Association of leukocyte mitochondrial DNA copy number with longitudinal C-reactive protein levels and survival in older adults: a cohort study.

BACKGROUND: Systemic chronic inflammation occurs with age. The association of the leukocyte mitochondrial DNA copy number, a measure of mitochondrial function in aging, with the temporal profile of serum high-sensitivity C-reactive protein and mortality risk remains uncertain. The objectives of this study were to examine the association of the leukocyte mitochondrial DNA copy number with longitudinal high-sensitivity C-reactive protein levels and the association of the longitudinal high-sensitivity C-reactive protein levels with mortality risk. METHODS: This prospective cohort study included 3928 adults aged ≥ 55 years without systemic inflammation in the baseline examination of the Healthy Aging Longitudinal Study in Taiwan, which started in 2009. Each participant received leukocyte mitochondrial DNA copy number measurement using a fluorescence-based quantitative polymerase chain reaction at baseline, serum high-sensitivity C-reactive protein measurements at baseline and the follow-up examination five years later, and the ascertainment of all-cause death (until November 30, 2021). The relationships among the leukocyte mitochondrial DNA copy number, longitudinal serum high-sensitivity C-reactive protein levels, and time to all-cause mortality were examined using the joint longitudinal and survival modeling analysis. RESULTS: Of the 3928 participants (mean age: 69 years; 2060 [52%] were women), 837 (21%) died during follow-up. In the adjusted analysis, one standard deviation lower natural log-transformed baseline leukocyte mitochondrial DNA copy number was associated with an increase of 0.05 (95% confidence interval [CI], 0.02 to 0.08) standard deviation in serum high-sensitivity C-reactive protein in subsequent years. An increase of 1 standard deviation in instantaneous high-sensitivity C-reactive protein levels was associated with a hazard ratio (HR) for all-cause mortality of 1.22 (95% CI, 1.14 to 1.30). Similar results were obtained after further adjusting for baseline high-sensitivity C-reactive protein levels (HR [95% CI], 1.27 [1.16 to 1.38]) and after excluding those with serum high-sensitivity C-reactive protein above 10 mg/L (HR [95% CI], 1.21[1.11 to 1.31]) or 3 mg/L (HR [95% CI], 1.19 [1.06 to 1.31]) during follow-up. CONCLUSIONS: A lower leukocyte mitochondrial DNA copy number was associated with persistently higher high-sensitivity C-reactive protein levels. Moreover, these higher time-varying high-sensitivity C-reactive protein levels were instantaneously associated with a higher risk of death.

Exercise Test for Patients with Long QT Syndrome.

Congenital long QT syndrome (LQTS) causes life-threatening cardiac arrhythmias and is the leading cause of sudden cardiac death in young people. Measurements of QT prolongation during exercise or postural change have been recommended to assist in the diagnosis of LQTS, particularly in those with hidden phenotypes. However, most evidence has come from single-center studies without external validation in an independent cohort. Inter-study heterogeneity leads to significant difficulties in interpreting and applying consistent diagnostic criteria for LQTS. A comprehensive systematic review is critically needed to summarize the evidence and validate the diagnostic performance of QT intervals during exercise or postural change across a variety of studies. In this study, we review cross-sectional and cohort studies evaluating the efficacy and feasibility of exercise tests or postural changes in diagnosing LQTS, and propose possible problems resulting from exercise tests.

STRESS-responsive deacetylase SIRT3 is up-regulated by areca nut extract-induced oxidative stress in human oral keratinocytes.

Areca chewing is an important environmental risk factor for development of oral premalignant lesions and cancer. Epidemiological evidence indicates that areca chewing is tightly linked to oral carcinogenesis. However, the pathogenetic impacts of areca nut extract (ANE) on normal human oral keratinocytes (HOKs) are unclear and possibly involve oxidative stress via redox imbalance. Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that play an important role in regulating cellular reactive oxygen species (ROS) production. Recent studies have confirmed that ANE and other areca ingredients can induce ROS. In this study, we examined the role of SIRT3 in the regulation of ANE-induced ROS in HOK cells. We examined HOK cell viability following treatment with various ANE concentrations. ANE-induced cytotoxicity increased in a dose-dependent manner and was approximately 48% at a concentration of 50 µg/ml after 24 h. SIRT3 expression and enzyme activity were up-regulated in HOK cells by ANE-induced oxidative stress. Additionally, we identified that SIRT3 controls the enzymatic activity of mitochondrial proteins, such as forkhead box O3a (Foxo3a) transcription factor and antioxidant-encoding gene superoxide dismutase 2 (SOD2), by deacetylation in HOK cells. Moreover, SIRT3-mediated deacetylation and activation of Foxo3a promotes nuclear localization in vivo. These findings suggest that SIRT3 is an endogenous negative regulator in response to ANE-induced oxidative stress and demonstrate an essential role for redox balance in HOK cells.

Role of SIRT1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis.

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) process results in a loss of cell-cell adhesion, increased cell mobility, and is crucial for enabling the metastasis of cancer cells. Recently, the enzyme SIRT1 has been implicated in a variety of physiological processes; however, its role in regulating oral cancer metastasis and EMT is not fully elucidated. Here, we propose a mechanism by which the enzyme sirtuin1 (SIRT1) regulates the EMT process in oral cancer by deacetylating Smad4 and repressing the effect of TGF-ß signaling on matrix metalloproteinase-7 (MMP7). METHODS: The roles of SIRT1 in tumor cell migration/invasion and metastasis to the lungs were investigated using the Boyden chamber assay and orthotopic injections, respectively. RNA interference was used to knockdown either SIRT1 or Smad4 expression in oral squamous cell carcinoma (OSCC) cell lines. Immunoblotting, zymographic assays, and co-immunoprecipitation were used to examine the effects of SIRT1 overexpression on MMP7 expression and activity, as well as on SIRT1/ Smad4 interaction. RESULTS: We found that compared with normal human oral keratinocytes (HOKs), SIRT1 was underexpressed in OSCC cells, and also in oral cancer tissues obtained from 14 of 21 OSCC patients compared with expression in their matched normal tissues. Overexpression of SIRT1 inhibited migration of OSCC cells in vitro, as well as their metastasis to the lung in vivo. Furthermore, up-regulation of SIRT1 in metastatic OSCCs significantly inhibited the migration and invasion abilities of OSCC cells, while concomitantly increasing the expression of E-cadherin, and decreasing the expressions of mesenchymal markers. We also identified Smad4, a TGF-ß-activated transcription factor, as a direct target protein for SIRT1. Overexpression of SIRT1 in OSCC cells led to decreased levels of acetylated Smad4, and inhibition of TGF-ß-induced signaling. By associating and deacetylating Smad4, SIRT1 enzyme can influence MMP7 expression, MMP enzyme activity, and consequently, cell migration, invasion, and tumor metastasis in OSCCs. CONCLUSIONS: These findings provide a valuable insight into the potential role of the SIRT1 enzyme in regulating cell migration and invasion in oral squamous cell carcinoma. Our findings suggest the SIRT1/Smad4/MMP7 pathway as a target for oral cancer driven by EMT.

Role of SIRT3 in the regulation of redox balance during oral carcinogenesis.

BACKGROUND: Sirtuins (SIRT1-7) are a family of NAD-dependent deacetylases, which play an important role in regulating cancer tumorigenesis; however, their role in oral cancer has been controversial. SIRT3 is localized in the mitochondria, where it deacetylates and activates several enzymes involved in cellular redox balance and defense against oxidative damage. RESULTS: We found that compared with normal human oral keratinocytes (HOK), SIRT3 is highly expressed in oral squamous cell carcinoma (OSCC) cell lines, but the enzymatic deacetylation is significantly reduced. We also sequenced the entire coding region of SIRT3 and found the same mutation in 2 different OSCC cell lines. This point mutation is located in close proximity to the active site of deacetylase in the SIRT3 protein, and reduces the overall enzymatic efficiency of deacetylation. Furthermore, up-regulation of SIRT3 inhibited the cell growth of OSCCs and decreased the levels of basal reactive oxygen species (ROS) in both OSCC lines. To verify that the SIRT3 sequence variation was associated with oral carcinogenesis, we sequenced the SIRT3 gene from 21 OSCC patients, and 5 of the 21 patients (23.8%) carried the heterozygous missense mutation, p.Val208Ile. The heterozygous missense mutation in these patients was present in gremlin DNA isolated from both normal and tumor tissues. CONCLUSIONS: Our findings provide a valuable insight into the potential role of SIRT3 in the development of oral squamous cell carcinoma, by showing that a non-synonymous point mutation in SIRT3 contributes to reduced catalytic activity of the protein and affects redox balance in OSCCs.

