Cheng-Ta Yang

Obstructive sleep apnea: a stand-alone risk factor for chronic kidney disease

BACKGROUND Previous studies have found an association between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). However, subjects with confounding factors such as diabetes and hypertension were not excluded. The purpose of the present study was to determine whether patients with OSA without meeting criteria for diabetes or hypertension would also show increased likelihood of CKD. METHODS We prospectively enrolled adult patients with a chief complaint of habitual snoring. Overnight polysomnography, fasting blood triglyceride, cholesterol, glucose, insulin, creatinine, albumin and hemoglobin A1c, and first voiding urine albumin and creatinine were examined. Estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), homeostatic model assessment-insulin resistance and percentage of CKD were calculated. RESULTS The final analyses involved 40 patients who were middle-aged [44.8 (8.6) years] predominantly male (83%), obese [body mass index, 28.2 (5.1) kg/m(2)] and more severe OSA, with an apnea-hypopnea index (AHI) of 51.6 (39.2)/h. The mean eGFR and UACR were 85.4 (18.3) mL/min/1.73m(2) and 13.4 (23.4) mg/g, respectively. The prevalence of CKD in severe OSA subjects is 18%. With stepwise multivariate linear regression analysis, AHI and desaturation index were the only independent predictor of UACR (β = 0.26, P = 0.01, R(2) = 0.17) and eGFR (β = 0.32, P < 0.01, R(2) = 0.32), respectively. CONCLUSIONS High prevalence of CKD is present in severe OSA patients without hypertension or diabetes. Significantly positive correlations were found between severity of OSA and renal function impairment.

Cul4A is an oncogene in malignant pleural mesothelioma.

Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up‐regulation of p21 and p27 tumour suppressor proteins in a p53‐independent manner in H290, H28 and MS‐1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS‐1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down‐regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down‐regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.

The prevalence of restless legs syndrome in Taiwanese adults

Aim:  Few studies have examined the prevalence of restless legs syndrome (RLS) in Asian populations, with existing data suggesting substantially lower rates of RLS in Asian populations compared with Caucasians. However, varying definitions of RLS as well as problematic methodology make conclusions about RLS prevalence in Asian populations difficult to interpret. The current study therefore examines the prevalence of RLS in Taiwanese adults.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations

Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear. Methods: A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations. Results: One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p < 0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p < 0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005). Conclusion: Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.

Caffeic acid phenethyl ester decreases acute pneumonitis after irradiation in vitro and in vivo

BackgroundLung cancer is relatively resistant to radiation treatment and radiation pneumonitis is a major obstacle to increasing the radiation dose. We previously showed that Caffeic acid phenethyl ester (CAPE) induces apoptosis and increases radiosensitivity in lung cancer. To determine whether CAPE, an antioxidant and an inhibitor of NF-kappa B, could be a useful adjuvant agent for lung cancer treatment, we examine the effects of CAPE on irradiated normal lung tissue in this study.MethodsWe compared the effects of CAPE on cytotoxicity and intracellular oxidative stress in normal lung fibroblast and a lung cancer cell line. For in vivo analysis, whole thorax radiation (single dose 10 Gy and 20 Gy) was delivered to BALB/c male mice with or without CAPE pretreatment. NF- kappaB activation and the expression levels of acute inflammatory cytokines were evaluated in mice after irradiation.ResultsThe in vitro studies showed that CAPE cause no significant cytotoxicity in normal lung as compared to lung cancer cells. This is probably due to the differential effect on the expression of NF-kappa B between normal and malignant lung cells. The results from in vivo study showed that CAPE treatment decreased the expression of inflammatory cytokines including IL-1 alpha and beta, IL-6, TNF-alpha and TGF- beta, after irradiation. Moreover, histological and immunochemical data revealed that CAPE decreased radiation- induced interstitial pneumonitis and TGF-beta expression.ConclusionThis study suggests that CAPE decreases the cascade of inflammatory responses induced by thoracic irradiation without causing toxicity in normal lung tissue. This provides a rationale for combining CAPE and thoracic radiotherapy for lung cancer treatment in further clinical studies.

