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Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

The interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. Our study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor-associated dendritic cells and its effect on cancer development. The combination of HB-EGF (heparin-binding EGF-like growth factor) and CXCL5 (CXCL5/epithelial neutrophil-activating peptide-78) produced a strong synergistic effect on cancer proliferation, epithelial-mesenchymal transition, migration and invasion. CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB-EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. Knockdown of HSP27 by shRNA decreased HB-EGF plus CXCL5-mediated tumor spheroid formation in a three-dimensional culture system, suggesting that AKT/HSP27 was required for HB-EGF/CXCL5-mediated cancer progression. Inhibiting RSK also reduces the modulation of c-Fos phosphorylation, Snail upregulation and cell migration by HB-EGF plus CXCL5, suggesting a synergistic effect of ERK/RSK and HB-EGF plus CXCL5 on cell migration. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity. These results provide evidence that elucidates potential cross-points between extracellular signals affecting lung cancer progression. Targeting CXCL5 may provide therapeutic benefits for lung cancer chemotherapy or immunotherapy.

Lung cancer is the leading cause of cancer death worldwide as well as in Taiwan. Interleukin-6 (IL-6) is a multifunctional cytokine and has been implicated in tumor progression. This study recruited 245 patients with advanced (Stage 3B/4) nonsmall cell lung cancer (NSCLC) that had received chemotherapy, to evaluate associations between IL-6 and lung cancer-specific survival. Among these subjects, 112 gave blood samples before and 133 after the start of chemotherapy. Plasma IL-6 was measured using an enzyme linked-immunosorbent assay. The 33rd and 66th percentiles of IL-6 concentrations were 2.01 and 25.16 for the 245 patients and were defined as the cutoff points for dividing the patients into low, intermediate and high groups. Kaplan-Meier and Cox proportional-hazard models were used to evaluate the relationship between the IL-6 level and survival time. Results after adjusting for age, sex, smoking history, histologic type and stage of lung cancer revealed a significant relationship. For all patients, the hazard ratio with high IL-6 levels for lung cancer-specific survival was 2.10 [95% confidence interval (CI) = 1.49 - 2.96] compared with low IL-6 levels. The hazard ratio for patients who were recruited before and after the start of chemotherapy was1.25 (95% CI = 0.73 - 2.13) and 3.66 (95% CI = 2.18 - 6.15), respectively. Patients with high circulating IL-6 also responded poorly to chemotherapy. Therefore, a high level of circulating IL-6 was associated with an inferior response and survival outcome in NSCLC patients treated with chemotherapy.

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never-smoking patients with lung adenocarcinoma. Multivariate-adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in-frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0-4.8) in female never-smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in-frame deletion both in never-smokers (aOR, 1.7 with 95% CI, 1.0-3.0) and female never-smokers (aOR, 1.9 with 95% CI, 1.0-3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6-fold increase in the occurrence of the EGFR exon 19 in-frame deletion in female never-smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in-frame deletion both in never-smokers (p = 0.007 for trend) and female never-smokers (p = 0.002 for trend). Our findings suggest that the in-frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never-smoking lung adenocarcinoma patients, especially in females.

Features of airway remodelling have been described using tissue obtained from fatal cases of asthma and bronchial biopsies from mildly, moderately and severely asthmatic patients. Epithelial detachment and smooth muscle mass enhancement are common features of asthmatic bronchial tissue. This study is the first to investigate the inhibitory effect of nonylphenol (NP) on human bronchial epithelial cell lines BEAS-2B and HBE135-E6E7 (HBE). The results show that NP inhibits bronchial epithelial proliferation via the Fas/Fas ligand apoptotic system. We also treated BEAS-2B and HBE with NP and harvested the condition medium (CM), which was then added to bronchial smooth muscle cells (BSMC). Cultures of BSMC with NP-BEAS-2B-CM and NP-HBE-CM increased BSMC proliferation and migration. Exposure of BEAS-2B and HBE to NP caused epithelial cells to produce inflammatory cytokines IL-6 and IL-8, which subsequently induced BSMC proliferation and migration. Depleting both IL-6 and IL-8 completely reversed the effect of NP-BEAS-2B-CM- and NP-HBE-CM-mediated BSMC proliferation and migration, suggesting that this effect is a synergistic influence of IL-6 and IL-8. This study is the first to demonstrate that NP not only induces bronchial epithelial apoptosis via the Fas-mediated pathway but also stimulates the bronchial epithelium to secrete IL-6 and IL-8, which cause bronchial smooth muscle proliferation and migration - major features in asthma remodelling.

High-sensitivity C-reactive protein (hs-CRP) concentrations and obesity are proposed to have a significant relationship with impairment of lung function, but little has been reported to date on the association between CRP gene and lung function. We studied the association of three tagSNPs (tag single nucleotide polymorphisms) of CRP gene and their interactions with central obesity on lung function. A total of 384 asthmatic adults and 384 controls who were 1:1 matched by sex and age were recruited for this study. Three tagSNPs polymorphisms for CRP rs1417938, rs1800947 and rs1205 were selected from HapMap data and genotyping by using TaqMan allelic discrimination assay. A questionnaire interview, body composition and pulmonary function tests were performed. CRP single nucleotide polymorphisms (SNPs) did not increase the risk of asthma, but CRP rs1205 CC genotype significantly decreased the predictive value of forced vital capacity (FVC) in the asthma group (adjusted mean change = −7.54%, 95% CI = −13.82 to −1.25%). Waist-to-hip ratio, not body mass index, also decreased the predictive value of FVC in asthmatics. The subjects with central obesity who carried CRP SNPs have a significant reduction effect in lung function. The current results suggest that central obesity may play a major role in lung function, and these effects were modified significantly by the polymorphisms for CRP gene.

There is now increasing evidence from the experimental and clinical setting that therapeutic hypercapnia from intentionally inspired carbon dioxide (CO 2 ) or lower tidal volume might be a beneficial adjunct to the strategies of mechanical ventilation in critical illness. Although previous reports indicate that CO 2 exerts a beneficial effect in the lungs, the pulmonary vascular response to hypercapnia under various conditions remains to be clarified. The purpose of the present study is to characterize the pulmonary vascular response to CO 2 under the different conditions of pulmonary hypertension secondary to increased pulmonary blood flow and secondary to hypoxic pulmonary vasoconstriction. Isolated rat lung ( n = 32) was used to study (1) the vasoactive action of 5% CO 2 in either N 2 (hypoxic-hypercapnia) or air (normoxic-hypercapnia) at different pulmonary arterial pressure levels induced by graded speed of perfusion flow and (2) the role of nitric oxide (NO) in mediating the pulmonary vascular response to hypercapnia, hypoxia, and flow-associated pulmonary hypertension. The results indicated that inhaled CO 2 reversed pulmonary hypertension induced by hypoxia but not by flow alteration. Endogenous NO attenuates hypoxic pulmonary vasoconstriction but does not augment the CO 2 -induced vasodilatation. Acute change in blood flow does not alter the endogenous NO production.

This investigation explores the microinjection molding of light-guided plates (LGPs) using lithography, electroplating, and molding (LIGA)-like fabricated stampers. The 3.5-in. LGP has a thin wall (0.76 mm) and micron-sized features of truncated pyramidal prisms (70 μm wide and 38.3 μm deep, with a vertex angle of 70.5°) and v-grooves (9.8 μm deep). Stampers for LGP injection molding (IM) are fabricated precisely by combining the anisotropic wet etching of silicon-on-insulation wafers with electroforming. LGPs must have multiple quality characteristics, such as good replication effects on microfeatures and flatness of the plate. In this study, the Taguchi method and gray relational analysis are adopted to optimize the microinjection molding parameters. Various IM parameters, including mold temperature, melt temperature, holding pressure, and injection speed, are considered. Experimental results demonstrate that mold temperature and holding pressure dominate the performance. Gray relational analysis and the Taguchi method can be used to determine the optimal process parameters for LGP molding. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

In this study, we investigated the feasibility of injection molding (IM) and injection compression molding (ICM) for fabricating 3.5-in. light-guided plates (LGPs). The LGP was 0.4 mm thick with v-grooved microfeatures (10 μm wide and 5 μm deep). A mold was designed to fabricate LGPs by IM and ICM. Micromachining was used to make the mold insert. The Taguchi method and parametric analysis were applied to examine the effects of the process parameters on the molding quality. The following parameters were considered: barrel temperature, mold temperature, packing pressure, and packing time. Mold temperature in this investigation was in the conventional range. Increasing the barrel temperature and mold temperature generally improved the polymer melt fill in the cavities with microdimensions. The experimental results for the replication of microfeatures by IM and ICM are presented and compared. The height of the v-grooved microfeatures replicated by ICM was more accurate than those replicated by IM. Additionally, the flatness of the fabricated LGPs showed that ICM was better than IM for thin-walled molding. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Summary Background Several studies have suggested that the association between obesity and asthma may be stronger in females than in males, but the reason is still unclear. Objective The aim of this study was to investigate whether differences in high-sensitivity C-reactive protein (hs-CRP) levels explain why obesity is associated with asthma in females but not in males. Methods This study prospectively enrolled 754 subjects 18 years old from hospital-based asthma patients and population-based controls. We measured adiposity factors [body mass index (BMI), waist circumference and waist-hip ratio], hs-CRP and total IgE levels. Results After adjusting for potential confounding factors, we found a significant association between BMI and asthma in females with a significant interaction of gender and BMI on asthma (χ2=10.2, P=0.004). If hs-CRP was added to the logistic model, the interaction was attenuated but still significant (χ2=7.02, P=0.03). After adjusting for BMI, we did not find that circulating hs-CRP concentrations were significantly associated with asthma in males and females. Conclusion We found that BMI was associated with asthma in females, but our results do not support the suggestion that hs-CRP levels contribute significantly to the link between obesity and asthma with respect to gender disparity. Cite this as: T.-N. Wang, M.-C. Lin, C.-C. Wu, M.-S. Huang, S. Y. Leung, C.-C. Huang, P.-S. Ho and Y.-C. Ko, Clinical & Experimental Allergy, 2011 (41) 72–77.

This study applies a magnetic induction heating method for rapid and uniform heating of a mold surface for injection molding of 2-inch light-guided plates (LGPs). Mold temperature is an important process parameter that affects microinjection molding quality. This research investigates the effects of high mold surface temperature generated by induction heating in enhancing the replication rate of microfeatures of LGPs. This study has three stages. First, an appropriate power rate setting is determined for induction heating and injection molding process window. Second, all key parameters affecting microfeature quality are identified to determine the optimum LGP micromolding parameters using the Taguchi and ANOVA methods. Third, the quality of microfeature heights and angles are experimentally verified. Polymethyl methacrylate was molded under various injection molding conditions to replicate an electroformed nickel stamper with V grooves 10 µm in width and 5 µm in depth. In this investigation, injection speed was set in the conventional range. Experimental findings indicate that instead of high mold temperature, the combination of low mold temperature and high surface temperature obtained using induction heating improve replication quality and reduce cycle time. Wiley Periodicals, Inc. J Appl Polym Sci ,118: 3058-3065, 2010

Toona sinensis extracts have been shown to exhibit anti-cancer effects in human ovarian cancer cell lines, human promyelocytic leukemia cells and human lung adenocarcinoma. Its safety has also been confirmed in animal studies. However, its anti-cancer properties in human lung large cell carcinoma have not been studied. Here, we used a powder obtained by freeze-drying the super-natant of centrifuged crude extract from Toona sinensis leaves (TSL-1) to treat the human lung carcinoma cell line H661. Cell viability was evaluated by the 3-(4-,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Flow cytometry analysis revealed that TSL-1 blocked H661 cell cycle progression. Western blot analysis showed decreased expression of cell cycle proteins that promote cell cycle progression, including cyclin-dependent kinase 4 and cyclin D1, and increased the expression of proteins that inhibit cell cycle progression, including p27. Furthermore, flow cytometry analysis showed that TSL-1 induced H661 cell apoptosis. Western blot analysis showed that TSL-1 reduced the expression of the anti-apoptotic protein B-cell lymphoma 2, and degraded the DNA repair protein, poly(ADP-ribose) polymerase. TSL-1 shows potential as a novel therapeutic agent or for use as an adjuvant for treating human lung large cell carcinoma.

This work experimentally investigates the use of induction-heating to heat mold surfaces rapidly, and thus enhance the replication effect of the microstructure of light-guided plates (LGP) in the injection molding process. This investigation employs a 2-inch LGP injection mold as the experimental carrier, and compares the replication effect on the microstructure of induction heating with that of conventional oil-heating. Temperature increases on the mold plate are examined using a thermal video system. The experimental results show that (1) the flat induction coil design promotes rapid surface heating. (2) Induction-heating the mold surface to 110°C improves the replication rate of the height of the micro-structure by up to 95%. (3) The LGP produced by induction heating has no significant residual stress.

Combined interstitial lung disease and the presence of 'mechanic's hands' could be a clinical clue in the early diagnosis of the rare disease, amyopathic antisynthetase syndrome for which anti-Jo-1 antibody is a useful diagnostic tool. The case is reported of a patient who suffered from shortness of breath and dry cough, with pulmonary fibrosis on CXR and CT scan, and interstitial pneumonitis on trans-bronchial biopsy. She was also positive for anti-Jo-1 and anti-Ro antibodies. 'Mechanic's hands' were noted bilaterally but with no evidence of myopathy in either the electromyogram or on muscle biopsy. The patient was treated with prednisolone and her clinical picture, including the 'mechanic's hands' and lung fibrosis, subsided gradually, suggesting that the sign may be a useful follow up tool in this disease. Early diagnosis and corticosteroid therapy could be beneficial for these patients.

This study aimed to identify the clinical characteristics of culture-positive pulmonary tuberculosis (TB) patients from a southern Taiwan hospital-based survey between August 1, 2003 and July 31, 2006. Demographics, symptoms, susceptibility patterns, sputum acid-fast bacilli (AFB) stain status and treatment outcomes were recorded. The medical records of 154 patients who presented to the Kaohsiung Municipal Hsiao-Kang Hospital were analyzed retrospectively. The mean age of patients was 59.5 years; 115 patients were male and 39 were female. Diabetes mellitus (48/154; 31.2%) was the most frequent risk factor for pulmonary TB infection. Nearly all patients (139/154; 90.3%) had a cough. Fever was only seen in 27.9% and hemoptysis in 14.9% of patients. The combined resistance rates of Mycobacterium tuberculosis to the tested first-line agents were as follows: isoniazid, 3.2%; rifampin, 7.8%; ethambutol, 5.8%; and streptomycin, 2.6%. The combined resistance rate to any one of four first-line drugs was 12.3%. The combined resistance rate to ofloxacin was 3.9%. The combined resistance rate of multidrug resistant-TB was 1.9%. Sputum AFB stains were positive in 68.2% of cases. Analysis of treatment outcomes showed overall treatment success at 76.6%. The proportions of patients who died, defaulted treatment or in whom treatment failed were 16.2%, 3.9% and 0.0%, respectively. In conclusion, our study showed: (1) a higher frequency of pulmonary TB in male subjects than in other areas of Taiwan; (2) a higher frequency of cough and lower frequency of fever and hemoptysis than previous studies; (3) that the combined resistance rates to isoniazid and streptomycin were lower than both average levels in Taiwan and the global combined drug resistance rate; and (4) a higher proportion of patients responding to treatment and lower proportions of patients suffering mortality, defaulting treatment or not responding to treatment compared with other areas of Taiwan. With regard to resistance rates, the combined resistance rate to ethambutol was similar to the average level in Taiwan and higher than the global combined drug resistance rate. However, the combined resistance rate to rifampin was higher than both the average level in Taiwan and the global combined drug resistance rate. The combined resistance rates to at least any one of four first-line drugs and multidrug resistant-TB were lower than the average levels in Taiwan and higher than the global combined drug resistance rate. Our results may help to identify local variations in the disease and improve the effectiveness of TB infection control programs.

Studies have shown that weekend or night admissions to intensive care units (ICUs) are associated with increased mortality in critically ill patients. Our study aimed to evaluate the effects of admission time and day on patient outcomes in a medical ICU equipped with patient management guide-lines, and staffed by intensivists on call for 24 hours, who led the morning rounds on all days of the week but did not stay in-house overnight. The study enrolled 611 consecutive patients admitted to a 26-bed medical ICU in a university hospital during a 7-month period. We divided them into two groups, which we labeled as "office hours" (08:00-18:00 on weekdays) and "non-office hours" (18:00-08:00 on weekdays, and all times on weekends) according to their ICU admission times. The clinical outcomes were compared between the groups. The effects of admission on weekends, at night, and various days of the week on hospital mortality were also evaluated. Our results showed that there were no significant differences in ICU and hospital mortalities between patients admitted during office hours and those admitted during non-office hours (27.2% vs. 27.4%, p = 1.000; 38.9% vs. 37.6%, p = 0.798). The ICU length of stay, ICU-free time within 21 days, and length of stay in the hospital were also comparable in both groups. Among the 392 patients requiring mechanical ventilation, the ventilator outcomes were not significantly different between those in the office-hour group and the non-office-hour group. Multivariate logistic regression analyses showed that the adjusted odds of hospital mortality were not significantly higher for patients admitted to our ICU on weekends, at night, or on any days of the week. In conclusion, our results showed that non-office-hour admissions to our medical ICU were not associated with poorer ICU, hospital, and ventilator outcomes, compared with office-hour admissions. Neither were time of day and day of the week admissions to our ICU associated with significant differences in hospital mortality.

Background and objective: The value of routine culture for mycobacterium from bronchoscopic washings and the cost-effectiveness is still uncertain in countries where tuberculosis is endemic. This study examined the epidemiology of positive cultures for M. tuberculosis obtained by bronchoscopy to determine the health benefit and cost of a policy of routine culture and smear. Methods: All positive cultures for Mycobacterium tuberculosis in bronchial washings and the corresponding CXR features were analysed. Results: The incidence of tuberculosis in routine bronchoscopy was 3.71%, and in patients who presented with typical tuberculosis features on CXR was 6.5%. Up to 10.6% of culture-proven pulmonary tuberculosis relied on bronchoscopy for diagnosis. The total cost of routine mycobacterium culture and acid-fast bacillus smear during the 2-year period was approximately USD 24 800. Conclusion: Routine mycobacterium culture and acid-fast staining from bronchoscopic specimens appears to be valuable in countries where tuberculosis is prevalent.

Since its introduction in 1985 by Ciaglia et al, percutaneous dilational tracheostomy (PDT) has gradually become the procedure of choice in establishing a long-term airway in many intensive care units (ICU). However, the safety of performing PDT in patients with barotrauma is still unknown and has never been reported. We present the case of a 35-year-old man with AIDS, who was admitted to our medical ICU for pneumonia and acute respiratory distress syndrome. He developed subcutaneous emphysema and pneumomediastinum as complications of mechanical ventilation. After stabilization of the barotrauma, he underwent PDT with the standard Ciaglia Blue Rhino technique. However, rapid and extensive progression of preexisting barotraumas occurred shortly after PDT. This severe complication was nearly fatal. The prolonged procedure during which the susceptible lung was exposed to longer duration of high airway pressure was thought to be the mechanism of rapid deterioration of the preexisting barotrauma. With aggressive supportive care, the patient survived. To prevent further deterioration of preexisting barotraumas during and after PDT in future cases, we propose some principles that should be strictly followed. Under administration of these principles, we safely performed PDT in another case with preexisting barotrauma 1 month later.

Identifying biomarkers that predict patient outcome might provide opportunities for developing better therapeutic strategies to prolong metastatic lung cancer patient survival. The first enzyme of ...

Background The incidence of upper urinary tract tumors is relatively high in southern Taiwan. DNA analysis by means of flow cytometry is not well investigated with regard to tumors of the upper urinary tract and the differences in DNA ploidy between transitional cell carcinomas in endemic and nonendemic areas. Methods A retrospective nuclear DNA ploidy analysis by flow cytometry comprised 41 formaldehyde solution-fixed, paraffin-embedded tissue specimens of transitional cell carcinoma of the renal pelvis and ureter. The preparation of nuclear suspensions from paraffin-embedded tissue blocks and staining were modified by means of the techniques of Hedley and Vindelov. Results There was no statistical correlation between DNA ploidy, histologic grade, and pathologic stage, however, 82% of the DNA nondiploid tumors showed tumor progression. In contrast, only 46% of the DNA diploid tumors revealed tumor progression. Among Grade 2 tumors, 85% of the DNA nondiploid tumors showed postoperative tumor progression, whereas only 31% of the DNA diploid tumors showed tumor progression. Seventy-nine percent of the nondiploid patterns were present in patients native to the Pa Chang Valley, where the so-called "blackfoot disease" and urothelium tumor are endemic, whereas only 22% appeared in patients living in other areas. Conclusions DNA flow cytometry can identify a group of patients with poor outcome unpredictable by pathologic examination, and is an important tool in research into the pathogenesis of cancer.