Determinants of an elevated pulmonary arterial pressure in patients with pulmonary arterial hypertension

Given the difficulty of diagnosing early-stage pulmonary arterial hypertension (PAH) due to the lack of signs and symptoms, and the risk of an open lung biopsy, the precise pathological features of presymptomatic stage lung tissue remain unknown. It has been suggested that the maximum elevation of the mean pulmonary arterial pressure (Ppa) is achieved during the early symptomatic stage, indicating that the elevation of the mean Ppa is primarily driven by the pulmonary vascular tone and/or some degree of pulmonary vascular remodeling completed during this stage. Recently, the examination of a rat model of severe PAH suggested that the severe PAH may be primarily determined by the presence of intimal lesions and/or the vascular tone in the early stage. Human data seem to indicate that intimal lesions are essential for the severely increased pulmonary arterial blood pressure in the late stage of the disease. However, many questions remain. For instance, how does the pulmonary hemodynamics change during the course of the disease, and what drives the development of severe PAH? Although it is generally acknowledged that both pulmonary vascular remodeling and the vascular tone are important determinants of an elevated pulmonary arterial pressure, which is the root cause of the time-dependent progression of the disease? Here we review the recent histopathological concepts of PAH with respect to the progression of the lung vascular disease

An image cytometric technique is a concise method to detect adenoviruses and host cell proteins and to monitor the infection and cellular responses induced

BackgroundGenetically modified adenoviruses (Ad) with preferential replications in tumor cells have been examined for a possible clinical applicability as an anti-cancer agent. A simple method to detect viral and cellular proteins is valuable to monitor the viral infections and to predict the Ad-mediated cytotoxicity.MethodsWe used type 5 Ad in which the expression of E1A gene was activated by 5′-regulatory sequences of genes that were augmented in the expression in human tumors. The Ad were further modified to have the fiber-knob region replaced with that derived from type 35 Ad. We infected human mesothelioma cells with the fiber-replaced Ad, and sequentially examined cytotoxic processes together with an expression level of the viral E1A, hexon, and cellular cleaved caspase-3 with image cytometric and Western blot analyses.ResultsThe replication-competent Ad produced cytotoxicity on mesothelioma cells. The infected cells expressed E1A and hexon 24 h after the infection and then showed cleavage of caspase-3, all of which were detected with image cytometry and Western blot analysis. Image cytometry furthermore demonstrated that increased Ad doses did not enhance an expression level of E1A and hexon in an individual cell and that caspase-3-cleaved cells were found more frequently in hexon-positive cells than in E1A-positive cells. Image cytometry thus detected these molecular changes in a sensitive manner and at a single cell level. We also showed that an image cytometric technique detected expression changes of other host cell proteins, cyclin-E and phosphorylated histone H3 at a single cell level.ConclusionsImage cytometry is a concise procedure to detect expression changes of Ad and host cell proteins at a single cell level, and is useful to analyze molecular events after the infection

CA-ARBAC: privacy preserving using context-aware role-based access control on Android permission system

Existing mobile platforms are based on manual way of granting and revoking permissions to applications. Once the user grants a given permission to an application, the application can use it without limit, unless the user manually revokes the permission. This has become the reason for many privacy problems because of the fact that a permission that is harmless at some occasion may be very dangerous at another condition. One of the promising solutions for this problem is context-aware access control at permission level that allows dynamic granting and denying of permissions based on some predefined context. However, dealing with policy configuration at permission level becomes very complex for the user as the number of policies to configure will become very large. For instance, if there are A applications, P permissions, and C contexts, the user may have to deal with A × P × C number of policy configurations. Therefore, we propose a context-aware role-based access control model that can provide dynamic permission granting and revoking while keeping the number of policies as small as possible. Although our model can be used for all mobile platforms, we use Android platform to demonstrate our system. In our model, Android applications are assigned roles where roles contain a set of permissions and contexts are associated with permissions. Permissions are activated and deactivated for the containing role based on the associated contexts. Our approach is unique in that our system associates contexts with permissions as opposed to existing similar works that associate contexts with roles. As a proof of concept, we have developed a prototype application called context-aware Android role-based access control. We have also performed various tests using our application, and the result shows that our model is working as desired

The Gender–Age–Physiology system as a prognostic model in patients with idiopathic pulmonary fibrosis treated with nintedanib: a longitudinal cohort study

Introduction: The Gender-Age-Physiology (GAP) system is a tool for predicting prognosis in patients with idiopathic pulmonary fibrosis (IPF). Yet, to date, the GAP system has not been evaluated in patients with IPF who received nintedanib. Material and methods: This single-center retrospective study included 89 patients with IPF who received Nintedanib for at least 3 months. All-cause mortality was set as the end point. Clinical parameters, including the GAP stage, were statistically analyzed for risk factors leading to mortality using the Cox proportional hazard model.Results: The median follow-up was 16.4 months (range 3.7–37.4 months), during which 23 patients died. Univariate analysis revealed that the GAP stage (hazard ratio [HR] 3.00, 95% confidence interval [CI] 1.52–5.92, p = 0.0014) and PaO2 (HR 0.95, 95% CI 0.92–0.98, p = 0.0063) were significant prognostic factors. Multivariate analysis revealed that the GAP stage was a significant prognostic factor (HR 2.26, 95% CI 1.07–4.78, p = 0.031). Log-rank analysis revealed that there were no significant differences in “Gender” (p = 0.47) and “Age” (p = 0.18) factors. However, there were significant differences in “Physiology” factors (% of forced vital capacity, p = 0.018; % of diffusing capacity of lung carbon monoxide, p < 0.001). The cumulative incidences of mortality at 1 and 2 years were as follows: GAP I: 5.1% and 6.8%; GAP II: 9.5% and 29.3%; and GAP III: 18.9% and 84.2%.Conclusions: The GAP system is useful as a prognostic tool in patients with IPF who have been treated with nintedanib

Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways

BackgroundMesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma.MethodsWe examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53.ResultsMetformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells.ConclusionThese data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways

Risk factors for acute exacerbation following bronchoalveolar lavage in patients with suspected idiopathic pulmonary fibrosis: A retrospective cohort study

Introduction: Bronchoalveolar lavage (BAL) is useful for diagnosing diffuse lung disease and excluding other conditions. However, acute exacerbations (AEs) are recognized as important complications of BAL in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to identify risk factors for BAL-induced AEs in patients with IPF.Material and methods: We retrospectively analyzed the data of 155 patients with suspected IPF who had undergone BAL between January 2013 and December 2018. BAL-related AE was defined as the development of AE within 30 days after the procedure. We compared clinical features and parameters between patients with AE (AE group) and without AE (non-AE group). We also reviewed the relevant reported literature.Results: Among the 155 patients, 5 (3.2%) developed AE within 30 days after BAL. The average duration from BAL to AE onset was 7.8 days (2–16 days). Results from the univariate analysis revealed PaO2 < 75 mm Hg (p = 0.036), neutrophil content in BAL ≥ 7% (p = 0.0061), %DLCO < 50% (p = 0.019), Gender-Age-Physiology (GAP) stage III (p = 0.034), and BAL recovery rates < 30% (p < 0.001) as significant risk factors for post-BAL AE. All five patients who developed AE recovered and were discharged.Conclusions: Disease severity, high neutrophil levels in BAL, and poor BAL recovery rates may be risk factors for BAL-induced AE

Cytotoxicity of replication-competent adenoviruses powered by an exogenous regulatory region is not linearly correlated with the viral infectivity/gene expression or with the E1A-activating ability but is associated with the p53 genotypes

BackgroundReplication-competent adenoviruses (Ad) produced cytotoxic effects on infected tumors and have been examined for the clinical applicability. A biomarkers to predict the cytotoxicity is valuable in a clinical setting.MethodsWe constructed type 5 Ad (Ad5) of which the expression of E1A gene was activated by a 5′ regulatory sequences of survivin, midkine or cyclooxygenase-2, which were highly expressed in human tumors. We also produced the same replication-competent Ad of which the fiber-knob region was replaced by that of Ad35 (AdF35). The cytotoxicity was examined by a colorimetric assay with human tumor cell lines, 4 kinds of pancreatic, 9 esophageal carcinoma and 5 mesothelioma. Ad infectivity and Ad-mediated gene expression were examined with replication-incompetent Ad5 and AdF35 which expressed the green fluorescence protein gene. Expression of cellular receptors for Ad5 and AdF35 was also examined with flow cytometry. A transcriptional activity of the regulatory sequences was investigated with a luciferase assay in the tumor cells. We then investigated a possible correlation between Ad-mediated cytotoxicity and the infectivity/gene expression, the transcriptional activity or the p53 genotype.ResultsWe found that the cytotoxicity was greater with AdF35 than with Ad5 vectors, but was not correlated with the Ad infectivity/gene expression irrespective of the fiber-knob region or the E1A-activating transcriptional activity. In contrast, replication-competent Ad produced greater cytotoxicity in p53 mutated than in wild-type esophageal carcinoma cells, suggesting a possible association between the cytotoxicity and the p53 genotype.ConclusionsSensitivity to Ad-mediated cytotoxic activity was linked with the p53 genotype but was not lineally correlated with the infectivity/gene expression or the E1A expression