The mast cell exosome-fibroblast connection: A novel pro-fibrotic pathway.

Introduction: In addition to the traditional activation of resident receptors by release of local mediators, new evidence favors the existence of exosomes in cell-to-cell communication that mediates delivery of specific cargo to modulate recipient cell function. We report that mast cell exosomes are an additional source of pro-fibrotic substances and constitute a unique pathway for the generation of excess collagen.

Methods: We use primary human lung fibroblasts (HLFs) to demonstrate the uptake of labeled exosomes isolated from the human mast cell line HMC-1 (MC-EXOs), previously shown to contain protein cargo in common with human mast cell exosomes.

Extracellular vesicles from human airway basal cells respond to cigarette smoke extract and affect vascular endothelial cells.

The human airway epithelium lining the bronchial tree contains basal cells that proliferate, differentiate, and communicate with other components of their microenvironment. One method that cells use for intercellular communication involves the secretion of exosomes and other extracellular vesicles (EVs). We isolated exosome-enriched EVs that were produced from an immortalized human airway basal cell line (BCi-NS1.

Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.

Rationale: Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder.

Objectives: On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium (SAE).

Methods: The proximal and distal airway signatures were identified by comparing the transcriptomes of large and small airway epithelium samples obtained by bronchoscopy from healthy nonsmokers.

Endothelial Cell Mediated Promotion of Ciliated Cell Differentiation of Human Airway Basal Cells via Insulin and Insulin-Like Growth Factor 1 Receptor Mediated Signaling.

Human airway basal cells (BC) function as stem/progenitor cells of the human airway epithelium, capable of differentiating into ciliated and secretory cells during turnover and repair. The positioning of BC along the basement membrane allows for potential paracrine signaling from non-epithelial cells in the mesenchyme to regulate BC function. Based on the knowledge that interaction between the airway epithelium and mesenchyme is critical for proper maintenance of both tissues, and that endothelial cells (EC) can regulate multiple functions of BC, the present study was designed to help understand the role of BC and EC cross-talk in regulating BC stem/progenitor function.

JAG1-Mediated Notch Signaling Regulates Secretory Cell Differentiation of the Human Airway Epithelium.

Basal cells (BC) are the stem/progenitor cells of the human airway epithelium capable of differentiating into secretory and ciliated cells. Notch signaling activation increases BC differentiation into secretory cells, but the role of individual Notch ligands in regulating this process in the human airway epithelium is largely unknown. The objective of this study was to define the role of the Notch ligand JAG1 in regulating human BC differentiation.

Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells.

Human airway basal cells are the stem (or progenitor) population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of basal cells allows for potential paracrine signaling between them and the underlying non-epithelial stromal cells. In support of this, we have previously demonstrated that endothelial cells support growth of basal cells during co-culture through vascular endothelial growth factor A (VEGFA)-mediated signaling.

Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway.

Airway basal cells (BC) function as stem/progenitor cells capable of differentiating into the luminal ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. The objective of this study was to define the role of Notch signaling in regulating human airway BC differentiation into a pseudostratified mucociliated epithelium. Notch inhibition with γ-secretase inhibitors demonstrated Notch activation is essential for BC differentiation into secretory and ciliated cells, but more so for the secretory lineage.

Generation of a human airway epithelium derived basal cell line with multipotent differentiation capacity.

Background: As the multipotent progenitor population of the airway epithelium, human airway basal cells (BC) replenish the specialized differentiated cell populations of the mucociliated airway epithelium during physiological turnover and repair. Cultured primary BC divide a limited number of times before entering a state of replicative senescence, preventing the establishment of long-term replicating cultures of airway BC that maintain their original phenotype.

Methods: To generate an immortalized human airway BC cell line, primary human airway BC obtained by brushing the airway epithelium of healthy nonsmokers were infected with a retrovirus expressing human telomerase (hTERT).

Reduction of virulence factor pyocyanin production in multidrug-resistant Pseudomonas aeruginosa.

Nosocomial infections caused by metallo-β-lactamase (MBL)-producing multidrug-resistant (MDR) Pseudomonas aeruginosa have become a worldwide problem. Pyocyanin, a representative pigment produced by P. aeruginosa, is the major virulence factor of this organismThe aim of this study was to investigate the pyocyanin-producing ability of MBL-producing MDR P.

Usefulness of linezolid in the treatment of hospital-acquired pneumonia caused by MRSA: a prospective observational study.

Clinical results for linezolid (LZD) treatment of hospital-acquired pneumonia (HAP) caused by methicillin-resistant Staphylococcus aureus (MRSA), particularly microbiologically evaluable or severe cases, are limited in Japan. A prospective observational study was conducted in order to assess the usefulness of LZD in Japanese patients with MRSA pneumonia. The study tracked fifteen participants treated with LZD for pneumonia who met the criteria of the HAP guidelines and were confirmed to have pneumonia caused by MRSA.

Antibacterial activity of carbapenems against clinical isolates of respiratory bacterial pathogens in the northeastern region of Japan in 2007.

As the increasing prevalence of resistant strains of respiratory bacterial pathogens has recently been reported, continuous monitoring of the susceptibility of clinical isolates to antibacterial agents is important. We performed a surveillance study focusing on the susceptibility of major respiratory bacterial pathogens in the northeastern region of Japan to carbapenems and control drugs. A total of 168 bacterial strains isolated from patients with respiratory tract infections in 2007 were collected and the minimum inhibitory concentration (MIC) determined.

Antibacterial effects of brand-name teicoplanin and generic products against clinical isolates of methicillin-resistant Staphylococcus aureus.

Glycopeptide antibiotics, such as vancomycin and teicoplanin, have been used worldwide to treat infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Generic teicoplanin products were manufactured by many companies in 2009. We investigated the susceptibility of 147 MRSA strains to brand-name teicoplanin (TEIC-1) and seven generic products (TEIC-2 to TEIC-8).

Efficacy of clarithromycin plus vancomycin in mice with implant-related infection caused by biofilm-forming Staphylococcus aureus.

Background: Staphylococcal biofilms pose an important problem, especially after orthopedic surgery using foreign implants. Clarithromycin (CAM) eliminates the biofilms formed by a wide variety of aerobic and anaerobic bacteria. In a previous in vitro study, we showed that treatment with CAM and vancomycin (VCM) eradicated staphylococcal biofilms from surgical implants.

Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402.

Purpose: Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation.

Combined efficacy of clarithromycin plus cefazolin or vancomycin against Staphylococcus aureus biofilms formed on titanium medical devices.

In this study, we investigated the in vitro efficacy of clarithromycin (CLA) combined with cefazolin (CFZ) or vancomycin (VCM) against Staphylococcus aureus biofilms formed on titanium devices in order to confirm the efficacy of eradication therapies against device-related infection. The distribution of CLA in muscle tissue surrounding bone was also investigated by liquid chromatography/tandem mass spectrometry in 10 orthopaedic patients. Biofilm formation and eradication of S.

Adenocarcinoma with epidermal growth factor receptor gene mutations in three siblings.

Sensitivity to an inhibitor of epidermal growth factor receptor (EGFR) kinase strongly correlates with EGFR somatic mutations in non-small cell lung cancer. These mutations are frequently found in patients with adenocarcinoma, never- or light-smokers, women, and East Asians. In this study, we show an aggregation of three non-small cell lung cancer cases with EGFR gene mutations in one family.

[Results of a survey of community-acquired-pneumonia and evaluation of old and new Japanese Respiratory Society guidelines].

We evaluated the usefulness of domestic and foreign guidelines for the diagnosis and treatment of patients with community-acquired-pneumonia at 23 institutions in 6 prefectures of the Tohoku Area, from December 2003 to November 2004. Based on the old and new Japanese Respiratory Society (JRS) guidelines, we evaluated severity, clinical efficacy and detection of atypical pneumonia. As for severity, the old guidelines led to the diagnosis of an excessive number of 'severe' cases.

Evaluation of dosing designs of carbapenems for severe respiratory infection using Monte Carlo simulation.

Using the Monte Carlo simulation method, the influence of various doses and dosing frequencies of carbapenems on the antimicrobial activities against Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, which are the main causative organisms of respiratory infections, was studied with the aim of identifying optimized effectiveness. Based on pharmacokinetic (PK) parameters of individual carbapenems in healthy adults, data on changes in the respective blood concentrations in 2000 cases were simulated by applying a lognormal distribution to probability distributions of their volume of distributions and half-life periods. Based on minimum inhibitory concentration (MIC) distribution data of the individual carbapenems against these strains, MICs in the 2000 cases were also simulated.

Antibacterial activity of carbapenems against clinically isolated respiratory bacterial pathogens in Japan between 2005 and 2006.

The current status of the susceptibility of the main respiratory bacterial pathogens was evaluated by analysing the antibacterial activity of 21 drugs, including four carbapenems, against five species of the pathogens isolated between January 2005 and January 2006. A total of 157 strains were studied. Carbapenems inhibited the growth of all of the tested strains of Moraxella catarrhalis, Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus strains at concentrations that were below the breakpoints set by the Japanese Society of Chemotherapy (2 and 1mug/mL for pneumonia and chronic respiratory tract infection, respectively).

Mouse and human cell activation by N-dodecanoyl-DL-homoserine lactone, a Chromobacterium violaceum autoinducer.

Chromobacterium violaceum produces autoinducers, including homoserine lactones (HSLs), for genetic regulation. Among the seven HSLs derived from C. violaceum we evaluated, only C(12)-HSL stimulated the production of inflammatory cytokines in mammalian monocytic cell lines through the activation of the NF-kappaB signaling pathway besides their quorum-sensing role, like 3-oxo-C(12)-HSL from Pseudomonas aeruginosa.

A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer.

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (> or = 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70 mg/m2 on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles.