Delivery Capacity and Anticancer Ability of the Berberine-Loaded Gold Nanoparticles to Promote the Apoptosis Effect in Breast Cancer.

Gold nanoparticles (AuNPs) were fabricated with biocompatible collagen (Col) and then conjugated with berberine (BB), denoted as Au-Col-BB, to investigate the endocytic mechanisms in Her-2 breast cancer cell line and in bovine aortic endothelial cells (BAEC). Owing to the superior biocompatibility, tunable physicochemical properties, and potential functionalization with biomolecules, AuNPs have been well studied as carriers of biomolecules for diseases and cancer therapeutics. Composites of AuNPs with biopolymer, such as fibronectin or Col, have been revealed to increase cell proliferation, migration, and differentiation. BB is a natural compound with impressive health benefits, such as lowering blood sugar and reducing weight. In addition, BB can inhibit cell proliferation by modulating cell cycle progress and autophagy, and induce cell apoptosis in vivo and in vitro. In the current research, BB was conjugated on the Col-AuNP composite ("Au-Col"). The UV-Visible spectroscopy and infrared spectroscopy confirmed the conjugation of BB on Au-Col. The particle size of the Au-Col-BB conjugate was about 227 nm, determined by dynamic light scattering. Furthermore, Au-Col-BB was less cytotoxic to BAEC vs. Her-2 cell line in terms of MTT assay and cell cycle behavior. Au-Col-BB, compared to Au-Col, showed greater cell uptake capacity and potential cellular transportation by BAEC and Her-2 using the fluorescence-conjugated Au-Col-BB. In addition, the clathrin-mediated endocytosis and cell autophagy seemed to be the favorite endocytic mechanism for the internalization of Au-Col-BB by BAEC and Her-2. Au-Col-BB significantly inhibited cell migration in Her-2, but not in BAEC. Moreover, apoptotic cascade proteins, such as Bax and p21, were expressed in Her-2 after the treatment of Au-Col-BB. The tumor suppression was examined in a model of xenograft mice treated with Au-Col-BB nanovehicles. Results demonstrated that the tumor weight was remarkably reduced by the treatment of Au-Col-BB. Altogether, the promising findings of Au-Col-BB nanocarrier on Her-2 breast cancer cell line suggest that Au-Col-BB may be a good candidate of anticancer drug for the treatment of human breast cancer.

Characteristics of Chinese herbal medicine usage and its effect on survival of lung cancer patients in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: In Taiwan, lung cancer remains one of the deadliest cancers. Survival of lung cancer patients remains low, ranging from 6% to 18%. Studies have shown that Chinese herbal medicine (CHM) can be used to induce cell apoptosis and exhibit anti-inflammatoryanti-inflammatory activities in cancer cells. AIM OF THE STUDY: This study aimed to investigate the frequencies and patterns of CHM treatment for lung cancer patients and the effect of CHM on their survival probability in Taiwan. MATERIALS AND METHODS: We identified 6939 lung cancer patients (ICD-9-CM: 162). We allocated 264 CHM users and 528 CHM-non users, matched for age, gender, duration, and regular treatment. Chi-square test, conditional multivariable logistic regression, Kaplan-Meier method, and the log-rank test were used in this study. RESULTS: The CHM group was characterized by a longer follow up time and more cases of hyperlipidemia and liver cirrhosis. This group exhibited a lower mortality hazard ratio (0.48, 95% confidence interval [0.39-0.61], p < 0.001), after adjusting for comorbidities. The trend was also observed that the cumulative survival probability was higher in CHM than in non-CHM users (p < 0.0001, log rank test). Analysis of their CHM prescription pattern revealed that Bu-Zhong-Yi-Qi-Tang (BZYQT), Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), and Bai-He-Gu-Jin-Tang (BHGJT); and Bei-Mu (BM), Xing-Ren (XR) and Ge-Gen (GG) were found to be the top three formulas and herbs, respectively. Among them, BM was the core CHM of the major cluster, and Jie-Geng (JG) and Mai-Men-Dong-Tang (MMDT) were important CHMs by CHM network analysis. CONCLUSION: The use of CHM as an adjunctive therapy may reduce the mortality hazard ratio of lung cancer patients. The investigation of their comprehensive CHM prescription patterns might be useful in future large-scale, randomized clinical investigations of agent effectiveness, safety, and potential interactions with conventional treatments for lung cancer patients.

