM2.5 exposure during pregnancy and preterm birth in the MEDLINE, PUBMED and Embase databases as well as the China Biological Medicine and Wanfang databases. A pooled OR for preterm birth in association with each 10 μg/m3 increase in PM2.5 exposure was calculated by a random-effects model (for studies with significant heterogeneity) or a fixed-effects model (for studies without significant heterogeneity).ResultsA total of 18 studies were included in this analysis. The pooled OR for PM2.5 exposure (per 10 μg/m3 increment) during the entire pregnancy on preterm birth was 1.13 (95 % CI = 1.03–1.24) in 13 studies with a significant heterogeneity (Q = 80.51, p < 0.001). The pooled ORs of PM2.5 exposure in the first, second and third trimester were 1.08 (95 % CI = 0.92–1.26), 1.09 (95 % CI = 0.82–1.44) and 1.08 (95 % CI = 0.99–1.17), respectively. The corresponding meta-estimates of PM2.5 effects in studies assessing PM2.5 exposure at individual, semi-individual and regional level were 1.11 (95 % CI = 0.89–1.37), 1.14 (95 % CI = 0.97–1.35) and 1.07 (95 % CI = 0.94–1.23). In addition, significant meta-estimates of PM2.5 exposures were found in retrospective studies (OR = 1.10, 95 % CI = 1.01–1.21), prospective studies (OR = 1.42, 95 % CI = 1.08–1.85), and studies conducted in the USA (OR = 1.16, 95 % CI = 1.05–1.29).ConclusionsMaternal PM2.5 exposure during pregnancy may increase the risk of preterm birth,but significant heterogeneity was found between studies. Exposure assessment methods, study designs and study settings might be important sources of heterogeneity, and should be taken into account in future meta-analyses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12884-015-0738-2) contains supplementary material, which is available to authorized users.

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Purpose Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential roles of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated. Experimental Design Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway. Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences of the identified mutations were validated in cultured cells. Results We analyzed 32 patients with acquired cetuximab resistance in a development cohort. Of them, 7 (22%) carried five novel PIK3CA mutations, whereas 8 (25%) carried previously reported KRAS mutations. Functional studies showed that novel PIK3CA mutations (all in exon 19; p.K944N, p.F930S, p.V955G, p.V955I, and p.K966E) promote cell viability in the presence of cetuximab. Only one novel PIK3CA mutation (p.K944N) was verified in one of the 27 patients with acquired resistance in a validation cohort, simultaneous KRAS and PIK3CA hotspot mutations were detected in 2 patients. Among the above 59 acquired resistance patients, those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation. Conclusions The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC.

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Chemokine (C-C motif) ligand 2 (CCL2) has been shown to play an important role in the regulation of tumor cell growth, metastasis and host immune response. CCL2 preferentially binds to the C-C chemokine receptor type 2 (CCR2), which is expressed in various tissues. However, the role of the CCL2/CCR2 axis in hepatocellular carcinoma (HCC) invasion and its molecular mechanisms remain unclear. The aim of this study was to elucidate this issue. The human HCC cell line MHCC-97H was treated with CCL2. Cyclopamine, a smoothened (SMO) antagonist, was used to inhibit SMO activity. CCR2 siRNA and Gli-1 siRNA were used to inhibit CCR2 and Gli-1 expression respectively. The effect of CCL2 and Hedgehog (Hh) signaling on cancer cell epithelial-mesenchymal transition (EMT) and invasion was evaluated by quantitative real-time PCR analysis, western blotting and Transwell invasion assay. Our results revealed that CCL2 induced HCC cell invasion and EMT. This effect was accompanied by the activation of Hh signaling, the upregulation of Snail and vimentin and the reduction of E-cadherin. Notably, prior silencing of CCR2 with siRNA abolished CCL2-induced Hh signaling activation, Snail and vimentin upregulation, E-cadherin reduction, as well as HCC cell invasion and EMT. Furthermore, pretreatment with cyclopamine or predepletion of Gli-1 by siRNA also eliminated the changes of Snail, vimentin and E-cadherin, and HCC invasion and EMT caused by CCL2. Collectively, our results revealed that the link between the CCL2/CCR2 axis and the Hh pathway plays an important role in HCC progression. Therefore, the CCL2/CCR2 axis may represent a promising therapeutic target to prevent HCC progression.

A design and optimization method based on vectorial angular spectrum theory is proposed in this paper for the vectorial design of a super-oscillatory lens (SOL), so that the radially polarized vector beam can be tightly focused. The structure of a SOL is optimized using genetic algorithm and the computational process is accelerated using fast Hankel transform algorithm. The optimized results agree well with what is obtained using the vectorial Rayleigh-Sommerfeld diffraction integral. For an oil immersed SOL, a subwavelength focal spot of about 0.25 illumination wavelength without any significant side lobe can be created at a distance of 184.86 μm away from a large SOL with a diameter of 1mm. The proposed vectorial design method can be used to efficiently design a SOL of arbitrary size illuminated by various vector beams, with the subwavelength hotspot located in a post-evanescent observation plane.