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Sugawara S.,Sendai Kousei Hospital | Oizumi S.,Hokkaido University | Minato K.,Gunma Prefectural Cancer Center | Harada T.,JCHO Hokkaido Hospital | And 15 more authors.
Annals of Oncology | Year: 2015

Background: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. Patients and methods: Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/ pemetrexed [area under the curve (AUC) = 6 and 500 mg/m2; 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. Results: All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). Conclusion: This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | Kanagawa Cardiovascular and Respiratory Center, Tohoku Pharmaceutical University, Sapporo Medical University, Saiseikai Kumamoto Hospital and 5 more.
Type: Journal Article | Journal: Respiratory investigation | Year: 2015

A phase III clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) in Japan has revealed that pirfenidone attenuated the decline in vital capacity (VC) and improved progression-free survival (PFS). We conducted an extended analysis of the pirfenidone trial to investigate its efficacy with respect to IPF severity in the trial population.Patients in the phase III trial were stratified by baseline pulmonary functions including %VC predicted, %diffusion capacity for carbon monoxide predicted, and oxygen saturation by pulse oximetry on exertion and were categorized into mild, moderate, and severe groups of functional impairment. The efficacy of pirfenidone for VC and PFS over 52 weeks was compared among the three sub-populations.Of 264 patients, 102 (39%), 90 (34%), and 72 patients (27%) were classified as having mild, moderate, and severe grades of functional impairment, respectively. This classification was associated with arterial oxygen partial pressure at rest and degree of dyspnea at baseline. While pirfenidone attenuated VC decline at all grades of severity, covariance analysis revealed pirfenidone to have better efficacy in the sub-population with mild-grade IPF. Mixed model repeated measures analysis confirmed that pirfenidone markedly attenuated VC decline in patients with mild-grade IPF compared to its effects in patients with moderate or severe IPF. Pirfenidone also improved PFS markedly in patients with mild-grade IPF.This extended analysis suggested that pirfenidone exerted better therapeutic effects in patients with milder IPF. Further analysis with a larger population is needed to confirm these results.


Furukawa Y.,Nara Women's University | Furukawa Y.,Japan National Cardiovascular Center Research Institute | Kokubo Y.,Japan National Cardiovascular Center Research Institute | Okamura T.,Japan National Cardiovascular Center Research Institute | And 7 more authors.
Stroke | Year: 2010

Background and Purpose:Body mass index is most commonly used as the obesity index. Recently, waist circumference (WC) has been shown to be associated with the risk of cardiovascular disease (CVD). However, no studies have observed an association between WC and CVD in Japan. We examined the relationships of WC and body mass index with CVD in a Japanese urban population. Methods-We studied 5474 Japanese individuals (aged 30 to 79 years without CVD at baseline) who completed a baseline survey and received follow-up through December 2005. WC was measured at the umbilical level of participants in the standing position to the nearest 1 cm. The Cox proportional hazard ratios for CVD according to the quartiles of WC were calculated after adjustment for age, smoking, and drinking status. Results-During a mean follow-up of 11.7 years, 207 strokes and 133 myocardial infarctions were documented. In women, compared with the lowest quartile (WC <70 cm), the hazard ratio (95% CIs) after adjusting for age, smoking, and drinking in the highest quartile (WC ≥84 cm) were 1.85 (1.03 to 3.31) for CVD and 2.64 (1.16 to 6.03) for stroke. However, no such relationships of WC with CVD or stroke risk were observed in men. After further adjustment of hypertension, diabetes, and hypercholesterolemia, all of the mentioned relationships were not statistically significant. No associations of body mass index with CVD or strokes were observed. Conclusions:s:WC may be a better predictor for CVD or stroke in Japanese women. © 2010 American Heart Association, Inc.


Ono M.,Tohoku University | Ohkouchi S.,Tohoku University | Kanehira M.,Tohoku University | Tode N.,Tohoku University | And 10 more authors.
Molecular Therapy | Year: 2015

Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-β1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-β1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-β1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF. © The American Society of Gene & Cell Therapy.


PubMed | Japan Anti Tuberculosis Association, Japan International Cooperation Agency Amhara Region Surveillance and Response Project and Amhara National Regional State Health Bureau
Type: | Journal: Malaria journal | Year: 2016

In the Amhara Region of Ethiopia, a steep decline of malaria cases was seen in early 2014. This study verified the decrease of the malaria cases along with the positivity rates among acute febrile illness patients, from late 2012 through 2014 in selected districts of the Amhara Region of Federal Republic of Ethiopia.Descriptive epidemiological analysis was conducted on the routine malaria surveillance data from the World Health Organization epidemiological week 28 of 2012 to week 52 of 2014 in three districts: Burie Zuria, Dembia and Mecha, the Amhara Region in Ethiopia. The authors visited the three district health offices, and health centres, when necessary, and collected the surveillance data on malaria for that period.The study found that the malaria cases, along with the positivity rates, decreased from late 2012 to early 2014 in all three districts. Though the situation had slightly reverted in late 2014, the numbers of cases were much smaller than in late 2012 in all three districts. Despite the different diagnostic techniques used at health centres (malaria microscopy) and health posts (rapid diagnostic tests), moderate to high correlations were found, suggesting that the trends were real and not caused by a defect in the reagent, differences in the technicians skills for microscopy, or a change of the health workers attitudes toward cases with acute febrile illness. The decrease in malaria cases in early 2014 may have resulted from successful implementation of the three pillars of malaria control-case management, indoor residual spraying and insecticide-treated nets-in the districts where a high percentage of households were protected by indoor residual spraying and/or insecticide-treated nets.While the current efforts for malaria control should be strengthened and maintained, the review of malaria surveillance data should also be used to verify the malaria trend in the region.