What if a tumor is significantly enlarged just before stereotactic body radiation therapy? A case report and review of the literature.

Stereotactic body radiation therapy (SBRT) plays an important role in early stage non-small cell lung cancer. Tumor growth before radiotherapy planning (RTP) or during SBRT has been reported in lung cancer patients; however, little is known of growth during the period in-between (i.e. after RTP but before SBRT). An 83-year-old man referred to our hospital and diagnosed with medically inoperable non-small cell lung cancer was noted to have significant tumor progression on day 1 of cone beam computed tomography just before the planned SBRT delivery. Because of uncertainty of the underlying etiology and unfamiliarity with this phenomenon, we made a clinical decision to arrange re-simulation and revise our treatment to conventional fractionated radiotherapy (CFRT). After an initial response, distant metastases occurred eight months after CFRT. The patient received best supportive care and was under hospice care at the last follow-up (27 months after CFRT). We report a case with significant tumor growth just before planned SBRT. Optimal management in this scenario requires further investigation.

Gender differences in effects of obesity and asthma on adolescent lung function: Results from a population-based study.

OBJECTIVE: To investigate lung function associated with asthma and body mass index (BMI) among adolescents at 96 northern Taiwan junior high schools participating in an asthma screening program. METHODS: The questionnaires and lung function test results measured for 3669 boys and 3523 girls were included in this study for data analysis. Measures of forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and FEV1/FVC ratio were compared by sex, asthma status and BMI. RESULTS: Overall mean FVC levels were similar between students with and without asthma, 3.71 L vs. 3.71 L for boys (p = 0.991) and 2.79 vs. 2.78 for girls (p = 0.517). The overall mean FEV1 levels were also similar between girls with and without asthma. Asthmatic boys had lower FEV1 than non-asthmatic boys. Mean FEV1/FVC was significantly lower in students with asthma than those without asthma. Mean FVC and FEV1 increased with BMI in both sexes. A lower mean FEV1/FVC was observed among students with asthma and high BMI, and was more pronounced in boys than in girls. Multivariable regression analysis also showed that FEV1/FVC ratios were negatively associated with asthma and high BMI, stronger in boys than in girls for asthma (ß = -2.176 (standard errors (SE) = 0.268) vs. -1.085 (SE = 0.258) and for BMI (ß = -0.309 (SE = 0.025) vs. -0.218 (SE = 0.029)). CONCLUSION: This northern Taiwan study suggests that FEV1/FVC is negatively associated with asthma and high BMI in adolescents, stronger for boys than for girls.

NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance.

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3'UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

Vascular endothelial growth factor-C upregulates cortactin and promotes metastasis of esophageal squamous cell carcinoma.

BACKGROUND: Vascular endothelial growth factor-C (VEGF-C) plays an important role during cancer progression and metastasis through activation of VEGF receptors. However, the role of VEGF-C in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: The expression of VEGF-C in advanced stages of esophageal cancer was examined by immunohistochemistry and its expression was correlated with the protein level of cortactin (CTTN) by Western blot. Knockdown and overexpression of the CTTN protein were respectively performed to investigate the effects on VEGF-C-enhanced ESCC migration/invasion by in vitro transwell assay, cell tracing assay, and tumor growth/experimental metastasis in animal models. RESULTS: The expression of VEGF-C was positively correlated with tumor status and poor clinical prognosis in patient with esophageal cancer. VEGF-C-upregulated CTTN expression contributed the migration/invasive abilities of ESCC cell lines through Src-mediated downregulation of miR-326. Moreover, knockdown of CTTN expression significantly abolished VEGF-C-induced tumor growth and experimental lung metastasis in vivo. CONCLUSIONS: Upregulation of CTTN is critical for VEGF-C-mediated tumor growth and metastasis of ESCC. These finding suggest that VEGF-C upregulated CTTN expression through Src-mediated downregulation of miR-326. CTTN may be a crucial mediator of VEGF-C-involved ESCC metastasis, which provides a potential target for diagnosis and individualized treatment in clinical practice.

miR326 maturation is crucial for VEGF-C-driven cortactin expression and esophageal cancer progression.

