No abstract

Coronary artery disease (CAD) causes more than 700,000 deaths each year in China. Previous genome-wide association studies (GWAS) in populations of European ancestry identified several genetic loci for CAD, but no such study has yet been reported in the Chinese population. Here we report a three-stage GWAS in the Chinese Han population. We identified a new association between rs6903956 in a putative gene denoted as C6orf105 on chromosome 6p24.1 and CAD (P = 5.00 × 10⁻³, stage 2 validation; P = 3.00 × 10⁻³, P = 1.19 × 10⁻⁸ and P = 4.00 × 10⁻³ in three independent stage 3 replication populations; P = 4.87 × 10⁻¹², odds ratio = 1.51 in the combined population). The minor risk allele A of rs6903956 is associated with decreased C6orf105 mRNA expression. We report the first GWAS for CAD in the Chinese Han population and identify a SNP, rs6903956, in C6orf105 associated with susceptibility to CAD in this population.

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Emerging evidence indicates that reprogramming of energy metabolism involving disturbances in energy production from a defect in cellular respiration with a shift to glycolysis is a core hallmark of cancer. Alterations in cancer cell energy metabolism are linked to abnormalities in mitochondrial function. Mitochondrial dysfunction of cancer cells includes increased glycolysis, decreased apoptosis, and resistance to radiotherapy. The study was designed for two main points: firstly, to investigate whether exogenous functional mitochondria can transfer into glioma cells and explore the underlying molecular mechanisms from the perspective of endocytosis; secondly, to further verify whether the mitochondrial transplantation is able to rescue aerobic respiration, attenuate the Warburg effect and enhance the radiosensitivity of gliomas. Methods: Mitochondria were isolated from normal human astrocytes (HA) and immediately co-incubated with starved human glioma cells (U87). Confocal microscopy and gene sequencing were performed to evaluate the ability of isolated mitochondria internalization into U87 cells. The interaction between endocytosis and isolated mitochondria transfer were captured by 3D tomographic microscopy and transmission electron microscopy. NAD + , CD38, cADPR and Ca 2+ release were determined by commercial kits, western blot, HLPC-MS and Fluo-3 AM respectively. PCR array expression profiling and Seahorse XF analysis were used to evaluate the effect of mitochondrial transplantation on energy phenotypes of U87 cells. U87 cells and U87 xenografts were both treated with mitochondrial transplantation, radiation, or a combination of mitochondrial transplantation and radiation. Apoptosis in vitro and in vivo were detected by cytochrome C, cleaved caspase 9 and TUNEL staining. Results: We found that mitochondria from HA could be transferred into starved U87 cells by simple co-incubation. Starvation treatment slowed the rate of glycolysis and decreased the transformation of NAD + to NADH in U87 cells. A large amount of accumulated NAD + was released into the extracellular space. CD38 is a member of the NAD + glycohydrolase family that catalyzes the cyclization of extracellular NAD + to intracellular cADPR. cADPR triggered release of Ca 2+ to promote cytoskeleton remodeling and plasma membrane invagination. Thus, endocytosis involving isolated mitochondria internalization was mediated by NAD + -CD38-cADPR-Ca 2+ signaling. Mitochondrial transfer enhanced gene and protein expression related to the tricarboxylic acid (TCA) cycle, increased aerobic respiration, attenuated glycolysis, reactivated the mitochondrial apoptotic pathway, inhibited malignant proliferation of U87 cells. Isolated mitochondria injected into U87...

BackgroundHeparin saline (HS) is theoretically superior to normal saline (NS) for maintaining the patency of central venous catheters (CVCs), but the comparative efficacy of them remains controversial. The aim of this systematic review and meta-analysis was to assess the efficacy of NS versus HS in the maintenance of the patency of CVCs in adult patients.MethodsWe searched PubMed, Embase and the Cochrane library databases. Randomized controlled trials (RCTs) evaluating the use of NS vs. HS to maintain the permeability of CVCs among adult patients were included in our meta-analysis. References of relevant papers were reviewed manually. No language restriction was applied. Non-human studies were excluded. Pooled relative risk (RR) was calculated using a Mantel-Haenszel random-effects model. We also performed subgroup analysis examining the effect of the duration of catheter placement on the outcome. All statistical tests were two-sided using a significance level of 0.05.ResultsTen RCTs involving 7875 subjects (with analysis at patient, catheter, lumen and line access level) were included in this meta-analysis. Whether in terms of pooled or local analysis (RR with 95% confidence interval spans 1), NS can be equally, if not more effective, in keeping the CVCs open. Of studies reporting secondary outcomes (maneuver needed, heparin-induced thrombocytopenia, haemorrhage, central venous thrombosis and catheter-related bloodstream infection), heparinised saline was shown not to be superior to non-heparinised solution. Subgroup analysis in patients with short vs long term CVC placement was consistent with the main outcome partly and in particular for maintenance of catheter patency in patients with a long-term placement i.e. >30 days, the RR was 0.97 (n = 6589; 95% CI = 0.76 to 1.23; P = 0.796). However, for patients in whom the catheter was in place for <30 days, the RR was 1.52 (n = 1286; 95% CI = 1.02 to 2.27; P = 0.041).ConclusionsBased on the results of this meta-analysis, HS is not superior to NS in reducing CVCs occlusion. But in the short term, the use of HS is slightly superior to NS for flushing catheters from a statistical point of view.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1585-x) contains supplementary material, which is available to authorized users.