Diffuse alveolar damage associated mortality in selected acute respiratory distress syndrome patients with open lung biopsy

IntroductionDiffuse alveolar damage (DAD) is the pathological hallmark of acute respiratory distress syndrome (ARDS), however, the presence of DAD in the clinical criteria of ARDS patients by Berlin definition is little known. This study is designed to investigate the role of DAD in ARDS patients who underwent open lung biopsy.MethodsWe retrospectively reviewed all ARDS patients who met the Berlin definition and underwent open lung biopsy from January 1999 to January 2014 in a referred medical center. DAD is characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury. Clinical data including baseline characteristics, severity of ARDS, clinical and pathological diagnoses, and survival outcomes were analyzed.ResultsA total of 1838 patients with ARDS were identified and open lung biopsies were performed on 101 patients (5.5 %) during the study period. Of these 101 patients, the severity of ARDS on diagnosis was mild of 16.8 %, moderate of 56.5 % and severe of 26.7 %. The hospital mortality rate was not significant difference between the three groups (64.7 % vs 61.4 % vs 55.6 %, p = 0.81). Of the 101 clinical ARDS patients with open lung biopsies, 56.4 % (57/101) patients had DAD according to biopsy results. The proportion of DAD were 76.5 % (13/17) in mild, 56.1 % (32/57) in moderate and 44.4 % (12/27) in severe ARDS and there is no significant difference between the three groups (p = 0.113). Pathological findings of DAD patients had a higher hospital mortality rate than non-DAD patients (71.9 % vs 45.5 %, p = 0.007). Pathological findings of DAD (odds ratio: 3.554, 95 % CI, 1.385–9.12; p = 0.008) and Sequential Organ Failure Assessment score on the biopsy day (odds ratio: 1.424, 95 % CI, 1.187–1.707; p<0.001) were significantly and independently associated with hospital mortality. The baseline demographics and clinical characteristics were not significantly different between DAD and non-DAD patients.ConclusionsThe correlation of pathological findings of DAD and ARDS diagnosed by Berlin definition is modest. A pathological finding of DAD in ARDS patients is associated with hospital mortality and there are no clinical characteristics that could identify DAD patients before open lung biopsy.

Pulmonary cryptococcosis: Clinical, radiographical and serological markers of dissemination

Background and objective:  This study aimed to identify markers of disseminated infection in patients presenting with pulmonary cryptococcosis.

The 23-valent pneumococcal polysaccharide vaccine is effective in elderly adults over 75 years old—Taiwan's PPV vaccination program

BACKGROUND Pneumococcal infection is a serious cause of mortality and morbidity in the elderly. A nationwide pneumococcal polysaccharide vaccine (PPV) program for elderly adults aged 75 years and older was conducted in Taiwan in 2008. The efficacy of the PPV in this very elderly population was evaluated. METHODS The data were analyzed using the Taiwan National Health Insurance Research Database (NHIRD), the cause-of-death registration database and the invasive pneumococcal disease (IPD) notification database of Taiwans Ministry of Health and Welfare. The efficacy of PPV administration in this very elderly population was evaluated using multivariate logistic regression after propensity score matching (PSM). The rates of IPD, death from IPD, pneumonia hospitalization, death from pneumonia, and all-cause mortality were compared for those who did and did not receive the PPV. RESULTS Among the 1078,955 eligible people, 318,257 (29.5%) received the PPV, and 760,698 (70.5%) were not vaccinated. Using PSM to adjust for confounding factors, including age, gender, influenza vaccination status, associated chronic diseases and health care utilization, those who received the PPV had significantly lower odds ratios (ORs) for IPD (OR=0.24, 95% CI=0.123-0.461, p<0.001), death from IPD (OR=0.09, 95% CI=0.011-0.704, p<0.022, p<0.001), pneumonia hospitalization (OR=0.40, 95% CI=0.395-0.415, p<0.001), death from pneumonia (OR=0.07, 95% CI=0.059-0.082, p<0.001), and all-cause mortality (OR=0.07, 95% CI=0.069-0.072, p<0.001) compared with those who were not vaccinated. CONCLUSIONS PPV vaccination in the previous year was associated with a 60% reduction in pneumonia hospitalization, a 76% reduction in IPD, and a greater than 90% reduction in death from pneumonia, IPD and all causes among people over 75 years old in Taiwan. Data from subsequent years in Taiwan and similar populations elsewhere are needed to evaluate the contribution of underlying variations in the mortality rate and the confounding effects of prior disease severity to these findings.

Survival Predictors in Acute Respiratory Distress Syndrome With Extracorporeal Membrane Oxygenation

BACKGROUND Extracorporeal membrane oxygenation (ECMO) can be used as a salvage therapy, but the effectiveness is controversial. The aim of this study was to investigate the predictors of mortality and the influence of organ dysfunction scores in severe acute respiratory distress syndrome (ARDS) patients treated with ECMO. METHODS The records of adult severe ARDS patients receiving ECMO support from May 2006 to December 2011 at Chang Gung Memorial Hospital were retrospectively analyzed. RESULTS The records of 65 patients with severe ARDS who received venovenous ECMO were analyzed. The hospital survival rate was 47.7%. Survivors were younger than nonsurvivors (41.4 ± 15.4 versus 54.1 ± 16.9 years, respectively; p = 0.002) and had shorter duration of mechanical ventilation before ECMO (52.7 ± 51.1 versus 112.1 ± 101.0 hours, respectively; p = 0.01). Before ECMO, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction scores were significantly lower for survivors than for nonsurvivors. Mortality rate increased with rising predictive score. During 7 days of ECMO use, organ dysfunction scores were significantly lower for survivors than nonsurvivors. CONCLUSIONS Severe ARDS patients who are younger, have shorter duration of mechanical ventilation, and lower organ dysfunction scores before ECMO initiation have more favorable survival outcome. Early application of ECMO, especially if predictive score is below 2, may improve survival. Organ dysfunction scores before and during ECMO support are correlated with survival.

YAP promotes erlotinib resistance in human non-small cell lung cancer cells

Yes-associated protein (YAP) is a main mediator of the Hippo pathway, which promotes cancer development. Here we show that YAP promotes resistance to erlotinib in human non-small cell lung cancer (NSCLC) cells. We found that forced YAP overexpression through YAP plasmid transfection promotes erlotinib resistance in HCC827 (exon 19 deletion) cells. In YAP plasmid-transfected HCC827 cells, GTIIC reporter activity and Hippo downstream gene expression of AREG and CTGF increased significantly (P<0.05), as did ERBB3 mRNA expression (P<0.05). GTIIC reporter activity, ERBB3 protein and mRNA expression all increased in HCC827 erlotinib-resistance (ER) cells compared to parental HCC827 cells. Inhibition of YAP by small interfering RNA (siRNA) increased the cytotoxicity of erlotinib to H1975 (L858R+T790M) cells. In YAP siRNA-transfected H1975 cells, GTIIC reporter activity and downstream gene expression of AREG and CTGF decreased significantly (P<0.05). Verteporfin, YAP inhibitor had an effect similar to that of YAP siRNA; it increased sensitivity of H1975 cells to erlotinib and in combination with erlotinib, synergistically reduced migration, invasion and tumor sphere formation abilities in H1975 cells. Our results indicate that YAP promotes erlotinib resistance in the erlotinib-sensitive NSCLC cell line HCC827. Inhibition of YAP by siRNA increases sensitivity of erlotinib-resistant NSCLC cell line H1975 to erlotinib.