Esophageal cancer is an aggressive human malignancy with increasing incidence in the developed world. VEGF-C makes crucial contributions to esophageal cancer progression that are not well understood. Here, we report the discovery of regulatory relationship in esophageal cancers between the expression of VEGF-C and cortactin (CTTN), a regulator of the cortical actin cytoskeleton. Upregulation of CTTN expression by VEGF-C enhanced the invasive properties of esophageal squamous cell carcinoma in vitro and tumor metastasis in vivo. Mechanistic investigations showed that VEGF-C increased CTTN expression by downregulating Dicer-mediated maturation of miR326, thereby relieving the suppressive effect of miR326 on CTTN expression. Clinically, expression of Dicer and miR326 correlated with poor prognosis in patients with esophageal cancer. Our findings offer insights into how VEGF-C enhances the robust invasive and metastatic properties of esophageal cancer, which has potential implications for the development of new biomarkers or therapies in this setting.

Suppression of Dicer increases sensitivity to gefitinib in human lung cancer cells.

BACKGROUND: Accumulating evidence is revealing an important role of microRNA (miRNA) in tumor progression and chemotherapeutic resistance. Dicer is a cytoplasmic endoribonuclease type III crucial for production of mature miRNAs. The aberrant expression of Dicer has also been reportedly associated with clinical aggressiveness, prognosis, and patient survival in various cancer types. However, the molecular mechanisms of Dicer in acquired gefitinib resistance are still not clear. METHODS: In this study, we analyzed the protein level of Dicer between gefitinib-sensitive (PC9) and gefitinib-resistant (PC9/GR) non-small-cell lung cancer (NSCLC) cell lines by Western blot analysis. Silence and overexpression of the Dicer were performed to investigate the effects on gefitinib sensitivity, as assessed by (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and sub-G1 assay of flow cytometry. To further explore the mechanism of chemoresistance, we examined whether Dicer knockdown led to modulating specific miRNAs and its miRNA target genes. RESULTS: Dicer expression was significantly increased in PC9/GR compared with PC9 cells. Knockdown of Dicer restores gefitinib sensitivity in resistant cells, and overexpression of Dicer enhances resistance to gefitinib in sensitive cells. Silencing of Dicer induces sensitivity to gefitinib in NSCLC cells through the downregulation of miR-30b/c and miR-221/222 to increase the protein level of caspase-3, resulting in an increase in gefitinib-induced apoptosis. CONCLUSIONS: Dicer contributes to the resistance to gefitinib in lung cancer. These results indicate that Dicer may be a target for diagnosis and therapy of patients with resistance to gefitinib.

Density features of screened lung tumors in low-dose computed tomography.

RATIONALE AND OBJECTIVES: Using low-dose computed tomography (LDCT), small and heterogeneous lung tumors are detected in screening. The criteria for assessing detected tumors are crucial for determining follow-up or resection strategies. The purpose of this study was to investigate the capacity of density features in differentiating lung tumors. MATERIALS AND METHODS: From July 2008 to December 2011, 48 surgically confirmed tumors (29 malignancies, comprising 17 cases of adenocarcinoma and 12 cases of adenocarcinoma in situ [AdIs], and 19 benignancies, comprising 11 cases of atypical adenomatous hyperplasia [AAH] and eight cases of benign non-AAH) in 38 patients were retrospectively evaluated, indicating that the positive predictive value (PPV) of physicians is 60.4% (29/48). Three types of density features, tumor disappearance rate (TDR), mean, and entropy, were obtained from the CT values of detected tumors. RESULTS: Entropy is capable of differentiating malignancy from benignancy but is limited in differentiating AdIs from benign non-AAH. The combination of entropy and TDR is effective for predicting malignancy with an accuracy of 87.5% (42/48) and a PPV of 89.7% (26/29), improving the PPV of physicians by 29.3%. The combination of entropy and mean adequately clarifies the four pathology groups with an accuracy of 72.9% (35/48). For tumors with a mean below -400 Hounsfield units, the criterion of an entropy larger than 5.4 might be appropriate for diagnosing malignancy. For others, the pathology is either benign non-AAH or adenocarcinoma; adenocarcinoma has a higher entropy than benign non-AAH, with the exception of tuberculoma. CONCLUSIONS: Combining density features enables differentiating heterogeneous lung tumors in LDCT.