Lower HbA1C of glycemic control is associated with higher risk of depressive symptoms in elderly with type 2 diabetes mellitus-A Nationwide Community-based study.

OBJECTIVE: We investigated the correlation between glycemic control status and depressive symptoms in type 2 diabetes elderly. METHODS: A total of 1527 participants with type 2 diabetes aged 55 years and older from the Healthy Aging Longitudinal Study in Taiwan study were included in this cross-sectional study. The Center for Epidemiologic Studies Depression Scale (CESD) (20 items) score of ≥16 was indicative of depressive symptoms. The participants were divided into HbA1c ≥ 6.5% and < 6.5% representing the glycemic control. Multiple logistic regression (MLR) and Generalized linear model (GLM) were used. RESULTS: The MLR analysis showed that the low HbA1c group had significant two-fold increased odds of depressive symptoms compared to the high HbA1c group (OR 1.89, 95% CI 1.17-3.05). The risk of depressive symptoms was lower among males (OR 0.49, 95% CI 0.30-0.80) and those with higher BMI (OR 0.93, 95% CI 0.86-1.00); whereas the risk was higher among those who lived alone (OR 2.37, 95% CI 1.31-4.27) and with ADL disability (OR 3.01, 95% CI 1.85-4.89). The GLM showed that the dimension of depressive affect reached statistical significance with lower HbA1c. CONCLUSION: This nationwide community-based study shows that depressive symptoms are associated with lower HbA1C, reminding us that more attention should be paid to the presence of depressive symptoms in those with lower HbA1C. Further research is needed to clarify the causal relationship.

Artificial Intelligence-Enabled Electrocardiogram Improves the Diagnosis and Prediction of Mortality in Patients With Pulmonary Hypertension.

Background: Pulmonary hypertension is a disabling and life-threatening cardiovascular disease. Early detection of elevated pulmonary artery pressure (ePAP) is needed for prompt diagnosis and treatment to avoid detrimental consequences of pulmonary hypertension. Objectives: This study sought to develop an artificial intelligence (AI)-enabled electrocardiogram (ECG) model to identify patients with ePAP and related prognostic implications. Methods: From a hospital-based ECG database, the authors extracted the first pairs of ECG and transthoracic echocardiography taken within 2 weeks of each other from 41,097 patients to develop an AI model for detecting ePAP (PAP > 50 mm Hg by transthoracic echocardiography). The model was evaluated on independent data sets, including an external cohort of patients from Japan. Results: Tests of 10-fold cross-validation neural-network deep learning showed that the area under the receiver-operating characteristic curve of the AI model was 0.88 (sensitivity 81.0%; specificity 79.6%) for detecting ePAP. The diagnostic performance was consistent across age, sex, and various comorbidities (diagnostic odds ratio >8 for most factors examined). At 6-year follow-up, the patients predicted by the AI model to have ePAP were independently associated with higher cardiovascular mortality (HR: 3.69). Similar diagnostic performance and prediction for cardiovascular mortality could be replicated in the external cohort. Conclusions: The ECG-based AI model identified patients with ePAP and predicted their future risk for cardiovascular mortality. This model could serve as a useful clinical test to identify patients with pulmonary hypertension so that treatment can be initiated early to improve their survival prognosis.

Artificial Intelligence-Enabled Model for Early Detection of Left Ventricular Hypertrophy and Mortality Prediction in Young to Middle-Aged Adults.

BACKGROUND: Concealed left ventricular hypertrophy (LVH) is a prevalent condition that is correlated with a substantial risk of cardiovascular events and mortality, especially in young to middle-aged adults. Early identification of LVH is warranted. In this work, we aimed to develop an artificial intelligence (AI)-enabled model for early detection and risk stratification of LVH using 12-lead ECGs. METHODS: By deep learning techniques on the ECG recordings from 28 745 patients (20-60 years old), the AI model was developed to detect verified LVH from transthoracic echocardiography and evaluated on an independent cohort. Two hundred twenty-five patients from Japan were externally validated. Cardiologists' diagnosis of LVH was based on conventional ECG criteria. The area under the curve (AUC), sensitivity, and specificity were applied to evaluate the model performance. A Cox regression model estimated the independent effects of AI-predicted LVH on cardiovascular or all-cause death. RESULTS: The AUC of the AI model in diagnosing LVH was 0.89 (sensitivity: 90.3%, specificity: 69.3%), which was significantly better than that of the cardiologists' diagnosis (AUC, 0.64). In the second independent cohort, the diagnostic performance of the AI model was consistent (AUC, 0.86; sensitivity: 85.4%, specificity: 67.0%). After a follow-up of 6 years, AI-predicted LVH was independently associated with higher cardiovascular or all-cause mortality (hazard ratio, 1.91 [1.04-3.49] and 1.54 [1.20-1.97], respectively). The predictive power of the AI model for mortality was consistently valid among patients of different ages, sexes, and comorbidities, including hypertension, diabetes, stroke, heart failure, and myocardial infarction. Last, we also validated the model in the international independent cohort from Japan (AUC, 0.83). CONCLUSIONS: The AI model improved the detection of LVH and mortality prediction in the young to middle-aged population and represented an attractive tool for risk stratification. Early identification by the AI model gives every chance for timely treatment to reverse adverse outcomes.

The potentially inappropriate prescription of new drug: thiazolidinediones for patients with type II diabetes in Taiwan.

PURPOSE: To examine the potentially inappropriate prescription of thiazolidinediones (TZD). METHODS: Data on TZD prescriptions were collected from Taiwan's National Health Insurance dataset from 2001 to 2006. TZDs were considered inappropriately prescribed when they were prescribed to patients who were (1) under 18 years old, (2) pregnant, who had (3) type 1 diabetes, (4) severe heart failure, (5) hepatic insufficiency, or (6) renal insufficiency and taking TZD + metformin in combination. We aggregated potentially inappropriate prescriptions of TZD for each health-care institution in each month starting from March 2001, when TZD was introduced to Taiwan's market. RESULTS: The potentially inappropriate prescription of TZD increased from 9.41% in 2001 to 12.50% in 2006. Prior inappropriate prescription led to a 0.06% (95%CI: 0.04-0.08) further increase in its later inappropriate prescription. Accumulated months of experience prescribing TZD was found associated with higher proportion of inappropriate prescription of TZD (0.03%, 95%CI: 0.01-0.05). However, it was negatively associated with new incidence of inappropriate prescription of TZD (-0.20, 95%CI: -0.22 to -0.18). The greater the volume of prior TZD prescription (-0.87%, 95%CI: -0.93 to -0.81) and the greater the number of accumulated months since adoption (-0.14%, 95%CI: -0.16 to -0.12), the greater the decrease in rates of new inappropriate prescriptions. CONCLUSIONS: Along with the quick penetration of the new DM drug came an increased possibility that it would be prescribed inappropriately, a trend that persisted over time.

Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome.

BACKGROUND: There is conflicting evidence regarding the potential interaction between clopidogrel and proton pump inhibitors (PPIs), with observational studies suggesting an increased risk of adverse cardiovascular (CV) outcomes and clinical trials suggesting there is no such risk. METHODS: We conducted a retrospective cohort study to assess CV outcomes of 9753 patients taking dual antiplatelet therapy of aspirin plus clopidogrel with or without a PPI after hospitalization for acute coronary syndrome (ACS). Cox proportional hazards models were used to assess our primary endpoint of re-hospitalization for ACS in overall sample and a propensity score matching subsample. RESULTS: Among patients taking clopidogrel plus aspirin, concomitant use of PPI was not associated with the risk of re-hospitalization for ACS (adjusted hazard ratio [HR] 1.12 [95%CI 0.72-1.73]). The findings were consistent in the propensity score matching cohort (adjusted HR 0.82 [95%CI 0.43-1.54]). Compared with PPI nonusers, there is no significant association between each specific PPI users and the risk of re-hospitalization for ACS (adjusted HR; omeprazole 0.96 [95%CI 0.35-2.66], pantoprazole 1.05 [95%CI 0.38-2.92], rabeprazole 0.60 [95%CI 0.17-2.17], esomeprazole 0.31 [95%CI 0.10-0.99], and lansoprazole 0.82 [95%CI 0.32-2.07]). CONCLUSION: In conclusion, this population-based cohort study found that concomitant use of clopidogrel and PPI in patients who received dual antiplatelet therapy after ACS was not associated with risk of ACS re-hospitalization. Together, our study and findings of recently published clinical trials suggest that there was no apparent CV interaction between clopidogrel and PPI in patients who received dual antiplatelet therapy.

ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma.

Airway remodeling is the process of airway structural change that occurs in patients with asthma in response to persistent inflammation and leads to increasing disease severity. Drugs that decrease this persistent inflammation play a crucial role in managing asthma episodes. Mice sensitized (by intraperitoneal administration) and then challenged (by inhalation) with ovalbumin (OVA) develop an extensive eosinophilic inflammatory response, goblet cell hyperplasia, collagen deposition, airway smooth muscle thickening, and airway wall area increase, similar to pathologies observed in human asthma. We used OVA-sensitized/challenged mice as a murine model of chronic allergic airway inflammation with subepithelial fibrosis (i.e., asthma). In this OVA mouse model, mRNA and protein of macrophage migration inhibitory factor (MIF) are upregulated, a response similar to what has been observed in the pathogenesis of acute inflammation in human asthma. We hypothesized that MIF induces transforming growth factor-ß1 (TGF-ß1) synthesis, which has been shown to play an important role in asthma and airway remodeling. To explore the role of MIF in the development of airway remodeling, we evaluated the effects of an MIF small-molecule antagonist, (S,R)3-(4-hy-droxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), on pathologies associated with the airway-remodeling process in the OVA mouse model. We found that administration of ISO-1 significantly mitigated all symptoms caused by OVA treatment. In addition, the treatment of OVA-sensitized mice with the MIF antagonist ISO-1 significantly reduced TGF-ß1 mRNA levels in pulmonary tissue and its protein level in bronchial alveolar lavage fluid supernatants. We believe the repression of MIF in the ISO-1 treatment group led to the significant suppression observed in the inflammatory responses associated with the allergen-induced lung inflammation and fibrosis in our murine asthma (OVA) model. Our results implicate a possible function of MIF in the pathogenesis of chronic asthma and suggest that MIF might be an important therapeutic target for airway remodeling.

Relationship between cumulative dose of thiazolidinediones and clinical outcomes in type 2 diabetic patients with history of heart failure: a population-based cohort study in Taiwan.

BACKGROUND: Thiazolidinediones (TZDs) are widely used antidiabetic agents, but there is great concern and conflicting reports over their possible effect on cardiovascular morbidity, especially in patients with heart failure (HF). METHODS: Using 2000-2005 Taiwan's National Health Insurance (NHI) claims data, this population-based, retrospective cohort study investigated if there was an association between the cumulative TZD dose and clinical outcomes in type 2 diabetic patients recently hospitalized for HF. Study outcomes were death, first all-cause readmission, and first readmission for HF. Cox proportional hazard models were used to analyze the association between TZD versus sulfonylurea (SU) use and these outcomes. RESULTS: Out of a total of 8139 eligible patients, 224 were taking TZD (65.63% female; mean [SD] age, 68.30[10.60] years) and 7915 were taking SU (55.10% female; 70.30[10.50] years). Patients taking TZD were at higher risk for readmission for HF (59 cases; HR 1.58 (95% confidence interval, 95%CI 1.44-1.72)), all-cause readmission (147 cases; 1.40 (1.30-1.70)), and death (103 cases; 2.23 (1.58-3.14)). The higher the cumulative exposure to TZD, the greater the risk of HF readmission, all-cause readmission, and death. CONCLUSION: Among diabetic patients who had been hospitalized for HF, TZD users were at significantly greater risk for readmission for HF, all-cause readmission, and death than SU users. The risk of all adverse clinical outcomes appeared to highly relate to cumulative exposure to TZD. These findings provide empirical evidence supporting the latest black box warnings issued by the United States Food and Drug Administration in August, 2007 advising that TZD not be prescribed for diabetic patients with symptomatic heart failure.

