Bafilomycin A1-sensitive pathway is required for the maturation of cystic fibrosis transmembrane conductance regulator

AbstractCystic fibrosis (CF) is the most common lethal genetic disease in Caucasians caused by the trafficking defects of CF transmembrane conductance regulator (CFTR), which is a cAMP-dependent Cl− channel at the plasma membrane. The trafficking pathway of CFTR is thought to be non-conventional because CFTR maturation is inhibited by the dysfunction of syntaxin 13, which is involved in protein recycling via endosomal pathway. In this study, to clarify whether the endosomal trafficking is required for CFTR maturation, we utilized a specific vacuolar H+-ATPase inhibitor, bafilomycin A1 (BafA1), which inhibits the protein trafficking from early endosome. Our data showed that low concentration of BafA1 (50nM) decreased the expression of mature CFTR but induced the accumulation of immature CFTR in the juxta-nuclear region containing an early endosome marker. Pulse-chase analysis showed that BafA1 inhibited the maturation of CFTR, but it slightly stabilized immature CFTR. These results indicate that BafA1-sensitive pathway is required for CFTR maturation and emphasize that endosomal trafficking pathway might be involved in the maturation of CFTR

Predictions of NO and CO emissions in ammonia/methane/air combustion by LES using a non-adiabatic flamelet generated manifold

A large-eddy simulation (LES) employing a non-adiabatic flamelet generated manifold approach, which can account for the effects of heat losses due to radiation and cold walls, is applied to NH3/CH4/air combustion fields generated by a swirl burner, and the formation mechanisms of NO and CO for ammonia combustion are investigated in detail. The amounts of NO and CO emissions for various equivalence ratios, are compared with those predicted by LES employing the conventional adiabatic flamelet generated manifold approach and measured in the bespoke experiments. The results show that the amounts of NO and CO emissions predicted by the large-eddy simulations with the non-adiabatic flamelet generated manifold approach agree well with the experiments much better than the ones with the adiabatic flamelet generated manifold approach. This is because the NO and CO reactions for NH3/CH4/air combustion are quite susceptible to H and OH radicals’ concentrations and gas temperature. This suggests that it is essential to take into account the effects of various heat losses caused by radiation and cold walls in predicting the NO and CO emissions for the combustion of ammonia as a primary fuel

Accelerated tumor growth in mice deficient in DNAM-1 receptor

Since the identification of ligands for human and mouse DNAM-1, emerging evidence has suggested that DNAM-1 plays an important role in the T cell– and natural killer (NK) cell–mediated recognition and lysis of tumor cells. However, it remains undetermined whether DNAM-1 is involved in tumor immune surveillance in vivo. We addressed this question by using DNAM-1–deficient mice. DNAM-1–deficient cytotoxic T lymphocyte (CTL) and NK cells showed significantly less cytotoxic activity against DNAM-1 ligand-expressing tumors in vitro than wild-type (WT) cells. The methylcholanthrene (MCA)-induced fibrosarcoma cell line Meth A expressed the DNAM-1 ligand CD155, and DNAM-1–deficient mice showed increased tumor development and mortality after transplantation of Meth A cells. Moreover, the DNAM-1–deficient mice developed significantly more DNAM-1 ligand-expressing fibrosarcoma and papilloma cells in response to the chemical carcinogens MCA and 7,12-dimethylbenz[a]anthracene (DMBA), respectively, than did WT mice. These results indicate that DNAM-1 plays an important role in immune surveillance of tumor development

Single Nucleotide Polymorphism WRN Leu1074Phe Is Associated with Prostate Cancer Susceptibility in Chinese Subjects

Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR＝0.58, 95%CI:0.35-0.97, p＝0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age <_ 72 yr (OR＝0.27, 95%CI:0.12-0.61, p＝0.002) and in patients with localized diseases (OR＝0.36, 95%CI:0.19-0.70, p＝0.003). However, no statistically significant difference was found in the subgroup with age ＞72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects

The Relationship Between Attenuated Plaque Identified by Intravascular Ultrasound and No-Reflow After Stenting in Acute Myocardial Infarction

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Residual plaque burden in patients with acute coronary syndromes after successful percutaneous coronary intervention

Objectives: The aim of this study was to characterize and evaluate the clinical impact of untreated atherosclerotic disease after percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS). Background: Residual atherosclerotic disease after successful PCI may predispose future major adverse cardiovascular events (MACE). Compared with intravascular ultrasound (IVUS), angiography underestimates the presence and severity of coronary artery disease. Methods: Following successful PCI of all clinically significant lesions in 697 patients with ACS, 3-vessel grayscale and radiofrequency IVUS was performed. Lesions were prospectively characterized, and patients were followed for a median of 3.4 years. A total of 3,229 untreated lesions (4.89 ± 1.98 lesions/patient) were identified by IVUS, with mean plaque burden (PB) of 49.6 ± 4.2%. Results: By angiography these nonculprit lesions were mild, with mean diameter stenosis of 38.9 ± 15.3%. At least 1 lesion with a PB <70% (PB70 lesion) was found in 220 (33%) patients. By multivariable analysis, a history of prior PCI and angiographic 3-vessel disease were independent predictors of PB70 lesions. Patients with PB70 lesions had greater total percent plaque volume, normalized PB, fibroatheromas, thin-cap fibroatheromas, and normalized volumes of necrotic core and dense calcium. Patients with PB70 lesions had greater 3-year rates of MACE due to untreated nonculprit lesions (20.8% vs. 7.7%, p < 0.0001). Among imaged nonculprit lesions, the proportion of PB70 lesions causing MACE was significantly greater than non-PB70 lesions (8.7% vs. 1.0%, p < 0.0001). Conclusions: After successful PCI of all angiographically significant lesions, overall untreated atherosclerotic burden remains high, and PB70 lesions are frequently present in the proximal and mid-coronary tree. Patients with PB70 lesions have greater atherosclerosis throughout the coronary tree, have more thin-cap fibroatheromas, and are at increased risk for future cardiovascular events. (PROSPECT: An Imaging Study in Patients With Unstable Atherosclerotic Lesions; NCT00180466

The development of a brief and objective method for evaluating moral sensitivity and reasoning in medical students

BACKGROUND: Most medical schools in Japan have incorporated mandatory courses on medical ethics. To this date, however, there is no established means of evaluating medical ethics education in Japan. This study looks 1) To develop a brief, objective method of evaluation for moral sensitivity and reasoning; 2) To conduct a test battery for the PIT and the DIT on medical students who are either currently in school or who have recently graduated (residents); 3) To investigate changes in moral sensitivity and reasoning between school years among medical students and residents. METHODS: Questionnaire survey: Two questionnaires were employed, the Problem Identification Test (PIT) for evaluation of moral sensitivity and a portion of the Defining Issues Test (DIT) for moral reasoning. Subjects consisted of 559 medical school students and 272 residents who recently graduated from the same medical school located in an urban area of Japan. RESULTS: PIT results showed an increase in moral sensitivity in 4(th )and 5(th )year students followed by a decrease in 6(th )year students and in residents. No change in moral development stage was observed. However, DIT results described a gradual rising shift in moral decision-making concerning euthanasia between school years. No valid correlation was observed between PIT and DIT questionnaires. CONCLUSION: This study's questionnaire survey, which incorporates both PIT and DIT, could be used as a brief and objective means of evaluating medical students' moral sensitivity and reasoning in Japan