Development and preliminary validation of a questionnaire on regular exercise beliefs among patients with chronic obstructive pulmonary disease.

AIMS AND OBJECTIVES: To develop a Regular Exercise Belief Questionnaire and test its psychometric properties for patients with chronic obstructive pulmonary disease. BACKGROUND: Regular exercise has been shown to significantly improve physical capacity and the quality of life of patients with chronic obstructive pulmonary disease. However, their adherence to long-term exercise is low. To develop an effective strategy for promoting good exercise behaviours, it is important to have a validated instrument to evaluate factors related to engaging in exercise. DESIGN AND METHODS: A cross-sectional design was used for the study. Construction of the Regular Exercise Belief Questionnaire was based on the Theory of Planned Behaviour Reliability and validity were assessed using a sample of 136 male patients with chronic obstructive pulmonary disease. The construct validity of the questionnaire was confirmed through exploratory factor analysis and known group technique. RESULTS: Exploratory factor analysis resulted in an eight-factor solution that explained 70·4% of the total variance. The internal consistency of the Regular Exercise Belief Questionnaire was 0·83-0·93. The Regular Exercise Belief Questionnaire was preliminarily found to be reliable and exhibited satisfactory validity for patients with chronic obstructive pulmonary disease. CONCLUSION: The Regular Exercise Belief Questionnaire is the first theory-based measure of exercise beliefs among patients with chronic obstructive pulmonary disease. The questionnaire provides an effective method to examine behaviour beliefs, normative beliefs and control beliefs about regular exercise. CLINICAL RELEVANCE: The measure can be used to periodically evaluate the exercise beliefs in clinics and to examine the effectiveness of exercise programmes in patients with chronic obstructive pulmonary disease. The result of the evaluation could also apply to identify strategies related to promoting exercise behaviours.

Pleura detection in chest computed tomography with application for nodule detection.

This paper proposes an efficient algorithm for detecting pleural objects that come in contact with a nodule. To reduce complexity, the algorithm recursively performed a curve-fitting method on each slice of the volume of interest to locate the object between the parietal and visceral pleurae surfaces and measured the quality of the fitting curve. When a nodule contacted the surfaces of the chest wall or diaphragm, they were automatically separated using the fitting curve. The algorithm was performed on 864 slices of 40 nodules. The segmentation results were visually inspected by a consensus of attending physicians to search for any segmentation errors. The consensus accepted 93.6% of the segmentation results.

An exploration of beliefs regarding exercise among Taiwanese patients with chronic obstructive pulmonary disease.

OBJECTIVES: To explore the beliefs regarding regular exercise among patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: Low adherence to exercise has been observed in patients with COPD. It is important to identify factors regarding exercise from the patients' viewpoint. METHODS: Thirty-one patients were recruited from a medical center in Taiwan. Semi-structured, in-depth, one-on-one interviews were conducted to collect data. The narratives of the interviews were analyzed via content analysis. RESULTS: The majority of the participants affirmed the benefits of regular exercise; however, concerns about personal comfort and safety affected their actual exercise behavior. Five normative references were found to support exercise behavior, and several exercise promoters were identified. CONCLUSION: This study provides an understanding of exercise beliefs of Taiwanese patients with COPD stage II-IV and suggests several ideas for their exercise maintenance. There is a need to provide individualized exercise guides and reinforced programs for patients with chronic obstructive pulmonary disease.

Cell type-specific effects of Adenosine 5'-triphosphate and pyrophosphate on the antitumor activity of doxorubicin.

Extracellular ATP is an important signaling molecule mediating quite divergent specific biological effects. Even though recent studies suggest a potential role of ATP in cancer progress, its real impact in chemotherapeutic efficacy remains unclear. In the present study, we investigated the effect of ATP on the cytotoxicity of doxorubicin in various cancer cell types and found that ATP had no effect on doxorubicin cytotoxicity in colon, prostate, breast, and cervical cancers or in osteosarcoma. In contrast, ATP has divergent effects on lung cancer cells: it can protect against doxorubicin-induced cell death in non-metastatic lung cancer CL1.0 cells, but not in highly metastatic CL1.5 cells. Both apoptotic (characterized by sub-G(1) peak, caspase 3 activation, poly(ADP-ribose) polymerase-1 cleavage) and necrotic (characterized by propidium iodide uptake and ROS production) features induced by doxorubicin in CL1.0 cells were reduced by ATP. In addition, ATP attenuated p53 accumulation, DNA damage (assessed by poly(ADP-ribose) formation and the comet assay) and topoisomerase II inhibition after doxorubicin treatment, and doxorubicin cytotoxicity was diminished by the p53 inhibitor pifithrin-α. Moreover, UTP, UDP, ADP, and pyrophosphate sodium pyrophosphate tetrabasic decahydrate diminished the antitumor effect of doxorubicin in CL1.0 cells, whereas purinergic P2 receptors antagonists did not abrogate the action of ATP. In summary, ATP fails to alter the antitumor efficacy of doxorubicin in most cancer cell types, except in CL1.0 cells, in which pyrophosphate mediates the cell protection afforded by ATP via attenuation of reactive oxygen species production, DNA damage, p53 accumulation, and caspase activation.

Ganoderma tsugae Induces S Phase Arrest and Apoptosis in Doxorubicin-Resistant Lung Adenocarcinoma H23/0.3 Cells via Modulation of the PI3K/Akt Signaling Pathway.

Ganoderma tsugae (GT) is a traditional Chinese medicine that exhibits significant antitumor activities against many types of cancer. This study investigated the molecular mechanism by which GT suppresses the growth of doxorubicin-resistant lung adenocarcinoma H23/0.3 cells. Our results reveal that GT inhibits the viability of H23/0.3 cells in vitro and in vivo and sensitizes the growth suppression effect of doxorubicin on H23/0.3 cells. The data also show that GT induces S phase arrest by interfering with the protein expression of cyclin A, cyclin E, CDK2, and CDC25A. Furthermore, GT induces cellular apoptosis via induction of a mitochondria/caspase pathway. In addition, we also demonstrate that the suppression of cell proliferation by GT is through down-regulation of the PI3K/Akt signaling pathway. In conclusion, this study suggests that GT may be a useful adjuvant therapeutic agent in the treatment of lung cancer.

STI571 reduces TRAIL-induced apoptosis in colon cancer cells: c-Abl activation by the death receptor leads to stress kinase-dependent cell death.

BACKGROUND: In an effort to achieve better cancer therapies, we elucidated the combination cancer therapy of STI571 (an inhibitor of Bcr-Abl and clinically used for chronic myelogenous leukemia) and TNF-related apoptosis-inducing ligand (TRAIL, a developing antitumor agent) in leukemia, colon, and prostate cancer cells. METHODS: Colon cancer (HCT116, SW480), prostate cancer (PC3, LNCaP) and leukemia (K562) cells were treated with STI571 and TRAIL. Cell viability was determined by MTT assay and sub-G1 appearance. Protein expression and kinase phosphorylation were determined by Western blotting. c-Abl and p73 activities were inhibited by target-specific small interfering (si)RNA. In vitro kinase assay of c-Abl was conducted using CRK as a substrate. RESULTS: We found that STI571 exerts opposite effects on the antitumor activity of TRAIL. It enhanced cytotoxicity in TRAIL-treated K562 leukemia cells and reduced TRAIL-induced apoptosis in HCT116 and SW480 colon cancer cells, while having no effect on PC3 and LNCaP cells. In colon and prostate cancer cells, TRAIL caused c-Abl cleavage to the active form via a caspase pathway. Interestingly, JNK and p38 MAPK inhibitors effectively blocked TRAIL-induced toxicity in the colon, but not in prostate cancer cells. Next, we found that STI571 could attenuate TRAIL-induced c-Abl, JNK and p38 activation in HCT116 cells. In addition, siRNA targeting knockdown of c-Abl and p73 also reduced TRAIL-induced cytotoxicity, rendering HCT116 cells less responsive to stress kinase activation, and masking the cytoprotective effect of STI571. CONCLUSIONS: All together we demonstrate a novel mediator role of p73 in activating the stress kinases p38 and JNK in the classical apoptotic pathway of TRAIL. TRAIL via caspase-dependent action can sequentially activate c-Abl, p73, and stress kinases, which contribute to apoptosis in colon cancer cells. Through the inhibition of c-Abl-mediated apoptotic p73 signaling, STI571 reduces the antitumor activity of TRAIL in colon cancer cells. Our results raise additional concerns when developing combination cancer therapy with TRAIL and STI571 in the future.

The role of the VEGF-C/VEGFRs axis in tumor progression and therapy.

Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis. VEGF-C is not only expressed in endothelial cells, but also in tumor cells. VEGF-C signaling is important for progression of various cancer types through both VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3). Likewise, both receptors are expressed mainly on endothelial cells, but also expressed in tumor cells. The dimeric VEGF-C undergoes a series of proteolytic cleavage steps that increase the protein binding affinity to VEGFR-3; however, only complete processing, removing both the N- and C-terminal propeptides, yields mature VEGF-C that can bind to VEGFR-2. The processed VEGF-C can bind and activate VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers to elicit biological responses. High levels of VEGF-C expression and VEGF-C/VEGFRs signaling correlate significantly with poorer prognosis in a variety of malignancies. Therefore, the development of new drugs that selectively target the VEGF-C/VEGFRs axis seems to be an effective means to potentiate anti-tumor therapies in the future.

The short-term effects of air pollution on adolescent lung function in Taiwan.

A mass screening of lung function associated with air pollutants for children is limited. This study assessed the association between air pollutants exposure and the lung function of junior high school students in a mass screening program in Taipei city, Taiwan. Among 10,396 students with completed asthma screening questionnaires and anthropometric measures, 2919 students aged 12-16 received the spirometry test. Forced vital capacity (FVC) and forced expiratory flow in 1s (FEV(1)) in association with daily ambient concentrations of particulate matter with diameter of 10 µm or less (PM(10)), sulfur dioxide (SO(2)), carbon monoxide (CO), nitrogen dioxide (NO(2)), and ozone (O(3)) were assessed by regression models controlling for the age, gender, height, weight, student living districts, rainfall and temperature. FVC, had a significant negative association with short-term exposure to O(3) and PM(10) measured on the day of spirometry testing. FVC values also were reversely associated with means of SO(2), O(3), NO(2), PM(10) and CO exposed 1 d earlier. An increase of 1-ppm CO was associated with the reduction in FVC for 69.8 mL (95% CI: -115, -24.4 mL) or in FEV(1) for 73.7 mL (95% CI: -118, -29.7 mL). An increase in SO(2) for 1 ppb was associated with the reductions in FVC and FEV(1) for 12.9 mL (95% CI: -20.7, -5.09 mL) and 11.7 mL (95% CI: -19.3, -4.16 mL), respectively. In conclusion, the short-term exposure to O(3) and PM(10) was associated with reducing FVC and FEV(1). CO and SO(2) exposure had a strong 1-d lag effect on FVC and FEV(1).

Lung cancer and incidence of stroke: a population-based cohort study.