PubMed | Japan Anti tuberculosis Association, Tohoku University and Tohoku Pharmaceutical University
Type: Journal Article | Journal: Molecular therapy : the journal of the American Society of Gene Therapy | Year: 2015

Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.


Higashiyama A.,Hyogo College of Medicine | Okamura T.,Keio University | Watanabe M.,National Cerebral and Cardiovascular Center | Kokubo Y.,National Cerebral and Cardiovascular Center | And 3 more authors.
Hypertension Research | Year: 2013

The relationship between alcohol consumption and the risk for cardiovascular disease (CVD) is U-shaped, whereas alcohol drinking is linearly associated with blood pressure, and the CVD risk also increases linearly according to blood pressure level. Accordingly, we investigated the net effect of alcohol consumption and hypertension on CVD and its subtypes in this study. A 13-year prospective study of 2336 Japanese men who were free from CVD was performed; ex-drinkers were excluded. The participants were divided into eight groups classified by the combination of the presence of hypertension (systolic/diastolic blood pressure ≥140/90 mm Hg) and alcohol consumption (never-, current-(light, moderate and heavy) drinkers). Multivariate-adjusted hazard ratios (HRs) for the incidence of CVD, coronary artery disease (CAD) and stroke due to the combination of hypertension and alcohol consumption were calculated and compared with non-hypertensive never-drinkers. The HRs for CVD and its subtypes were higher in hypertensives than those in non-hypertensives; in hypertensives without medication for hypertension, the relationship between alcohol consumption and the risks for CVD and CAD was U-shaped, with the highest and most significant increase in never-drinkers. The risk for total stroke was the highest in heavy-drinkers, which was significant. In non-hypertensives, there was no evident increase or decrease in the HRs for CVD and its subtypes in drinkers. Accordingly, controlling blood pressure is important to prevent CVD. In hypertensives, heavy drinking should be avoided to prevent CVD, although light-to-moderate drinking could be protective for CAD. Furthermore, in non-hypertensives, drinkers may need to continuously monitor their blood pressure. © 2013 The Japanese Society of Hypertension All rights reserved.


Higashiyama A.,Hyogo College of Medicine | Wakabayashi I.,Hyogo College of Medicine | Ono Y.,National Cerebral and Cardiovascular Center | Watanabe M.,National Cerebral and Cardiovascular Center | And 4 more authors.
Stroke | Year: 2011

Background And Purpose- Light-to-moderate alcohol consumption is associated with reduced risk for cardiovascular disease, whereas high serum γ-glutamyltransferase (GGT) level is associated with cardiovascular disease. However, whether light-to-moderate alcohol drinking is still related to reduced risk of cardiovascular disease irrespective of GGT level is uncertain. Methods- We performed a 12.5-year cohort study of 2336 men (excluding exdrinkers) who were free from cardiovascular disease. They were classified into 4 groups according to alcohol consumption: never, and current light, moderate, or heavy drinker. The multivariate-adjusted hazard ratios of alcohol consumption for incidence of coronary artery disease, total stroke, and ischemic stroke compared with those of never drinkers were assessed with stratification by GGT median (32 IU/L). Results- In participants with GGT >32 IU/L, the hazard ratios of all current drinkers for total and ischemic stroke were higher than those of never drinkers. However, in all current drinkers with GGT ≤32 IU/L, the multivariate-adjusted hazard ratios for total and ischemic stroke were lower than in never drinkers. Conclusions- In men with above GGT median, alcohol drinking even with light-to-moderate consumption could be a risk factor for ischemic stroke. © 2011 American Heart Association, Inc.


Moustafa G.A.I.,Osaka University | Nojima S.,Osaka University | Yamano Y.,Osaka University | Aono A.,Japan Anti Tuberculosis Association | And 4 more authors.
MedChemComm | Year: 2013

The potent antimycobacterial activity of (±)-platencin is reported. Complete inhibition of Mycobacterium smegmatis growth was observed at MICs of 0.5 μg mL-1 and 0.3 μg mL-1 under aerobic and hypoxic conditions, respectively. Notably, the compound exhibited potent bacteriostatic activities towards Mycobacterium tuberculosis H37Rv (MIC = 2 μg mL-1), multi-drug-resistant M. tuberculosis (MIC = 1 μg mL-1), and extensively drug-resistant M. tuberculosis (MIC = 1 μg mL-1). An overexpression study of the transformants of M. smegmatis revealed that platencin selectively targeted Mt-KasB and modestly inhibited Mt-KasA and Mt-FabH. © 2013 The Royal Society of Chemistry.

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