Association of blood lipid profiles and asthma: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Observational studies and meta-analyses have indicated associations between blood lipid profiles and asthma. However, the causal association is unknown. Therefore, this study investigated the causal relationship between blood lipid profiles and asthma using bidirectional Mendelian randomization analysis. METHODS AND MATERIALS: Our analyses were performed using individual data from the Taiwan Biobank and summary statistics from the Asian Genetic Epidemiology Network (AGEN). The causal estimates between all genetic variants, exposures of interest and asthma were calculated using an inverse-variance weighted method based on Taiwan Biobank data from 24,853 participants (mean age, 48.8 years; 49.8% women). Sensitivity analyses, including the weighted median, MR Egger regression, MR-PRESSO, mode-based estimate, contamination mixture methods, and leave-one-out analysis, were applied to validate the results and detect pleiotropy. RESULTS: In the inverse-variance weighted (IVW) analyses, we found evidence of a significant causal effect of an increased level of low-density lipoprotein cholesterol on asthma risk (ßIVW = 1.338, p = 0.001). A genetically decreased level of high-density lipoprotein cholesterol was also associated with asthma risk (ßIVW = -0.338, p = 0.01). We also found that an increased level of total cholesterol was associated with an increased risk of asthma (ßIVW = 1.343, p = 0.001). Several sensitivity analyses generated consistent findings. We did not find evidence to support the causality between asthma and blood lipid profiles in either direction. CONCLUSION: Our results supported the causal relationship between higher levels of LDL cholesterol and total cholesterol and lower levels of HDL cholesterol with an increased risk of asthma.

Cluster analysis of phenotypes, job exposure, and inflammatory patterns in elderly and nonelderly asthma patients.

BACKGROUND: Asthma has been identified as different phenotypes due to various risk factors. Age differences may have potential effects on asthma phenotypes. Our study aimed to identify potential asthma phenotypes among adults divided by age as either younger or older than 65 years. We also compared differences in blood granulocyte patterns, occupational asthmagens, and asthma control-related outcomes among patient phenotype clusters. METHODS: We recruited nonelderly (<65 years old) (n = 726) and elderly adults (≥65 years old) (n = 201) with mild-to-severe asthma. We conducted a factor analysis to select 17 variables. A two-step cluster analysis was used to classify subjects with asthma phenotypes, and a discriminant analysis was used to verify the classification of cluster results. RESULTS: There were three clusters with different characteristics identified in both the nonelderly and elderly asthmatic adults. In the nonelderly patient group, cluster 2 (obese, neutrophilic phenotypes) had a 1.85-fold significantly increased risk of asthma exacerbations. Cluster 3 (early-onset, atopy, and smoker with an eosinophil-predominant pattern) had a 2.37-fold risk of asthma exacerbations and higher oral corticosteroid (OCS) use than cluster 1 (late-onset and LMW exposure with paucigranulocytic blood pattern). Among elderly patients, cluster 2 had poor lung function and more ex-smokers. Cluster 3 (early-onset, long asthma duration) had the lowest paucigranulocytic blood pattern percentages in the elderly group. CONCLUSIONS: The novelty of the clusters was found in age-dependent clusters. We identified three distinct phenotypes with heterogeneous characteristics, asthma exacerbations and medicine use in nonelderly and elderly asthmatic patients, respectively. Classification of age-stratified asthma phenotypes may lead to precise identification of patients, which provides personalized disease management.

Phthalate derivative DEHP disturbs the antiproliferative effect of camptothecin in human lung cancer cells by attenuating DNA damage and activating Akt/NF-κB signaling pathway.

