Anti-tumor effects of interferon-beta cell therapy in murine model of melanoma

Purpose: Recombinant interferon beta (IFN-β) has been used for a treatment of cancers. However, the efficacy of recombinant IFN-β is limited because of its short half-life and side effects. To overcome these problems, we focused on the efficacy of cell-based therapy (cell therapy) using IFN-β-producing cells in the treatment of melanoma.Methods: IFN-β-producing therapeutic cells were constructed by gene transduction using retrovirus vector. Anti-tumor effects of the cell therapy were investigated by a murine melanoma model.Results: IFN-β cell therapy significantly suppressed the proliferation of B16 melanoma in vitro and the growth of B16-derived tumor in vivo, accompanied with the activation of natural killer (NK) cells. IFN-β cell therapy did not show any systemic side-effects concerning hepatic dysfunction and bone marrow suppression.Conclusion: IFN-β cell therapy could be a candidate as a novel cancer treatment.

Postprandial hyperglycemia and endothelial function in type 2 diabetes: focus on mitiglinide

<p>Abstract</p> <p>The risk of cardiovascular complication in a diabetes patient is similar to that in a nondiabetic patient with a history of myocardial infarction. Although intensive control of glycemia achieved by conventional antidiabetic agents decreases microvascular complications such as retinopathy and nephropathy, no marked effect has been reported on macrovascular complications or all-cause mortality. Evidence from VADT, ACCORD, and ADVANCE would suggest that glycemic control has little effect on macrovascular outcomes. Moreover, in the case of ACCORD, intensive glycemic control may be associated with an increased risk of mortality. There is sufficient evidence that suggests that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease in diabetes patients. However, there are no prospective clinical trials supporting the recommendation that lowering postprandial blood glucose leads to lower risk of cardiovascular outcomes. Mitiglinide is a short-acting insulinotropic agent used in type 2 diabetes treatment. It has a rapid stimulatory effect on insulin secretion and reduces postprandial plasma glucose level in patients with type 2 diabetes. Because of its short action time, it is unlikely to exert adverse effects related to hypoglycemia early in the morning and between meals. Mitiglinide reduces excess oxidative stress and inflammation, plays a cardioprotective role, and improves postprandial metabolic disorders. Moreover, mitiglinide add-on therapy with pioglitazone favorably affects the vascular endothelial function in type 2 diabetes patients. These data suggest that mitiglinide plays a potentially beneficial role in the improvement of postprandial hyperglycemia in type 2 diabetes patients and can be used to prevent cardiovascular diseases. Although the results of long-term, randomized, placebo-controlled trials for determining the cardiovascular effects of mitiglinide on clinical outcomes are awaited, this review is aimed at summarizing substantial insights into this topic.</p

Design of functional electrospun scaffolds based on poly(glycerol sebacate) elastomer and poly(lactic acid) for cardiac tissue engineering

International audienceMany works focus on the use of polyesters like poly(lactic acid) (PLA) to produce nanofibrous scaffolds for cardiac tissue engineering. However, such scaffolds are hydrophobic and difficult to functionalize. Here, we show that adding 30% of poly(glycerol sebacate) (PGS) elastomer within PLA leads to PLA:PGS scaffolds with improved biological properties, depending on the processing parameters. Two categories of fibers were produced by blend electrospinning, with diameters of 600 and 1300 nm. The resulting fibers were cured at 90°C or 120°C in order to achieve two different crosslinking densities. The designed scaffolds were considered for cytocompatibility, biocompatibility, biodegradability, chemical and mechanical properties. Our results demonstrated that the presence of PGS increases the hydrophilicity of the material and thus improves surface functionalization by Matrigel and laminin coating, a commonly used cell culture matrix. PLA:PGS scaffolds associated with Matrigel and laminin allow an increased material-cell interaction. Moreover, the cardiomyocytes seeded on such scaffolds acquire a morphology similar to that observed in native tissue, this result being more remarkable on fibers having the smallest diameter and the highest PGS crosslinking density. In addition, these scaffolds induce neovascularization without inflammatory response and foreign body giant cell response after grafting on mice’s heart. Hence, the improved biocompatibility and the ability to support cardiomyocytes development suggest that thin PLA:PGS scaffolds could be promising biomaterials for cardiac application

Variation in heart rate range by 24‐h Holter monitoring predicts heart failure in patients with atrial fibrillation

Abstract Aims The analysis of heart rate (HR) changes, such as the HR variability or HR turbulence, has been reported as a marker of cardiovascular events during sinus rhythm; however, those relationships during atrial fibrillation (AF) remain controversial, and those parameters are not commonly used in AF patients. We sought to investigate the relationship between a simple index focused on the HR and heart failure (HF) events in patients with permanent AF. Methods and results We enrolled 198 patients with permanent AF and evaluated the HR range, defined as the maximum HR minus the minimum HR on 24‐h Holter electrocardiogram recordings. The patients were divided into two groups, i.e., the larger (n = 101) and smaller (n = 97) HR range (HRR) groups, determined by the median value. The HF events were defined as hospitalizations for HF or urgent hospital visits due to exacerbations of one's HF status. The observation period of this study was set at 5 years from registration. The median age was 73 (68–77) years, and 29% were female. The median HRR was 84 (63–118) beats per minutes (bpm). During the observational period of 1825 days (median), HF events occurred in 37 (0.047 per patient‐year) patients. In a log‐rank test, the larger HRR group had more frequent HF events than the smaller HRR group (P = 0.0078). In the adjusted Cox proportional hazards model using the significantly different factors from the univariate analysis (Model 1) and factors and medications associated with HF (Model 2), the larger HRR group had a higher prevalence of HF events than the smaller HRR group for both models [Model 1, adjusted hazard ratio = 3.21, 95% confidence interval (CI) 1.593–6.708, P = 0.0009; Model 2, adjusted hazard ratio = 3.12, 95% CI 1.522–6.685, P = 0.002]. When analysed using the time‐dependent Cox proportional hazards model, the HRR was associated with HF with a statistically significant difference in both the univariate and multivariate analyses [hazard ratio = 1.01, 95% CI 1.006–1.020, P = 0.0002; Model 1, adjusted hazard ratio = 1.02, 95% CI 1.011–1.027, P < 0.0001; Model 2, adjusted hazard ratio = 1.01, 95% CI 1.008–1.021, P = 0.0003). There was no significant difference in the chronotropic medications between the two groups. Conclusions In patients with permanent AF, a larger HRR was associated with HF events

Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth

International audienceAlthough in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus. The nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. We, therefore, identify Amotl1, which is not present in flies, as a mammalian intermediate for non-canonical Hippo signalling, downstream of Fat4. This work uncovers a mechanism for the restriction of heart growth at birth, a process which impedes the regenerative potential of the mammalian heart