Kuan Jen Bai

Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-κB-mediated matrix metalloproteinase-9 expression.

The induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of various cancer cells. Osthole, a natural coumarin derivative extracted from traditional Chinese medicines, is known to inhibit the proliferation of a variety of tumor cells, but the effect of osthole on the invasiveness of tumor cells is largely unknown. This study determines whether and by what mechanism osthole inhibits invasion in CL1-5 human lung adenocarcinoma cells. Herein, we found that osthole effectively inhibited the migratory and invasive abilities of CL1-5 cells. A zymographic assay showed that osthole inhibited the proteolytic activity of MMP-9 in CL1-5 cells. Inhibition of migration, invasion, and MMP2 and/or MMP-9 proteolytic activities was also observed in other lung adenocarcinoma cell lines (H1299 and A549). We further found that osthole inhibited MMP-9 expression at the messenger RNA and protein levels. Moreover, a chromatin immunoprecipitation assay showed that osthole inhibited the transcriptional activity of MMP-9 by suppressing the DNA binding activity of nuclear factor (NF)-κB in the MMP-9 promoter. Using reporter assays with point-mutated promoter constructs further confirmed that the inhibitory effect of osthole requires an NF-κB binding site on the MMP-9 promoter. Western blot and immunofluorescence assays demonstrated that osthole inhibited NF-κB activity by inhibiting IκB-α degradation and NF-κB p65 nuclear translocation. In conclusion, we demonstrated that osthole inhibits NF-κB-mediated MMP-9 expression, resulting in suppression of lung cancer cell invasion and migration, and osthole might be a potential agent for preventing the invasion and metastasis of lung cancer.

The Influence of Diabetes, Glycemic Control, and Diabetes-Related Comorbidities on Pulmonary Tuberculosis

Background To assess the influence of diabetes mellitus (DM), glycemic control, and diabetes-related comorbidities on manifestations and outcome of treatment of pulmonary tuberculosis (TB). Methodology/Principal Findings Culture positive pulmonary TB patients notified to health authorities in three hospitals in Taiwan from 2005–2010 were investigated. Glycemic control was assessed by glycated haemoglobin A1C (HbA1C) and diabetic patients were categorized into 3 groups: HbA1C<7%, HbA1C 7–9%, HbA1C>9%. 1,473 (705 with DM and 768 without DM) patients were enrolled. Of the 705 diabetic patients, 82 (11.6%) had pretreatment HbA1C<7%, 152 (21.6%) 7%–9%, 276 (39.2%) >9%, and 195 (27.7%) had no information of HbA1C. The proportions of patients with any symptom, cough, hemoptysis, tiredness and weight loss were all highest in diabetic patients with HbA1C>9%. In multivariate analysis adjusted for age, sex, smoking, and drug resistance, diabetic patients with HbA1C>9% (adjOR 3.55, 95% CI 2.40–5.25) and HbA1C 7–9% (adjOR 1.62, 95% CI 1.07–2.44) were significantly more likely to be smear positive as compared with non-diabetic patients, but not those with HbA1C<7% (adjOR 1.16, 95% CI 0.70–1.92). The influence of DM on outcome of TB treatment was not proportionately related to HbA1C, but mainly mediated through diabetes-related comorbidities. Patients with diabetes-related comorbidities had an increased risk of unfavorable outcome (adjOR 3.38, 95% CI 2.19–5.22, p<0.001) and one year mortality (adjOR 2.80, 95% CI 1.89–4.16). However, diabetes was not associated with amplification of resistance to isoniazid (p = 0.363) or to rifampicin (p = 0.344). Conclusions/Significance Poor glycemic control is associated with poor TB treatment outcome and improved glycemic control may reduce the influence of diabetes on TB.

Glycemic Control and Radiographic Manifestations of Tuberculosis in Diabetic Patients

Background Radiographic manifestations of pulmonary tuberculosis (TB) in patients with diabetes mellitus (DM) have previously been reported, with inconsistent results. We conducted a study to investigate whether glycemic control has an impact on radiographic manifestations of pulmonary TB. Methods Consecutive patients with culture-positive pulmonary TB who had DM in three tertiary care hospitals from 2005–2010 were selected for review and compared with a similar number without DM. Glycemic control was assessed by glycated haemoglobin A1C (HbA1C). A pre-treatment chest radiograph was read independently by two qualified pulmonologists blinded to patients’ diabetic status. Films with any discordant reading were read by a third reader. Results 1209 culture positive pulmonary TB patients (581 with DM and 628 without DM) were enrolled. Compared with those without DM, TB patients with DM were significantly more likely to have opacity over lower lung fields, extensive parenchymal lesions, any cavity, multiple cavities and large cavities (>3 cm). The relative risk of lower lung field opacities was 0.80 (95% CI 0.46–1.42) for those with DM with A1C<7%, 2.32 (95% CI 1.36 - 3.98) for A1C 7%–9%, and 1.62 (95% CI 1.12–2.36) for A1C>9%; and that of any cavity over no cavity was 0.87 (95% CI 0.46–1.62) for patients with DM with A1C<7%, 1.84 (95% CI 1.20–2.84) for A1C 7%–9%, and 3.71 (95% CI 2.64–5.22) for A1C>9%, relative to patients without DM. Conclusions Glycemic control significantly influenced radiographic manifestations of pulmonary TB in patients with DM.

Plasma endothelial cell-specific molecule-1 (ESM-1) in management of community-acquired pneumonia

Abstract Background: Endothelial cell-specific molecule (ESM)-1 is a soluble proteoglycan expressed by the vascular endothelium and which also circulates in the bloodstream. Inflammatory cytokines and proangiogenic growth factors increase its expression, and increased serum levels are found in immunocompetent patients with sepsis. The aim of this study was to investigate differential changes in plasma levels of ESM-1 before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). Methods: Plasma ESM-1 levels were measured in 82 adult patients with CAP and 82 healthy controls using a commercial enzyme-linked immunosorbent assay (ELISA). Upon initial hospitalization, Acute Physiology and Chronic Health Evaluation II (APACHE II), CURB-65, and Pneumonia Severity Index (PSI) scores were determined to assess CAP severity in these patients. Results: Results showed a decline in the number of white blood cells (WBCs) and neutrophils, and decreases in the concentrations of C-reactive protein (CRP) and ESM-1 after antibiotic treatment. The plasma concentration of ESM-1, but not CRP or the WBC count, was correlated with the severity of CAP based on the PSI (r=0.554, p<0.001), CURB-65 (r=0.510, p<0.001), and APACHE II scores (r=0.447, p<0.001). Conclusions: Plasma levels of ESM-1 may be able to play a role in the diagnosis and clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies.

Plasma long pentraxin 3 (PTX3) concentration is a novel marker of disease activity in patients with community-acquired pneumonia

Abstract Background: Long pentraxin 3 (PTX3) is an acute-phase protein secreted by various cells, including leukocytes and endothelial cells. Like C-reactive protein (CRP), it belongs to the pentraxin superfamily. The aim of this study was to investigate the differential changes in plasma levels of PTX3 between before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). Methods: Plasma PTX3 levels were measured in 61 adult patients with CAP and 60 healthy controls using a commercial enzyme-linked immunosorbent assay (ELISA). Upon initial hospitalization, APACHE II, CURB-65, and pneumonia severity index (PSI) scores were determined to assess CAP severity in patients. Results: The results showed a decline in the number of white blood cells (WBCs) and neutrophils, and decreases in the concentrations of CRP and PTX3 observed after antibiotic treatment. The plasma concentration of PTX3, but not CRP, was correlated with the severity of CAP based on the PSI (r=0.290, p=0.023), CURB-65 (r=0.312, p=0.015), and APACHE II scores (r=0.427, p=0.001). The PTX3 level also exhibited a significant correlation with the length of hospital stay (r=0.500, p<0.0001). Conclusions: PTX3 may be able to play a role in the diagnosis and clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies.