Plasticizers/phthalates play a facilitating role in the development of cancer and help the tumor to grow and metastasize. Camptothecin (CPT) and its derivatives are known to have anticancer properties of inhibiting cell growth, promoting cell apoptosis, and increasing autophagy. Therefore, in this study, we investigated whether the presence of di(2-ethylhexyl) phthalate (DEHP) could hinder apoptosis and autophagy caused by CPT in non-small cell lung cancer (NSCLC) cells. We found that DEHP interferes with CPT-induced apoptosis and autophagy and increases the prosurvival pathway by reducing the DNA damage marker γ-H2AX and activating the Akt and NF-κB pathways. Furthermore, we also confirmed that combining DEHP with 3-MA has additive effects in inhibiting autophagy and apoptosis in NSCLC cells. Taken together, our findings show that DEHP could affect CPT-induced anticancer treatment and provide evidence to show that DEHP induces chemoresistance in CPT-based chemotherapy.

Association of early-onset breast cancer with body mass index, menarche, and menopause in Taiwan.

BACKGROUND: The trend of women suffering from early-onset breast cancer is increasing in Taiwan. The association of early-onset breast cancer with body mass index (BMI), menarche, and menopausal status has focused interest on the field of cancer epidemiology; however, few studies have explored the interaction of these factors on early-onset risk. This study aimed to estimate the interaction effects of BMI, menarche, and menopausal status on 40-year-old early-onset breast cancer. METHODS: Breast cancer patients were recruited from Kaohsiung Medical University Chung-Ho Memorial Hospital from 2013 to 2020. Multivariable logistic regression was used to estimate odds ratios (ORs) for early-onset breast cancer risk associated with menarcheal age stratified by sociodemographic factors and for the interaction between BMI and menopausal status on early-onset risk. RESULTS: A total of 775 participants were divided into 131 early-onset cases (≤ 40 years) and 644 late-onset cases (> 40 years). Compared to the age of 13 years at menarche, the age ≤ 11 years was significantly positively associated (OR: 2.62, 95% CI: 1.38-4.97) and ≥ 16 years was negatively associated (OR: 0.13, 95% CI: 0.03-0.53) with 40-year-old early-onset breast cancer respectively. In an adjusted model, the status of BMI < 24 and premenopause had 1.76- and 4.59-fold risk of early-onset breast cancer respectively. Especially in BMI < 24 status, premenopause also had a 6.47-fold early-onset risk and the early-onset risk increased by a significant amount per one year younger at menarche (aOR: 1.26, 95% CI: 1.03-1.55). There was also a positive interaction effect on an additive scale between BMI and menopausal status on early-onset breast cancer (RERIOR = 4.62, Pinteraction = 0.057). Compared to both BMI ≥ 24 and peri-/postmenopausal status, both the status of BMI < 24 and premenopause were associated with early-onset breast cancer (aOR: 7.16, 95% CI: 3.87-13.25). CONCLUSIONS: This study suggests that the status of BMI < 24 and premenopause were associated with an increased risk of early-onset breast cancer and there was a positive interaction on an additive scale. Understanding how obesity and menopausal status affect early-onset breast cancer is important for drafting preventive measures for early-onset breast cancer in Taiwan.

Asthma and early smoking associated with high risk of panic disorder in adolescents and young adults.

PURPOSE: Studies have reported a strong link between asthma and panic disorder. We conducted a 17-year community-based large cohort study to examine the relationship between asthma, early smoking initiation, and panic disorder during adolescence and early adulthood. METHODS: A total of 162,766 participants aged 11-16 years were categorized into asthma and nonasthma groups at baseline and compared within the observation period. Covariates during late childhood or adolescence included parental education, cigarette smoking by family members of participants, and participant's gender, age, alcohol consumption, smoking, and exercise habits. Data for urbanicity, prednisone use, allergic comorbidity, and Charlson comorbidity index were acquired from the National Health Insurance Research Database. The Cox proportional-hazards model was used to evaluate the association between asthma and panic disorder. RESULTS: Our findings revealed that asthma increased the risk of panic disorder after adjustment for key confounders in the Cox proportional hazard regression model (adjusted HR: 1.70, 95% CI 1.28-2.26). Hospitalizations or visits to the emergency department for asthma exhibited a dose-response effect on the panic disorder (adjusted HR: 2.07, 95% CI 1.30-3.29). Patients with asthma with onset before 20 years of age who smoked during late childhood or adolescence had the greatest risk for panic disorder (adjusted HR: 4.95, 95% CI 1.23-19.90). CONCLUSIONS: Patients newly diagnosed with asthma had a 1.7-times higher risk of developing panic disorder. Smoking during late childhood or adolescence increased the risk for developing the panic disorder in patients with asthma.

Predictor of slower gastric emptying in gastroesophageal reflux disease: Survey of an Asian-Pacific cohort.

BACKGROUND AND AIM: Asian populations have relatively lower prevalence of gastroesophageal reflux disease and tend to exhibit symptoms of prolonged gastric retention. However, it remains unknown if slower gastric emptying influences its features in Asian countries. We prospectively assessed the potential implications of slower gastric emptying in an Asian-Pacific cohort of gastroesophageal reflux disease by a hospital-based survey. METHODS: One hundred fifty-two patients of gastroesophageal reflux disease complete the scintigraphic measurement of solid phase of gastric emptying. Clinical symptoms and psychological stress are recorded by self-report questionnaire. The status of Helicobacter pylori infection, blood level of pepsinogen I, and I/II ratio are assessed. RESULTS: Forty-seven percent and 28% of the patients have slower gastric emptying rate, depending on the incremental defined cut-off values of slower gastric emptying, respectively. Multiple logistic regression analysis indicates that older age and depression score are independently related to slower gastric emptying. Subgroup analysis discloses that patients with slower gastric emptying and higher depression score tend to present with non-erosive esophagitis whereas higher body mass index level and male gender in patients with normal gastric emptying predict the presence of erosive reflux disease. CONCLUSIONS: Our study cohort of Asian patients indicates distinctive clinical implications of slower gastric emptying in patients with gastroesophageal reflux disease.

Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes.

Di(2-ethylhexyl)phthalate (DEHP) has been considered as an estrogen receptor alpha (ERα) agonist due to its ability to interact with ERα and promote the cell proliferation of ERα-positive breast cancer cells. The impact of DEHP on the chemical therapy in breast cancer is little known. Two breast cancer cell lines, MCF-7 (ERα-dependent) and MDA-MB-231 (ERα-independent) were examined. We found that DEHP impaired the effectiveness of camptothecin (CPT) and alleviated the CPT-induced formation of reactive oxygen species in ERα-positive MCF-7 cells, but not in ERα-negative MDA-MB-231 cells. DEHP also significantly protected MCF-7 cells against the genotoxicity of CPT. Genome-wide DNA methylation profiling revealed that after 48 hours of exposure to 100 µM DEHP, MCF-7 cells exhibited a significant change in their DNA methylation pattern, including hypermethylation of 700 genes and hypomethylation of 221 genes. The impaired therapeutic response to CPT in DEHP-exposed MCF-7 cells is probably mediated by epigenetic changes, especially through Wnt/ß-catenin signaling. A zebrafish xenograft model confirmed the disruptive effect of DEHP on CPT-induced anti-growth of MCF-7 cells. In summary, DEHP exposure induces acquired CPT-resistance in breast cancer cells and epigenetic changes associated with Wnt/ß-catenin signaling activation are probably depending on an ER-positive status.

SSRIs associated with decreased risk of hepatocellular carcinoma: A population-based case-control study.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cancer-related cause of mortality worldwide. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are commonly used worldwide. Available evidence investigating the association between SSRIs use and HCC risk is limited. OBJECTIVE: The present study aimed to investigate if the effect of all kinds of SSRIs on HCC was the same or not using population-based study. METHODS: The nationwide population-based study herein using Taiwan's National Health Insurance Research Database included a total of 59 859 cases with HCC and 285 124 matched controls. Conditional logistic regression analyses were adjusted for confounding variables. RESULTS: All common kinds of SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine were associated with lower HCC risk, and the findings were dose-dependent (eg, fluoxetine: 1-28 DDD [defined daily dose]: adjusted odds ratio [aOR]: 0.81, 95% confidence interval [CI], 0.73-0.89; 29-365 DDD: aOR: 0.71, 95% CI, 0.64-0.79; and ≥366 DDD: aOR: 0.55, 95% CI, 0.45-0.67) (P for trend < .001). CONCLUSIONS: All kinds of SSRIs were associated with decreased risk of HCC.

Dosage of methylphenidate and traumatic brain injury in ADHD: a population-based study in Taiwan.

Preventive effect of stimulants on the risk of brain injuries had been reported. The aim of this study is to determine the extent to which methylphenidate (MPH) prescription moderates the risk of traumatic brain injuries (TBI) in individuals with attention-deficit/hyperactivity disorder (ADHD). Individuals with a recent diagnosis of ADHD between January 1997 and December 2013 (n = 163,618) were identified from Taiwan's National Health Insurance Research Database. A total of 124,438 adolescents and children with ADHD and without prior TBI diagnoses were included and evaluated for subsequent TBI. Methylphenidate prescription duration was subgrouped by the annual average cumulative defined daily dose (DDD): 0, >0 to ≤28, > 28 to ≤84, and >84. We identified 11,463 diagnoses of TBI among 124,438 adolescents and children with ADHD. A Cox regression model was used to investigate whether MPH prescription influenced the risk for TBI after adjusting for sex, age, level of urbanization, seizure, autism and sedative-anxiolytics use. A reduced TBI incidence was observed with MPH prescription DDDs > 84. The protective effect of MPH against TBI persisted after adjusting for confounding factors [hazard ratio (HR) = 0.49; 95% confidence interval (CI): 0.47-0.51]. There was also statistically significant difference in risk for TBI in subjects receiving > 0 to ≤28 or >28 to ≤84 DDDs of MPH treatment (HR = 0.88, 95% CI = 0.83-0.92; HR = 0.76, 95% CI = 0.72-0.80, respectively) when compared with subjects not receiving treatment with MPH. Treatment with MPH for greater than 84 DDDs reduced the risk for TBI among children with ADHD.

Fructose-Rich Beverage Intake and Central Adiposity, Uric Acid, and Pediatric Insulin Resistance.

OBJECTIVE: To determine the association between sugar-sweetened beverage (SSB) consumption with biomarkers of insulin resistance (IR) and investigate whether/how this relates to obesity and serum uric acid in adolescents. STUDY DESIGN: Adolescents (n = 1454, aged 12-16 years) were assessed in a study conducted to monitor Multilevel Risk Profiles for Adolescent Metabolic Syndrome in Taiwan. Detailed information about demographics, diet, physical, anthropometric, and clinical variables was collected. An original homeostatic model assessment of IR (HOMA1-IR), updated nonlinear homeostatic model assessment of IR (HOMA2-IR) model, and several IR markers were measured. RESULTS: Adolescents who consumed a greater amount of SSBs were more likely to have elevated fasting serum insulin, HOMA1-IR, and HOMA2-IR (P for trends, ≤.028). Compared with SSB nondrinkers, those with >350 mL/d intake of heavy high-fructose corn syrup-containing SSBs had a 0.52 and 0.30 higher multivariate-adjusted HOMA1-IR and HOMA2-IR, respectively. Waist circumference and serum uric acid were correspondingly found to explain 25.4% and 23.6%, as well as 23.2% and 20.6%, of the increases in the 2 IR markers. Both the elevations of HOMA1-IR and HOMA2-IR for high-fructose corn syrup-rich SSB intake were strengthened among obese adolescents (P for interaction, ≤.033). CONCLUSIONS: Fructose-rich SSB intake is associated with elevated levels of IR, and this relationship may be partially mediated by central adiposity and serum uric acid. Obesity may modify the effect of this type of SSB consumption in intensifying the elevation of IR in adolescents.