BACKGROUND AND PURPOSE: Stroke is a known cerebrovascular complication in lung cancer patients; however, whether lung cancer patients are at elevated risk of developing stroke relative to the noncancer population remains unclear. METHODS: The present study used population-based claims data from the Taiwan National Health Insurance, which identified 52,089 patients with an initial diagnosis of lung cancer between 1999 and 2007, and 104,178 matched noncancer subjects from all insured subjects age 20 years and older. Subsequent occurrence of stroke was measured until 2008, and the association between lung cancer and the hazard of developing stroke was estimated using Cox proportional hazard models. RESULTS: The incidence of stroke was 1.5 times higher (25.9 versus 17.4 per 1000 person-years) in the lung cancer group compared with the comparison group. The multivariate-adjusted hazard ratio (HR) comparing lung cancer patients with the noncancer group was 1.47 (95% CI, 1.39-1.56) for stroke, 1.78 (95% CI, 1.54-2.05) for hemorrhagic stroke, and 1.43 (95% CI, 1.34-1.51) for ischemic stroke. The risk of stroke fell over time, decreasing after 1 year of follow-up for men and after 2 years of follow-up for women. Within the first year of follow-up, the risk of stroke peaked during the first 3 months for men and within 4 to 6 months for women. CONCLUSIONS: Lung cancer is associated with increased risk of subsequent stroke within 1 year after diagnosis for men and 2 years after diagnosis for women.

Dual roles of NOD2 in TLR4-mediated signal transduction and -induced inflammatory gene expression in macrophages.

NOD2 of the NLRs and TLR4 of the TLRs are major pattern-recognition receptors, which sense different microbial pathogens and have important roles in innate immunity. Herein, we investigated the roles of NOD2 in TLR4-mediated signalling and gene regulation in RAW264.7 macrophages. We found that MDP (a NOD2 ligand) increased LPS-induced expressions of TNF-α, IL-1ß, IL-6, iNOS and COX-2. MDP did not affect LPS-induced activation of MAPKs or IKK, while it potentiated LPS-induced NF-κB activation. Meanwhile TLR4 activation increased NOD2 mRNA expression, and upregulated NOD2 upon MDP treatment is a positive regulator of TLR4-mediated signalling. Intriguingly we found that NOD2 silencing led to increases in LPS-induced signal transduction and inflammatory responses, and a decrease in LPS-elicited homologous tolerance. We thus propose that NOD2 in the absence of MDP treatment might also play a negative regulatory role in the action of TLR4. Further, we demonstrated that both CARD and LRR domains of the NOD2 protein were responsible for the negative regulatory action on TLR4. In summary, it is the first time to demonstrate that NOD2 have dual effects on TLR4 signalling and exert a novel ligand-independent action. Elucidating molecular mechanisms by which NOD2 exerts its ligand-independent action on TLR4 requires further investigation.

Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study.

INTRODUCTION: Given one third of the human population have been infected with tuberculosis, it is important to delineate the relationship between tuberculosis and lung cancer. This study explored whether contracting pulmonary tuberculosis is associated with an increased risk of developing lung cancers. METHODS: In a cohort of 716,872 insured subjects, free from cancers, aged 20 years and older, 4480 patients with newly diagnosed tuberculosis were identified from the universal insurance claims in 1998-2000 and tracked until 2007 with the remaining insured without tuberculosis. We compared the incidence of lung cancers between the two cohorts and measured the associated hazard of developing lung cancer. RESULTS: The incidence of lung cancers was approximately 11-fold higher in the cohort of patients with tuberculosis than nontuberculosis subjects (26.3 versus 2.41 per 10,000 person-years). Cox proportional hazard regression analysis showed a hazard ratio of 4.37 (95% confidence interval [CI]: 3.56-5.36) for the tuberculosis cohort after adjustment for the sociodemographic variables or 3.32 (95% CI: 2.70-4.09) after further adjustment for chronic obstructive pulmonary disease (COPD), smoking-related cancers (other than lung cancer), etc. The hazard ratio increased to 6.22 (95% CI: 4.87-7.94) with the combined effect with COPD or to 15.5 (95% CI: 2.17-110) with the combined effect with other smoking-related cancers. CONCLUSIONS: This study provides a compelling evidence of increased lung cancer risk among individuals with tuberculosis. The risk may increase further with coexisting COPD or other smoking-related cancers.