ZNRF1 can inhibit proliferation and stemness properties of leukemia NB4 cells

As a newly discovered E3 ubiquitin ligase, ZNRF1 protein participates in controlling Wallerian degeneration, but the role in cancer biology has been seldom reported. We analyzed the change of proliferation, apoptosis, stemness and protein levels of AKT and STAT5 after leukemia NB4 cells were treated with ZNRF1 siRNA and with expression vector. The results showed that over-expression of ZNRF1 inhibited proliferation and increased apoptosis of NB4 cells, but ZNRF1 siRNA did not influence the proliferation and apoptosis. Over-expression of ZNRF1 diminished cancer stem cell properties and down-regulated AKT and STAT5. This is the first study to show that ZNRF1 inhibited proliferation and stemness properties of leukemia NB4 cells possibly through AKT signal and STAT5 signal.     

L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice

New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (T_CM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R⁺ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R⁺ T_CM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R⁺ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.     

Effects of Methane-Rich Saline on the Capability of One-Time Exhaustive Exercise in Male SD Rats

Purpose

To explore the effects of methane-rich saline (CH₄ saline) on the capability of one-time exhaustive exercise in male SD rats.

Methods

Thirty rats were equally divided into to three groups at random: control group (C), placebo group (P) and methane saline group (M). Rats in M group underwent intraperitoneal injection of CH₄ saline, and the other two groups simultaneously underwent intraperitoneal injection of normal saline. Then, the exercise capability of rats was tested through one-time exhaustive treadmill exercise except C group. Exercise time and body weight were recorded before and after one-time exhaustive exercise. After exhaustive exercise, the blood and gastrocnemius samples were collected from all rats to detect biochemical parameters in different methods.

Results

It was found that the treadmill running time was significantly longer in rats treated with CH₄ saline. At the same time, CH₄ saline reduced the elevation of LD and UN in blood caused by one-time exhaustive exercise. The low level of blood glucose induced by exhaustive exercise was also normalized by CH₄ saline. Also CH₄ saline lowered the level of CK in plasma. Furthermore, this research indicated that CH₄ saline markedly increased the volume of T-AOC in plasma and alleviated the peak of TNF-α in both plasma and gastrocnemius. From H&E staining, CH₄ saline effectively improved exercise-induced structural damage in gastrocnemius.

Conclusions

CH₄ saline could enhance exercise capacity in male SD rats through increase of glucose aerobic oxidation, improvement of metabolic clearance and decrease of exhaustive exercise-induced gastrocnemius injury.     

Protective Effects of Ferulic Acid against Heat Stress-Induced Intestinal Epithelial Barrier Dysfunction In Vitro and In Vivo

Heat stress is important in the pathogenesis of intestinal epithelial barrier dysfunction. Ferulic acid (FA), a phenolic acid widely found in fruits and vegetables, can scavenge free radicals and activate cell stress responses. This study is aimed at investigating protective effects of FA on heat stress-induced dysfunction of the intestinal epithelial barrier in vitro and in vivo. Intestinal epithelial (IEC-6) cells were pretreated with FA for 4 h and then exposed to heat stress. Heat stress caused decreased transepithelial electrical resistance (TER) and increased permeability to 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4). Both effects were inhibited by FA in a dose-dependent manner. FA significantly attenuated the decrease in occludin, ZO-1 and E-cadherin expression observed with heat stress. The distortion and redistribution of occludin, ZO-1 and E-cadherin proteins were also effectively prevented by FA pretreatment. Moreover, heat stress diminished electron-dense material detected in tight junctions (TJs), an effect also alleviated by FA in a dose-dependent manner. In an in vivo heat stress model, FA (50 mg/kg) was administered to male Sprague–Dawley rats for 7 consecutive days prior to exposure to heat stress. FA pretreatment significantly attenuated the effects of heat stress on the small intestine, including the increased FD4 permeability, disrupted tight junctions and microvilli structure, and reduced occludin, ZO-1 and E-cadherin expression. Taken together, our results demonstrate that FA pretreatment is potentially protective against heat stress-induced intestinal epithelial barrier dysfunction.     

A Meta-Analysis of the Association between ESR1 Genetic Variants and the Risk of Breast Cancer

BackgroundSingle nucleotide polymorphisms (SNPs) in the estrogen receptor gene (ESR1) play critical roles in breast cancer (BC) susceptibility. Genome-wide association studies have reported that SNPs in ESR1 are associated with BC susceptibility; however, the results of recent studies have been inconsistent. Therefore, we performed this meta-analysis to obtain more accurate and credible results.MethodsWe pooled published literature from PubMed, EMBASE, and Web of Science and calculated odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of associations using fixed effects models and random effects models. Twenty relevant case-control and cohort studies of the 3 related SNPs were identified.ResultsThree SNPs of the ESR1 gene, rs2077647:T>C, rs2228480:G>A and rs3798577:T>C, were not associated with increased BC risk in our overall meta-analysis. Stratified analysis by ethnicity showed that in Caucasians, the rs2228480 AA genotype was associated with a 26% decreased risk of BC compared with the GG genotype (OR = 0.740, 95% CI: 0.555–0.987). The C allele of the rs3798577:T>C variant was associated with decreased BC risk in Asians (OR = 0.828, 95% CI: 0.730–0.939), while Caucasians with this allele were found to experience significantly increased BC risk (OR = 1.551, 95% CI: 1.037–2.321). A non-significant association between rs2077647 and BC risk was identified in all of the evaluated ethnic populations.ConclusionRs3798577 was associated with an increased risk of BC in Caucasian populations but a decreased risk in Asians. Rs2228480 had a large protective effect in Caucasians, while rs2077647 was not associated with BC risk.     

Speckle Tracking Based Strain Analysis Is Sensitive for Early Detection of Pathological Cardiac Hypertrophy

Cardiac hypertrophy is a key pathological process of many cardiac diseases. However, early detection of cardiac hypertrophy is difficult by the currently used non-invasive method and new approaches are in urgent need for efficient diagnosis of cardiac malfunction. Here we report that speckle tracking-based strain analysis is more sensitive than conventional echocardiography for early detection of pathological cardiac hypertrophy in the isoproterenol (ISO) mouse model. Pathological hypertrophy was induced by a single subcutaneous injection of ISO. Physiological cardiac hypertrophy was established by daily treadmill exercise for six weeks. Strain analysis, including radial strain (RS), radial strain rate (RSR) and longitudinal strain (LS), showed marked decrease as early as 3 days after ISO injection. Moreover, unlike the regional changes in cardiac infarction, strain analysis revealed global cardiac dysfunction that affects the entire heart in ISO-induced hypertrophy. In contrast, conventional echocardiography, only detected altered E/E’, an index reflecting cardiac diastolic function, at 7 days after ISO injection. No change was detected on fractional shortening (FS), E/A and E’/A’ at 3 days or 7 days after ISO injection. Interestingly, strain analysis revealed cardiac dysfunction only in ISO-induced pathological hypertrophy but not the physiological hypertrophy induced by exercise. Taken together, our study indicates that strain analysis offers a more sensitive approach for early detection of cardiac dysfunction than conventional echocardiography. Moreover, multiple strain readouts distinguish pathological cardiac hypertrophy from physiological hypertrophy.     

A Unidirectional Cell Switching Gate by Engineering Grating Length and Bending Angle

On a microgrooved substrate, cells migrate along the pattern, and at random positions, reverse their directions. Here, we demonstrate that these reversals can be controlled by introducing discontinuities to the pattern. On “V-shaped grating patterns”, mouse osteogenic progenitor MC3T3-E1 cells reversed predominately at the bends and the ends. The patterns were engineered in a way that the combined effects of angle- and length-dependence could be examined in addition to their individual effects. Results show that when the bend was placed closer to one end, migration behaviour of cells depends on their direction of approach. At an obtuse bend (135°), more cells reversed when approaching from the long segment than from the short segment. But at an acute bend (45°), this relationship was reversed. Based on this anisotropic behaviour, the designed patterns effectively allowed cells to move in one direction but blocked migrations in the opposing direction. This study demonstrates that by the strategic placement of bends and ends on grating patterns, we can engineer effective unidirectional switching gates that can control the movement of adherent cells. The knowledge developed in this study could be utilised in future cell sorting or filtering platforms without the need for chemotaxis or microfluidic control.     

Increased Risk of Post-Thrombolysis Intracranial Hemorrhage in Acute Ischemic Stroke Patients with Leukoaraiosis: A Meta-Analysis

BackgroundLeukoaraiosis is common in patients with acute ischemic stroke. The results from many studies investigating the association between leukoaraiosis and intracranial hemorrhage after thrombolysis remain conflicting.MethodsA meta-analysis was performed to compare the risk of post-thrombolytic intracranial hemorrhage in patients with and without leukoaraiosis. Relevant reports were identified by searching PubMed, EmBase, Cochrane Library, and ISI Web of Science through December 2015 using a combination of subjective and random terms. Eligible studies that were original articles with a clear definition of leukoaraiosis and intracranial hemorrhage were selected and analyzed. Funnel plots, Egger’s test, and Begg’s test were conducted to assess the publication bias. Sensitivity analysis was also performed to evaluate the influence of each individual study.ResultsEleven trials that enrolled 6912 participants were included. There was a significantly increased risk for acute ischemic stroke patients with leukoaraiosis (odds ratio: 1.89, 95% confidence interval 1.51–2.37, P<0.001). Low heterogeneity and less publication bias was detected among these studies. The results of both computed tomography and magnetic resonance imaging performed on the subgroups of leukoaraiosis were significant. Furthermore, an association between leukoaraiosis and symptomatic intracranial hemorrhage was also confirmed. The odds ratios remained stable with no obvious variations on the sensitivity analysis. The limitations consisted of types of including trials and not matching some baseline variables.ConclusionsThe results of this meta-analysis show that leukoaraiosis approximately doubles the incidence of intracranial hemorrhage after thrombolytic therapy. However, it does not critically affect decision making regarding thrombolysis for patients with acute ischemic stroke. Additional investigations are required.     

Combined Effect of Textured Patterns and Graphene Flake Additives on Tribological Behavior under Boundary Lubrication

A ball-on-plate wear test was employed to investigate the effectiveness of graphene (GP) nanoparticles dispersed in a synthetic-oil-based lubricant in reducing wear. The effect by area ratio of elliptically shaped dimple textures and elevated temperatures were also explored. Pure PAO4 based oil and a mixture of this oil with 0.01 wt% GP were compared as lubricants. At pit area ratio of 5%, GP-base oil effectively reduced friction and wear, especially at 60 and 100°C. Under pure PAO4 oil lubrication, the untextured surfaces gained low friction coefficients (COFs) and wear rates under 60 and 100°C. With increasing laser—texture area ratio, the COF and wear rate decreased at 25 and 150°C but increased at 60 and 100°C. Under the GP-based oil lubrication, the textured surface with 5% area ratio achieved the lowest COF among those of the area ratios tested at all test temperatures. Meanwhile, the textured surface with 20% area ratio obtained the highest COF among those of the area ratios. With the joint action of GP and texture, the textured surface with 10% area ratio exhibited the best anti-wear performance among all of the textured surfaces at all test temperatures.