Immunosuppressive medication use and risk of herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE): A nationwide case-control study.

BACKGROUND: The association between immunosuppressive medication use and herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) has not been clearly defined. OBJECTIVE: We evaluated the risk of HZ in patients with SLE treated with different immunosuppressants. METHODS: A nationwide population-based case-control study was conducted using the Taiwanese National Health Insurance Research Database. Cases (1555 patients with SLE who developed HZ) and controls (3049 age- and sex-matched patients with SLE but without HZ) were analyzed for use of various immunosuppressive medications in the preceding 3-month period, and dose-response relationships were determined. Logistic regression was performed to estimate the adjusted odds ratio for HZ development. RESULTS: Medications associated with greater HZ risk in patients with SLE included oral corticosteroids, intravenous methylprednisolone, hydroxychloroquine, oral cyclophosphamide, intravenous cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil. Combination immunosuppressive therapy was common in patients with SLE and was associated with greatly increased HZ risk. For oral corticosteroids and hydroxychloroquine, the risk of HZ was strongly dependent on the medication dose. LIMITATIONS: This study is retrospective in nature. CONCLUSION: Recent immunosuppressive medication use is associated with increased HZ risk in patients with SLE, particularly those receiving high-dose oral corticosteroids and multiagent immunosuppressive therapy.

Comprehensive risk factors, asthma control, and life quality pathways in adults with asthma: A structural equation modeling analysis.

OBJECTIVES: Previous studies reported that environmental factors, particularly the work environment, were related to quality of life (QoL) in patients with asthma. However, the pathway that links workplace and QoL in adults with asthma is still not clear. The aim of this study was to explore the comprehensive environmental factors, asthma control, and QoL pathways in patients with asthma. STUDY DESIGN AND SETTING: Two cohorts of patients with asthma were established, including a prospective phase cohort in 2006 and a cross-sectional phase cohort in 2012. The Asthma Control Test was used to determine the level of disease control, and QoL was assessed by using the Taiwanese version of an asthma quality-of-life questionnaire. In 2014, a structural equation model was applied to explore the pathways from the risk factors to QoL. RESULTS: The structural equation model for predicting QoL provided a good fit (χ(2) [degrees of freedom] = 43.81 [38]; root mean square error of approximation 0.021 [90% confidence interval, 0.001-0.044]) after combining the two cohorts. The wheeze frequency, allergic response frequency, parental asthma, and asthma control were directly associated with QoL. We found that patients who were obese and who worked in poor environments had increased work symptoms and wheeze frequency during the previous year in a cross-sectional phase cohort. However, we did not find that body mass index was a significant factor in a prospective cohort. The patients with obesity and with frequent work symptoms, which induced poor asthma control, were possible mechanisms in the pathway from workplace exposure to poor QoL in the observed adults with asthma in our combined data. CONCLUSION: Body mass index, the work environment, and the wheeze frequency should be considered when assessing asthma control and QoL in adult patients with asthma. Patients who reduce their body weight or avoid exposure to poor workplaces may find this useful for their asthma control and improvement of their QoL.

Protective effects of elafin against adult asthma.