NAT2 fast acetylator genotypes are associated with an increased risk for lung cancer with wildtype epidermal growth factor receptors in Taiwan

Identifying the risk factors responsible for lung cancer especially for nonsmokers is critical for both its prevention and treatment. Studies have linked the polymorphisms in N-acetyltransferases (NAT2), a key enzyme for metabolism of hydrocarbons, with lung cancer in Asian female nonsmokers. Since a high percentage of lung adenocarcinoma in Asian female nonsmokers contains activating hotspot mutations in epidermal growth factor receptors (EGFR), we hypothesized that NAT2 polymorphisms might represent a risk factor in lung cancer with EGFR mutations. We studied NAT polymorphisms in 117 nonsmall cell lung cancer (NSCLC) patients and in 119 healthy controls and EGFR hotspot mutations in exons 18-21 in 100 of the 117 patients using polymerase chain reactions. NAT2 fast acetylator genotypes were significantly associated with patients with lung cancer (P = 0.04, odds ratio (OR): 1.90, 95% confidence interval (CI): 1.02-3.57). Further analyses revealed that NAT2 fast acetylator genotypes were significantly associated with NSCLC with wildtype EGFR (P = 0.008, OR: 3.16, 95% CI: 1.31-7.63), but not with those with EGFR mutations (P = 0.40). Therefore, NAT2 fast acetylator genotypes are a potential risk factor especially for lung cancer with wildtype EGFR.

Human papillomavirus infections as a marker to predict overall survival in lung adenocarcinoma

Human papillomavirus (HPV) has been implicated in multiple cancers, but its significance in lung cancer has remained controversial. As the prevalence of HPV 16/18 infection was higher in lung adenocarcinoma among Taiwanese females, the aim of our study was to evaluate the clinical impact of HPV infections in lung adenocarcinoma. Two hundred and ten patients were enrolled to investigate the associations of HPV status in tumors with clinical characteristics as well as its impact on overall survival. The methods to assess HPV status were by immunohistochemistry for HPV L1 capsid protein and E6 protein and by nested polymerase chain reaction for HPV 16 and HPV 18. HPV infections were identified in 35.2% of patients, and associated with localized and smaller sized tumors (p = 0.022 and p = 0.002, respectively). Patients with HPV infections had a significantly better survival (p = 0.023, by log‐rank test) and a significantly reduced mortality risk after adjustments of age, tumor extent, epidermal growth factor receptor (EGFR) mutations status and treatments [adjusted hazard ratio = 0.68, 95% confidence interval (CI) = 0.49–0.96, p = 0.026, by multivariate Cox proportional hazards models]. Specifically, patients with both HPV infections and EGFR mutations had the best survival outcome [1‐year survival rate, 68.5% (95% CI = 52.2–4.8%)]. Our findings indicate that HPV infections represent an independent prognostic factor for overall survival in patients with lung adenocarcinoma.

Tuberculosis incidence and mortality in aboriginal areas of Taiwan, 1997-2001

BACKGROUND AND PURPOSE People living in aboriginal areas of Taiwan are known to be at especially high risk of developing tuberculosis (TB). This study investigated the incidence and mortality of TB in aboriginal areas of Taiwan. METHODS The TB death statistics and notification data from the National TB Register and Department of Health in 1997-2001 were analyzed. RESULTS From 1997 to 2001, people living in aboriginal areas bore a disproportionate burden of TB disease in Taiwan, with mortality rates 5.5-6.5 times and incidence rates 3.6-5.2 times higher than those of people living in non-aboriginal areas. Among patients with TB living in aboriginal areas, 381 died, accounting for 5.1% of the 7480 TB deaths in Taiwan. A large proportion of the patients with TB who died were older than 65 years, in both aboriginal (40.2%) and non-aboriginal (78.5%) areas; however, the age of TB patients who died in non-aboriginal areas was significantly older (p < 0.001). TB patients living in the aboriginal areas accounted for 3.6% (2618/71,447) of the total number of reported TB patients in Taiwan, and 32.7% were in the age range from 24-45 years. In contrast, TB patients living in non-aboriginal areas were typically older, with only 20.1% in the 24-45 age range (p < 0.001) and 44.4% older than 65 years (p < 0.001). In terms of incidence and mortality rates, men predominated in both groups; however, this pattern was less prominent in aboriginal areas than in non-aboriginal areas. CONCLUSIONS The mortality rates and incidence of TB in aboriginal areas are much higher than those in non-aboriginal areas in Taiwan. Concentration of resources and programs to control TB in aboriginal areas may represent the most effective use of resources for fighting TB.

Impact of food intake on the pharmacokinetics of first-line antituberculosis drugs in Taiwanese tuberculosis patients

BACKGROUND/PURPOSE Under the directly observed treatment, short course (DOTS) program, antituberculosis (anti-TB) medications were possibly taken at random time, regardless of whether it was prior to or after meals. This study was to evaluate the impact of food intake on pharmacokinetic profiles of first-line TB drugs in Taiwanese TB patients, as well as the relationship between drug levels and pharmacogenetics. METHODS This open-label, randomized, cross-over study included newly diagnosed Taiwanese TB patients treated between January 2010 and February 2011 at Taipei Medical University-Wan Fang Hospital. Rifater [a fixed-dose combination formulation of isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA)] and ethambutol (EMB) were given according to national TB guidelines. Blood samples were collected prior to and 1 hour, 2 hours, 4 hours, 6 hours, and 10 hours after dosing under fasting or postprandial conditions. Pharmacokinetic parameters of the maximum serum concentration (Cmax), time to Cmax, and area under the serum concentration-time curve from the beginning to the 10(th) hour (AUC0-10) were calculated. RESULTS Sixteen TB patients were included and received anti-TB treatment under the DOTS program after discharge. The overall effects showed that food intake reduced the mean Cmax (INH: 40.6%, RIF: 40.2%, EMB 34.4%, PZA: 24.4%) and AUC0-10 (INH: 21.3%, RIF: 26.4%, EMB: 12.2%, PZA: 12.0%). Meanwhile, food increased the time to Cmax (INH: 78.1%, RIF: 151.3%, EMB: 41.4%, PZA: 148.9%). CONCLUSION Significantly lower serum drug concentrations were observed under postprandial conditions than fasting conditions for INH, RIF, and PZA. The impact of taking random anti-TB drugs under the DOTS program instead of taking drugs regularly prior to meals requires further study.

Plasma Monocyte Chemoattractant Protein-1 Level as a Predictor of the Severity of Community-Acquired Pneumonia

Monocyte chemoattractant protein (MCP)-1 increases in the serum of immunocompetent patients with community-acquired pneumonia (CAP). However, the correlation between the circulating level of MCP-1 and severity of CAP remains unclear. This study investigated differential changes in the plasma MCP-1 levels of patients with CAP before and after an antibiotic treatment and further analyzes the association between the CAP severity and MCP-1 levels. We measured the plasma MCP-1 levels of 137 patients with CAP and 74 healthy controls by using a commercial enzyme-linked immunosorbent assay. Upon initial hospitalization, Acute Physiology and Chronic Health Evaluation II (APACHE II); confusion, urea level, respiratory rate, blood pressure, and age of >64 years (CURB-65); and pneumonia severity index (PSI) scores were determined for assessing the CAP severity in these patients. The antibiotic treatment reduced the number of white blood cells (WBCs) and neutrophils as well as the level of C-reactive protein (CRP) and MCP-1. The plasma MCP-1 level, but not the CRP level or WBC count, correlated with the CAP severity according to the PSI (r = 0.509, p < 0.001), CURB-65 (r = 0.468, p < 0.001), and APACHE II (r = 0.360, p < 0.001) scores. We concluded that MCP-1 levels act in the development of CAP and are involved in the severity of CAP.