Extracellular Vesicles Inhibit the Response of Pancreatic Ductal Adenocarcinoma Cells to Gemcitabine and TRAIL Treatment

Pancreatic ductal adenocarcinoma remains an aggressive cancer with a low 5-year survival rate. Although gemcitabine has been a standard treatment for advanced pancreatic cancer, patients often develop resistance to this therapeutic. We have previously shown that treating pancreatic cancer cells in vitro with a combination of gemcitabine and the cytokine TRAIL significantly reduced both cell viability and survival. The data presented here demonstrate that this response to treatment is inhibited when cells are incubated with a conditioned medium derived from untreated cells. We show that this inhibition is specifically mediated by extracellular vesicles present in the conditioned medium, as seen by a significant decrease in apoptosis. Additionally, we further demonstrate that this effect can be reversed in the presence of GW4869, an inhibitor of exosome biogenesis and release. These results show that pancreatic cancer cell-derived extracellular vesicles can confer resistance to treatment with gemcitabine and TRAIL. The implications of these findings suggest that removal of EVs during treatment can improve the response of cells to gemcitabine and TRAIL treatment in vitro.     

Familial cortical tremor, epilepsy, and mental retardation: a distinct clinical entity?

OBJECTIVE: To describe a European family with cortical tremor, epilepsy, and mental retardation, the pedigree of which indicates an autosomal dominant inheritance of the disease. DESIGN: Clinical, laboratory, neurophysiological, and neuroimaging data were studied. SETTING: Institute for research on mental retardation. PATIENTS: Two siblings (aged 25 and 28 years) and their 49-year-old mother had postural and action tremor, seizures, and mental retardation. Only tremor was present in the maternal grandmother (aged 68 years). The electroencephalogram showed diffuse spike-and-wave complexes and/or posterior spikes, and a photoparoxysmal response in the 4 subjects. The typical electrophysiologic features of cortical reflex myoclonus, such as giant somatosensory evoked potentials, enhancement of the C-reflex, and jerk-locked premyoclonus spikes, were found in all patients. CONCLUSION: This syndrome may represent a specific form of familial cortical tremor with a benign form of epilepsy and a new genetic model of cortical hyperexcitability inherited with an autosomal dominant mechanism.     

Distribution and expression of pancreatic secretory trypsin inhibitor and its possible role in epithelial restitution

Pancreatic secretory trypsin inhibitor (PSTI) is a potent serine protease inhibitor that prevents excessive digestion of the gastrointestinal mucus but may also directly affect epithelial function. We therefore examined the distribution of PSTI in the human adult and fetus using immunohistochemistry and in situ hybridization and examined its effects on cell proliferation and migration in vitro. PSTI peptide and mRNA were found in the exocrine pancreas, mucus-producing cells of the normal gastrointestinal tract, acinar component of the normal breast, and surface epithelial cells at the edge of benign gastric ulcers. Peptide, but not message, was identified in the renal proximal tubule, probably reflecting reabsorption of filtered peptide. Purified human PSTI did not affect proliferation of the human colonic cell line HT-29 but caused a threefold increase in the rate of migration in an in vitro wounding model of restitution. This effect was inhibited by co-administering a PSTI-neutralizing antibody, a transforming growth factor-beta-neutralizing antibody, or an epidermal growth factor receptor-blocking antibody. As PSTI is widely distributed in several human organ systems and stimulates cell migration in vitro, we conclude that PSTI is likely to have additional roles to that of preserving the gastrointestinal mucous layer from excessive digestion.     

Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome

Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype–phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.     

沉睡的巨人

正这是一张通过合成制作的图片,这是位于印度尼西亚的Bromo山。事先我准备了三脚架和快门线.这可以避免因为机身晃动所造成的画面模糊。另外要带足衣物和食物,因为可能需要在夜晚长时间呆在野外。我先     

Evaluation of vehicle side airbag effectiveness in Victoria,Australia

Side airbag systems were first introduced into vehicles around 1995 to help protect occupants from injury in side impact crashes. International studies have shown that side airbags are effective in reducing the risk of death and injury, however, serious injuries can still occur even when side airbags deploy. The objective of this study was to use detailed injury information from insurance injury compensation claims data linked to Police reported crash data to determine the effectiveness of side airbags in reducing the risk of death or injury for occupants involved in side impact crashes in Victoria, Australia based on the specific body regions that side airbag systems are designed to protect. It was found that head and torso-protecting dual airbag systems designed to protect the head, neck, face, chest and abdomen are highly effective in reducing driver death or injury due to near side crashes. They were associated with a statistically significant reduction of 41.1% (25.9%, 53.2%) in the odds of death or injury across all body regions; and a 48.0% (28.0%, 62.4%) reduction in the odds of death or injury to the head, neck, face, chest and abdomen. The study did not find any evidence that torso-protecting airbags alone are effective in reducing death or injury. Analysis results indicate that head and torso-protecting side airbag systems in vehicles are a highly effective technology for reducing the risk of death or injury to vehicle occupants in near side crashes. The magnitude of the injury reduction benefits estimated indicate that fitment of this technology to all vehicles should be a high priority and will yield significant savings in overall road trauma.     

Home ownership and rent control in Switzerland

This paper discusses the reasons for two intriguing characteristics of the Swiss housing market: the small demand for owner occupancy in spite of high per capita income and the survival of a viable private rental sector after decades of rent control. The low rate of home ownership seems to be the result of the high cost of owning caused by the taxation of imputed rent and capital gains, and the lack of financial incentives to save for a down payment. The survival of private renting as the dominant housing sector, on the other hand, was made possible by the permissive second‐generation rent control regime which succeeded in maintaining the continuing profitability of private investments in rental housing. The main effects of rent control in Switzerland appear to be the reduction of housing costs of long‐standing tenants and the prevention of abuse through arbitrary eviction and exploitation of temporary shortages.     

Bilevel Parameter Learning for Nonlocal Image Denoising Models

We propose a bilevel optimization approach for the estimation of parameters in nonlocal image denoising models. The parameters we consider are both the fidelity weight and weights within the kernel of the nonlocal operator. In both cases, we investigate the differentiability of the solution operator in function spaces and derive a first-order optimality system that characterizes local minima. For the numerical solution of the problems, we use a second-order trust-region algorithm in combination with a finite element discretization of the nonlocal denoising models and introduce a computational strategy for the solution of the resulting dense linear systems. Several experiments illustrate the applicability and effectiveness of our approach.