BACKGROUND: Elafin inhibits serine proteases, such as human neutrophil elastase and proteinase 3, to prevent excessive damage during inflammation. However, the relationship between elafin and asthma is still unclear. Microarray technology was used to evaluate smoking- and asthma-related biomarkers in a discovery-driven manner. We identified candidate genes, e.g., proteinase inhibitor 3 (PI3), related to asthma and smoking from gene expression microarray data sets and evaluated their potential as biomarkers for asthma. METHODS: We used human genome microarray data sets from smoking- and asthma-related gene expression data sets and performed real-time quantitative polymerase chain reaction to measure and validate differences in gene expression. We also recruited adult patients with asthma and age- and sex-matched control patients who were administered a structured questionnaire and evaluated for lung function and plasma elafin levels, which are encoded by the PI3 gene. RESULTS: Six significantly altered candidate genes, PI3, protein kinase C iota, phosphoserine phosphatase, IQ motif-containing GTPase activating protein 1, interleukin 13 receptor α 1, and signal transducing adaptor molecule SH3 domain and ITAM motif 2, were identified from comparisons across the four asthma- and four smoking-related data sets included in this study. An in vitro study of human airway epithelial cells (A549) and a human monocytic cell line (THP-1) demonstrated that PI3 messenger RNA levels were significantly altered by nicotine exposure. Elafin concentration was significantly higher in control patients than in patients with asthma (p < 0.001). The plasma elafin concentration in the highest quartile (≥12.69 ng/mL) was inversely associated with asthma (adjusted odds ratio 0.122 [95% confidence interval, 0.053-0.278]) compared with the lowest quartile (<5.82 ng/mL) after adjusting for age, sex, smoking status, waist-to-hip ratio, percentage predicted forced expiratory volume in 1 second, cockroaches in the home, incense burning, and family history. CONCLUSION: Our study revealed that high elafin levels identified in smoking- and asthma-related microarray data sets and an epidemiologic study significantly reduced the risk of asthma. Further studies of elafin as a potential therapy for asthma are warranted.

Analysis of protein-protein interactions in MCF-7 and MDA-MB-231 cell lines using phthalic acid chemical probes.

Phthalates are a class of plasticizers that have been characterized as endocrine disrupters, and are associated with genital diseases, cardiotoxicity, hepatotoxicity, and nephrotoxicity in the GeneOntology gene/protein database. In this study, we synthesized phthalic acid chemical probes and demonstrated differing protein-protein interactions between MCF-7 cells and MDA-MB-231 breast cancer cell lines. Phthalic acid chemical probes were synthesized using silicon dioxide particle carriers, which were modified using the silanized linker 3-aminopropyl triethoxyslane (APTES). Incubation with cell lysates from breast cancer cell lines revealed interactions between phthalic acid and cellular proteins in MCF-7 and MDA-MB-231 cells. Subsequent proteomics analyses indicated 22 phthalic acid-binding proteins in both cell types, including heat shock cognate 71-kDa protein, ATP synthase subunit beta, and heat shock protein HSP 90-beta. In addition, 21 MCF-7-specific and 32 MDA-MB-231 specific phthalic acid-binding proteins were identified, including related proteasome proteins, heat shock 70-kDa protein, and NADPH dehydrogenase and ribosomal correlated proteins, ras-related proteins, and members of the heat shock protein family, respectively.

Global untargeted and individual targeted plasma metabolomics of breast cancer recurrence modified by hormone receptors.

BACKGROUND: Breast cancer is a heterogeneous and complex etiological disease. Understanding perturbations of circulating metabolites could improve prognosis. METHODS: We recruited breast cancer patients from Kaohsiung Medical University (KMU) to perform untargeted (case-control design) and targeted (patient cohort) metabolomics analyses in the discovery and validation phases to evaluate interaction effects between clinical factors and plasma metabolites using multivariable Cox proportional hazards model. RESULTS: In the discovery phase, partial least squares-discriminant analysis (PLS-DA) showed that plasma metabolites were significantly different between recurrent and non-recurrent breast cancer patients. Metabolite set enrichment analysis (MSEA) and metabolomic pathway analysis (MetPA) showed that valine, leucine, and isoleucine degradation was the significant pathway, and volcano plot showed significant ten upregulated and two downregulated metabolites between recurrent and non-recurrent cases. Combined with receiver operating characteristic (ROC) curve and biological significance, creatine, valine, methionine, and mannose were selected for the validation phase. In this patient cohort with 41 new-recurrent vs. 248 non-recurrent breast cancer cases, followed for 720.49 person-years, compared with low level of valine, high valine level was significantly negatively associated with recurrent breast cancer (aHR: 0.36, 95% CI: 0.18-0.72, P = 0.004), especially in ER-negative and PR-negative status. There were interaction effects between valine and ER (Pinteraction = 0.006) as well as PR (Pinteraction = 0.002) on recurrent breast cancer. After Bonferroni correction, stratification effects between valine and hormone receptors were still significant. CONCLUSION: Our study revealed that plasma metabolites were significantly different between recurrent and non-recurrent patients, proposing therapeutic insights for breast cancer prognosis.

The methylation patterns of a disintegrin and metalloproteinase 33 gene (ADAM33) in adult asthma.

BACKGROUND: Asthma is a common chronic inflammatory respiratory disease. Previous studies have suggested that the pathogenesis of asthma may be affected by epigenetic regulation. The purpose of this study is to characterize the effect of the methylation of each CpG site in the ADAM33 (a disintegrin and metalloproteinase 33) gene in adult asthma. METHODS: A human CpG island microarray was used to examine 4 asthmatic cases and 4 healthy controls, and the results suggested that there might be differences in methylation within exon 9 of the ADAM33 gene. Therefore, we designed a case-control study with 50 asthmatic patients and 50 age- and sex-matched healthy controls to examine the relationship between the CpG methylation of the ADAM33 gene and asthma using bisulfite deoxyribonucleic acid modification and sequencing. RESULTS: Bisulfite sequencing experiments showed that the 14 CpG sites in exon 9 of the ADAM33 gene were highly methylated (100%) in all individuals. The proportions of methylation of the 14 CpG sites in ADAM33 in the case group were not different from those of the control group. The methylation of exon 9 of this locus was not associated with age, sex, IgE levels, or lung function. This study found no association between the methylation of CpG sites in exon 9 of the ADAM33 gene and adult asthma. CONCLUSIONS: The 14 CpG sites were highly methylated in the case and control groups. Further investigation of exon 9 in ADAM33 in a larger population is needed to evaluate its role in asthma.

Significant overexpression of DVL1 in Taiwanese colorectal cancer patients with liver metastasis.

Undetected micrometastasis plays a key role in the metastasis of cancer in colorectal cancer (CRC) patients. The aim of this study is to identify a biomarker of CRC patients with liver metastasis through the detection of circulating tumor cells (CTCs). Microarray and bioinformatics analysis of 10 CRC cancer tissue specimens compared with normal adjacent tissues revealed that 31 genes were up-regulated (gene expression ratio of cancer tissue to paired normal tissue > 2) in the cancer patients. We used a weighted enzymatic chip array (WEnCA) including 31 prognosis-related genes to investigate CTCs in 214 postoperative stage I-III CRC patients and to analyze the correlation between gene expression and clinico-pathological parameters. We employed the immunohistochemistry (IHC) method with polyclonal mouse antibody against DVL1 to detect DVL1 expression in 60 CRC patients. CRC liver metastasis occurred in 19.16% (41/214) of the patients. Using univariate analysis and multivariate proportional hazards regression analysis, we found that DVL1 mRNA overexpression had a significant, independent predictive value for liver metastasis in CRC patients (OR: 5.764; 95% CI: 2.588-12.837; p < 0.0001 on univariate analysis; OR: 3.768; 95% CI: 1.469-9.665; p = 0.006 on multivariate analysis). IHC staining of the immunoreactivity of DVL1 showed that DVL1 was localized in the cytoplasm of CRC cells. High expression of DVL1 was observed in 55% (33/60) of CRC tumor specimens and was associated significantly with tumor depth, perineural invasion and liver metastasis status (all p < 0.05). Our experimental results demonstrated that DVL1 is significantly overexpressed in CRC patients with liver metastasis, leading us to conclude that DVL1 could be a potential prognostic and predictive marker for CRC patients.

Body composition modify the association between ambient particulate matter and lung function among asthma patients.