Virus load and virus shedding of SARS-CoV-2 and their impact on patient outcomes.

BACKGROUND: Understanding a virus shedding patterns in body fluids/secretions is important to determine the samples to be used for diagnosis and to formulate infection control measures. AIM: To investigate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding patterns and its risk factors. METHODS: All laboratory-confirmed coronavirus disease 2019 patients with complete medical records admitted to the Shenzhen Third People's Hospital from January 28, 2020 to March 8, 2020 were included. Among 145 patients (54.5% males; median age, 46.1 years), three (2.1%) died. The bronco-alveolar lavage fluid (BALF) had the highest virus load compared with the other samples. The viral load peaked at admission (3.3 × 108 copies) and sharply decreased 10 d after admission. RESULTS: The viral load was associated with prolonged intensive care unit (ICU) duration. Patients in the ICU had significantly longer shedding time compared to those in the wards (P < 0.0001). Age > 60 years [hazard ratio (HR) = 0.6; 95% confidence interval (CI): 0.4-0.9] was an independent risk factor for SARS-CoV-2 shedding, while chloroquine (HR = 22.8; 95%CI: 2.3-224.6) was a protective factor. CONCLUSION: BALF had the highest SARS-CoV-2 load. Elderly patients had higher virus loads, which was associated with a prolonged ICU stay. Chloroquine was associated with shorter shedding duration and increased the chance of viral negativity.

The presence of ectopic atrial rhythm predicts adverse cardiovascular outcomes in a large hospital-based population.

BACKGROUND: Whether ectopic atrial rhythm (EAR) is a high-risk cardiovascular phenotype (eg, the manifestation of a diseased sinoatrial node) or just a benign accelerated ectopic pacemaker remains unclear. OBJECTIVE: We aimed to analyze the cardiovascular outcomes and underlying mechanisms in patients with EAR. METHODS: From a 12-lead electrocardiogram hospital-based electrocardiogram database, a total of 2896 adults with EAR were propensity score matched at 1:5 with 14,480 patients with sinus rhythm (SR). Patients were retrospectively followed up for cardiovascular mortality (the primary outcome) and permanent pacemaker implantation (the secondary outcome). Heart rate variability was analyzed to compare autonomic function between patients with EAR and those with SR. RESULTS: The prevalence of EAR was 1.13%, which increased with age. Compared with the matched patients, those with EAR had a higher risk of cardiovascular mortality (adjusted hazard ratio 1.93; 95% confidence interval 1.52-2.44; P < .0001) and permanent pacemaker implantation (adjusted hazard ratio 5.94; 95% confidence interval 3.89-9.09; P < .0001) according to the Cox proportional hazards regression model. The risk of cardiovascular mortality was similar across the subgroups on the basis of age, sex, hypertension, type 2 diabetes mellitus, congestive heart failure, myocardial infarction, stroke, and chronic kidney diseases. In patients with EAR, the low frequency/high frequency and standard deviation of the mean normal-to-normal intervals/root mean square of successive RR interval differences ratios for heart rate variability were both lower than those in patients with SR. This implied autonomic imbalance in patients with EAR. CONCLUSION: Patients with EAR have a higher risk of cardiovascular mortality and permanent pacemaker implantation, which was associated with autonomic imbalance.

