Scores of Health-Related Quality of Life Questionnaire Worsen Consistently in Patients of COPD: Estimating Disease Progression over 30 Years by SReFT with Individual Data Collected in SUMMIT Trial.

The aim of this study was to elucidate the lifelong disease progression of chronic obstructive pulmonary disease (COPD) with biomarker changes and identify their influencing factors, by utilizing a new analysis method, Statistical Restoration of Fragmented Time-course (SReFT). Individual patient data (n = 1025) participating in the Study to Understand Mortality and MorbidITy (SUMMIT, NCT01313676), which was collected within the observational period of 4 years, were analyzed. The SReFT analysis suggested that scores of St. George's Respiratory Questionnaire and COPD assessment test, representative scores of the health-related quality of life (HRQOL) questionnaire, increased consistently for 30 years of disease progression, which was not detected by conventional analysis with a linear mixed effect model. It was estimated by the SReFT analysis that normalized forced expiratory volume in one second for age, sex, and body size (%FEV1) reduced for the initial 10 years from the onset of the disease but thereafter remained constant. The analysis of HRQOL scores and lung functions suggested that smoking cessation slowed COPD progression by approximately half and that exacerbation accelerated it considerably. In conclusion, this retrospective study utilizing SReFT elucidated the progression of COPD over 30 years and associated quantitative changes in the HRQOL scores and lung functions.

Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.

BACKGROUND AND OBJECTIVES: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 µg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population. RESULTS: Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa. CONCLUSIONS: Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: 201754, Clinicaltrials.gov, NCT02969655.

Hydrocortisone enhances the barrier properties of HBMEC/ciß, a brain microvascular endothelial cell line, through mesenchymal-to-endothelial transition-like effects.

BACKGROUND: Because in vitro blood-brain barrier (BBB) models are important tools for studying brain diseases and drug development, we recently established a new line of conditionally immortalized human brain microvascular endothelial cells (HBMEC/ciß) for use in such models. Since one of the most important functional features of the BBB is its strong intercellular adhesion, in this study, we aimed at improving HBMEC/ciß barrier properties by means of culture media modifications, thus enhancing their use for future BBB studies. In addition, we simultaneously attempted to obtain insights on related mechanistic properties. METHODS: Several types of culture media were prepared in an effort to identify the medium most suitable for culturing HBMEC/ciß. The barrier properties of HBMEC/ciß were examined by determining Na(+)-fluorescein permeability and transendothelial electric resistance (TEER). Endothelial marker mRNA expression levels were determined by quantitative real-time polymerase chain reaction. Adherens junction (AJ) formation was examined by immunocytochemistry. Cell migration ability was analyzed by scratch assay. Furthermore, cellular lipid composition was examined by liquid chromatography-time-of-flight mass spectrometry. RESULTS: Our initial screening tests showed that addition of hydrocortisone (HC) to the basal medium significantly reduced the Na(+)-fluorescein permeability and increased the TEER of HBMEC/ciß monolayers. It was also found that, while AJ proteins were diffused in the cytoplasm of HBMEC/ciß cultured without HC, those expressed in cells cultured with HC were primarily localized at the cell border. Furthermore, this facilitation of AJ formation by HC was in concert with increased endothelial marker mRNA levels and increased ether-type phosphatidylethanolamine levels, while cell migration was retarded in the presence of HC. CONCLUSIONS: Our results show that HC supplementation to the basal medium significantly enhances the barrier properties of HBMEC/ciß. This was associated with a marked phenotypic alteration in HBMEC/ciß through orchestration of various signaling pathways. Taken together, it appears that overall effects of HC on HBMEC/ciß could be summarized as facilitating endothelial differentiation characteristics while concurrently retarding mesenchymal characteristics.

Establishment of a new conditionally immortalized cell line from human brain microvascular endothelial cells: a promising tool for human blood-brain barrier studies.

The blood-brain barrier (BBB) is formed by brain microvascular endothelial cells (BMEC) working together with astrocytes and pericytes, in which tight junctions and various transporters strictly regulate the penetration of diverse compounds into the brain. Clarification of the molecular machinery that provides such regulation using in vitro BBB models has provided important insights into the roles of the BBB in central nervous system (CNS) disorders and CNS drug development. In this study, we succeeded in establishing a new cell line, hereinafter referred to as human BMEC/conditionally immortalized, clone ß (HBMEC/ciß), as part of our ongoing efforts to develop an in vitro human BBB model. Our results showed that HBMEC/ciß proliferated well. Furthermore, we found that HBMEC/ciß exhibited the barrier property of restricting small molecule intercellular penetration and possessed effective efflux transporter functions, both of which are essential to a functioning BBB. Because higher temperatures are known to terminate immortalization signals, we specifically examined the effects of higher temperatures on the HBMEC/ciß differentiation status. The results showed that higher temperatures stimulated HBMEC/ciß differentiation, marked by morphological alteration and increases in several mRNA levels. To summarize, our data indicates that the newly established HBMEC/ciß offers a promising tool for use in the development of a practical in vitro human BBB model that could make significant contributions toward understanding the molecular biology of CNS disorders, as well as to CNS drug development. It is also believed that the development of a specific culture method for HBMEC/ciß will add significant value to the HBMEC/ciß-based BBB model.