The effect of ambient PM10 and PM2.5 on lung function modified by body muscle and adipose tissue is not fully understood at present. Our aims were to investigate the association between seasonal average air pollutants and lung function in asthmatic patients modified by body composition indicators. In this cross-sectional study, we recruited 914 doctor-diagnosed asthmatic patients, and performed interaction and stratified analysis using the median values of total body muscle (TBM), total body fat (TBF), and percentage body fat (PBF) as well as body mass index (BMI) =25 as the cutoff points of the high/low body composition groups. The adjusted R2 values of the developed LUR models of PM2.5 and PM10 were 91.4% and 90.5% and also verified by cross-validation, respectively. After adjusting for confounding factors, we found that TBM significantly modified the association between PM10 and lung function among asthma patients (interaction P value <0.05). In the low TBM group, seasonal average concentrations of PM10 estimated by the LUR model increased by 10 µg/m3, and negative associations with lung function indicators were observed. For obese patients with BMI>25 and high TBF, the increase in PM10 was associated with the decrease in lung function. The asthma patients with obesity and low total body muscle were more susceptible to adverse effects of PM10 on lung function.

Lifestyle Factors and Energy Intakes with Risks of Breast Cancer among Pre- and Post- Menopausal Women in Taiwan.

Although the incidence of invasive breast cancer (BC) among women in Asian is generally lower than that in Western countries, the incidence of BC has been on the rise in the past three decades in Asian countries. This hospital-based case-control study aimed to explore the relationship between dietary and metabolic factors and BC risk in pre- and post-menopausal women. We enrolled 285 patients with newly diagnosed BC at the National Taiwan University Hospital and 297 controls from the local community and hospital staff. Before receiving anticancer therapy, all patients with BC and control participants completed a 57-question semi-quantitative Food Frequency Questionnaire. For pre-menopausal women, plant-based factor scores rich in seeds and nuts, soy, fruits, and seaweeds correlated significantly with reduced BC risks, whereas menarche occurring at <12 years of age, reduced physical activity, and high-density lipoprotein <40 mg/dL were associated with increased BC risks. For post-menopausal women, plant-based dietary factor scores were also associated with reduced risks, whereas increased body mass index and energy intake levels correlated with increased BC risks. Diets rich in plant-based dietary patterns are protective against BC risk, regardless of menopausal status. Habitual physical activity is protective against BC risk among pre-menopausal Taiwanese women. Maintaining optimal weight and caloric intake is beneficial for reducing post-menopausal BC risk.

Association between recurrent breast cancer and phthalate exposure modified by hormone receptors and body mass index.

The association between phthalate exposure and breast cancer remains controversial. We performed a prospective patient cohort design to explore the interaction between creatinine-corrected urinary phthalate metabolites and hormone receptors as well as body mass index (BMI) on recurrent breast cancer. In this follow-up study, 636 female breast cancer patients and 45 new recurrent cases diagnosed for a total of 1576.68 person-years of follow-up were recruited. Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively associated with breast cancer recurrence, with adjusted hazard ratio (aHR) 3rd vs. 1st quartile of 0.15 (95% CI 0.04-0.51). The MEOHP presented as a non-monotonic dose-response (NMDR) curve, being U-shaped. In the stratification of hormone receptors, MEOHP still exhibited a U-shaped dose-response curve. The third quartile of MEOHP showed significant lowest recurrent risk in the status of ER-positive (aHR 0.18, 95% CI 0.05-0.66), PR-negative (aHR 0.14, 95% CI 0.03-0.63), and HER2-negative (aHR 0.24, 95% CI 0.08-0.76). Whether in BMI < 25 or in BMI ≥ 25, the third quartile of MEOHP was negatively associated with recurrent breast cancer, and there was a negative interaction on an additive scale between MEOHP and BMI (pinteraction = 0.042). The association between MEOHP and recurrent breast cancer was modified by hormone receptors and BMI.