Activation of M1 macrophages plays a critical role in the initiation of acute lung injury.

The goal of the present study was to investigate the role of M1 macrophages in acute lung injury (ALI). To address this, we used lipopolysaccharide (LPS)-treated wild-type and CD11b-DTR mice, and examined their M1 macrophage levels, and the extent of their inflammation and pulmonary injuries. In addition, we evaluated pulmonary function by measuring the expressions of SP-A and SP-B in infiltrated M1 macrophages. Finally, we co-cultured the mouse type II-like alveolar epithelial cells (AT-II) and mouse pulmonary microvascular endothelial cells (PMECs) with M1 macrophages in the presence of TNF-α or H2O2 and assessed them for viability and apoptosis. After LPS treatment, we observed that the number of pulmonary M1/M2 macrophages and the serum levels of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), and reactive oxygen species (ROS) significantly increased. Furthermore, the increase in cytokines was accompanied with the initiation of lung injury indicated by the decreased levels of SP-A and SP-B. In macrophage-depleted CD11b-DTR mice, ALI was attenuated, serum levels of IL-1ß, TNF-α and ROS were reduced, and lung levels of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) were decreased. After administering TNF-α and H2O2, the proapoptotic effect of M1 macrophages on AT-II or PMECs significantly increased, the cell viabilities significantly decreased, and apoptosis significantly increased. Our results suggest that M1 macrophages are recruited to the lungs where they significantly contribute to an increase in TNF-α and ROS production, thus initiating ALI.

Sirtuin 3 Protects against Urban Particulate Matter-Induced Autophagy in Human Bronchial Epithelial Cells.

Urban particulate matter (urban PM) is a heterogeneous mixture of various types of particles originating from different sources. Exposure to high concentrations of urban PM leading to adverse health effects is evaluated by using in vitro cultures of human lung epithelial cells. However, the mechanism underlying the correlation between high concentrations of urban PM exposure and adverse health effects has not been fully elucidated; urban PM-induced oxidative stress is considered as an important mechanism of urban PM-mediated cytotoxicity. Sirtuin 3 (SIRT3), a primary mitrochondrial deacetylase, controls cellular reactive oxygen species (ROS) production, and expression of antioxidant enzymes. In this study, we examined the role of SIRT3 in the regulation of urban PM-induced oxidative stress in normal primary human bronchial epithelial cells (HBEpiCs). Cell viability showed a time- and concentration-dependent decrease when exposed to urban PM, which could indicate that the amount of lactate dehydrogenase released from the cell in response to urban PM is related to cell viability in HBEpiC. The effects of urban PM on morphological and biochemical markers of autophagy in HBEpiC were analyzed by electron microscopy and Western blotting. Overexpression of SIRT3 inhibited urban PM-induced ROS generation, while concomitantly increasing the expression of antioxidant enzymes, and decreasing NF-κB activation and release of inflammation factors. Up-regulation of SIRT3 significantly inhibited the expression of autophagy markers and autophagic vacuole formation. Our findings provide a valuable insight into the potential role of the SIRT3 enzyme in regulating urban PM-induced autophagy by mediating urban PM-induced oxidative stress, which may contribute to urban PM-induced impairment of airway epithelial cell function.

Association Between the CYP1B1 Polymorphisms and Lung Cancer Risk: A Meta-Analysis.

The previously published data on the association between the cytochrome P450 1B1 Leu432Val, Asn453Ser, and Ala119Ser polymorphisms and lung cancer risk have remained controversial. Hence, we performed a meta-analysis to investigate the association between cytochrome P450 1B1 Leu432Val, Asn453Ser, and Ala119Ser polymorphisms and lung cancer risk under different inheritance models. A total of 22 studies were identified, including 2881 cases and 3653 controls for Leu432Val polymorphism (from 13 studies), 3009 cases and 3887 controls for Asn453Ser polymorphism (from 5 studies), and 1301 cases and 2045 controls for Ala119Ser polymorphism (from 4 studies). Overall, significant association was observed between cytochrome P450 1B1 Leu432Val polymorphism and lung cancer risk (dominant model: odds ratio = 1.29, 95% confidence interval = 1.08-1.53; recessive model: odds ratio = 1.21, 95% confidence interval = 1.05-1.39; additive model: odds ratio = 1.43, 95% confidence interval = 1.21-1.69) when all the eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased lung cancer risk was also observed in caucasians and smokers. No significant association was observed between cytochrome P450 1B1Asn453Ser and Ala119Ser polymorphisms and lung cancer risk in overall analysis. In summary, this meta-analysis suggests that cytochrome P450 1B1Leu432Val polymorphism is associated with increased lung cancer risk in caucasians and smokers.

