Abnormal expression of activating/inhibitory receptors leads to natural killer (NK) cells dysfunction in tumor. Here we show that programmed cell death protein 1 (PD-1), a well-known immune checkpoint of T cells, is highly expressed on peripheral and tumor-infiltrating NK cells from patients with digestive cancers including esophageal, liver, colorectal, gastric and biliary cancer. The increased PD-1 expression on NK cells indicates poorer survival in esophageal and liver cancers. Blocking PD-1/PD-L1 signaling markedly enhances cytokines production and degranulation and suppresses apoptosis of NK cells in vitro. PD-1/PD-L1 exerts inhibitory effect through repressing the activation of PI3K/AKT signaling in NK cells. More importantly, a PD-1 blocking antibody was found to significantly suppress the growth of xenografts in nude mice, and this inhibition of tumor growth was completely abrogated by NK depletion. These findings strongly suggested that PD-1 is an inhibitory regulator of NK cells in digestive cancers. PD-1 blockade might be an efficient strategy in NK cell-based tumor immunotherapy.

Background More than 200 articles have been published in the past 20 years on associations between genetic variants and risk of cervical cancer but the results have generally been inconsistent.Objective To provide a synopsis of the current understanding of the genetic architecture of the risk of cervical cancer by conducting a systematic review and meta-analysis.Search strategy We conducted a systematic literature search by a two-stage strategy using PubMed and other databases on or before 31 March 2012.Selection criteria Cross-sectional, case-control or cohort studies about the relationship between genetic variants and cervical cancer were included.Data collection and analysis Study outcomes were presented as odds ratios (ORs) with a 95% confidence interval.We did the meta-analysis for genetic variants which had at least three data sources and for which the significant associations were assessed using the Venice criteria.Main results A total of 5605 publications were screened, of which 286 were eligible. Meta-analysis was conducted for 58 variants in 25 genes or loci. Fourteen variants in 11 genes or loci could increase the risk of cervical cancer and five variants in three genes or loci could decrease the risk. The epidemiological evidence of the association was graded as strong for four variants in CTLA4 and HLA DQB1, moderate for five variants in IL-1B, IL-10, XRCC3 and HLA DQA1, and weak for 10 variants.Conclusions Many genetic variants were associated with the risk of cervical cancer as supported by the epidemiological evidence in this meta-analysis.

Growing evidence suggests that exposure to environmental contaminants contributes to the current diabetes epidemic. Inorganic arsenic (iAs), a drinking water and food contaminant, is one of the most widespread environmental diabetogens according to epidemiological studies. Several schemes have been proposed to explain the diabetogenic effects of iAs exposure; however, the exact mechanism remains unknown. We have shown that in vitro exposure to low concentrations of arsenite (iAs) or its trivalent methylated metabolites, methylarsonite (MAs) and dimethylarsinite (DMAs), inhibits glucose-stimulated insulin secretion (GSIS) from isolated pancreatic islets, with little effect on insulin transcription or total insulin content. The goal of this study was to determine if exposure to trivalent arsenicals impairs mitochondrial metabolism, which plays a key role in the regulation of GSIS in β cells. We used a Seahorse extracellular flux analyzer to measure oxygen consumption rate (OCR), a proxy for mitochondrial metabolism, in cultured INS-1 832/13 β cells exposed to iAs, MAs, or DMAs and stimulated with either glucose or pyruvate, a final product of glycolysis and a substrate for the Krebs cycle. We found that 24-h exposure to 2 μM iAs or 0.375-0.5 μM MAs inhibited OCR in both glucose- and pyruvate-stimulated β cells in a manner that closely paralleled GSIS inhibition. In contrast, 24-h exposure to DMAs (up to 2 µM) had no effects on either OCR or GSIS. These results suggest that iAs and MAs may impair GSIS in β cells by inhibiting mitochondrial metabolism, and that at least one target of these arsenicals is pyruvate decarboxylation or downstream reactions.

The Breit-Wheeler process which produces matter and anti-matter from photon collisions is investigated experimentally through the observation of 6085 exclusive electron-positron pairs in ultraperipheral Au+Au collisions at √ s N N = 200 GeV. The measurements reveal a large fourth-order

Nd:LuVO 4 crystal was used for the most compact and the simplest laser, i.e. the microchip construction. LD (laser diode)-pumped, continuous-wave output property was detected on several Nd:LuVO 4 microchips with different Nd 3+ doping level, crystal length, and transmittance of output surface. With a 0.5 at.%, 1.5 mm, T = 1% crystal, 9.7 W maximum output was achieved, corresponding an optical-optical conversion efficiency of 32.0%. With a 1 at.%, 1.5 mm, T = 1% crystal, 9.1 W maximum output was achieved at a pump power of 20.5 W, which had the highest optical-optical conversion efficiency of 44.4%.