The end-of-treatment telephone response and prognosis of post-radiotherapy nasopharyngeal carcinoma patients in southern China.

Nasopharyngeal Carcinoma (NPC) patients' end-of-treatment survival status has drawn more attention in recent years. Telephone follow-up, as a most operative approach among all the clinical follow-ups, is an effective means to extend medical service to patients' home and is thus widely used in clinical practice. This study aimed to analyze the post-radiotherapy NPC patients' phone response rate and its factors, and to discuss the independent prognostic factors of NPC patients' radiotherapy. We prospectively designed a nurses-led telephone follow-up to include 2520 NPC patients who received simple radical radiotherapy between Jan. 2007 and Jun. 2012 at Sun Yat-sen University Cancer Center. The patients' response rate and its factors were calculated. Survival analysis was used to estimate the patients' survival and the influencing factors. The overall response rate was 90.5%; Patients with reserved contact type of mobile + landlinephone or landline phone had higher follow-up response rate than patients with mobile contact only; patients with 2 or more reserved contacts, and family cancer history had higher response rate than patients with only 1 number and those without family history. Patients' cumulative survival rate of 1, 3 and 5 years were 98.9%, 75.3%, 50.3%, respectively. T-staging, N-staging, higher clinical staging, with basicranial invasion were the influencing factors of the patients' poor prognosis. The telephone follow-up response was affected by reserved contact type, number of contacts and family medical history; T-staging, N-staging, higher clinical staging, with basicranial invasion were the influencing factors of the patients' poor prognosis. This study provides a scientific basis for increasing the NPC patients' end-of-treatment response and promoting the individualized clinical treatment.

Public opinion regarding earmarked cigarette tax in Taiwan.

BACKGROUND: Cigarette taxation has been perceived by academics and policy-makers as one of the most effective ways of reducing the use of cigarettes. On January 1 2002, the Taiwan government imposed a New Taiwan (NT) 5 dollars per pack tax earmarked for the purpose of tobacco control. This study uses a survey collected prior to taxation to assess public attitudes toward cigarette taxation, public beliefs about the effectiveness of cigarette taxation at reducing cigarette use and public opinions about the allocation of this tax revenue. METHODS: Data were drawn from a national face-to-face interview on cigarette consumption in 2000. A total of 3,279 adults were aged 18 to 64 years; 49.9% of whom were male and 50.1% female, and with a smoking prevalence of 49.1% and 4.1%, respectively. The attitudes toward cigarette tax were analysed using multi-logit regressions. We analysed by logistic regression the potential changes in smoking behaviour that smokers might make in response to the five NT (New Taiwan) dollar earmarked tax on cigarettes per pack. We summarized public opinions about the allocation of earmarked tax revenue using descriptive statistics. RESULTS: Current smokers (OR = 0.34) and former smokers (OR = 0.68) were less likely to support the cigarette tax than non-smokers. A favourable attitude toward the tax was positively associated with personal monthly income, especially among females. Among male smokers, the possibility of reducing/quitting smoking in response to the five-NT-dollar tax was negatively associated with the monthly expense for smoking. The two most frequently-suggested areas to receive money from the revenue collected from the earmarked tax were health education and cancer subsidy. CONCLUSIONS: Smoking status and economic factors determine the attitude and potential responses of people toward the cigarette tax. Taiwan's five NT-dollar earmarked tax for cigarettes may have only a limited effect upon the reduction in cigarette use.

Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy.

Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity.