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Background This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations. Methods The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models. Results A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31). Conclusions This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.

PurposeThis meta-analysis investigated the association between the risk of breast cancer and hormone replacement therapy (HRT). Various stratified analyses were performed according to race (Asian/Westerner), HRT type [all hormone therapies, estrogen-only therapy (ET), or combined estrogen–progestin therapy (EPT)], histological breast cancer type (ductal/lobular/mixed ductal–lobular), and estrogen receptor status (ER-positive/ER-negative).MethodsA literature search was performed using Pubmed, Embase, and KoreaMed. Twenty-five epidemiological studies including 23 cohort studies and two randomized controlled trials were included in this meta-analysis.ResultsUsing a random-effects model, HRT use was found to be positively associated with the risk of breast cancer with a pooled hazard ratio (HR) of 1.33 [95% confidence interval (CI) 1.24, 1.44]. Compared with ET, EPT was more strongly associated with breast cancer risk. EPT was associated with both ductal and lobular breast cancer risks [for ductal breast cancer, HR = 1.51 (95% CI 1.28, 1.78); for lobular breast cancer, HR = 1.38 (95% CI 1.20, 1.60)]. According to ER status, all HRTs were associated with the risk of ER-positive breast cancer, but not with that of ER-negative breast cancer.ConclusionsAsian HRT users had a higher risk of breast cancer than western HRT users. Both ET and EPT were significantly associated with the risk of all breast cancer histological types and ER-positive breast cancer.

The International Agency for Research on Cancer reported that some chemicals in hair dyes are probably carcinogenic to those exposed to them occupationally. Biological mechanisms through which hair dye use may be related to human metabolism and cancer risk are not well-established. We conducted the first serum metabolomic examination comparing hair dye users and nonusers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Metabolite assays were conducted using ultrahigh performance liquid chromatography-tandem mass spectrometry. The association between metabolite levels and hair dye use was estimated using linear regression, adjusting for age, body mass index, smoking, and multiple comparisons. Among the 1,401 detected metabolites, 11 compounds differed significantly between the two groups, including four amino acids and three xenobiotics. Redox-related glutathione metabolism was heavily represented, with L -cysteinylglycine disulfide showing the strongest association with hair dye (effect size (β) =  −  0.263; FDR adjusted p -value = 0.0311), along with cysteineglutathione disulfide (β =  − 0.685; FDR adjusted p -value = 0.0312). 5alpha-Androstan-3alpha,17beta-diol disulfate was reduced in hair dye users (β =  − 0.492; FDR adjusted p -value = 0.077). Several compounds related to antioxidation/ROS and other pathways differed significantly between hair dye users and nonusers, including metabolites previously associated with prostate cancer. Our findings suggest possible biological mechanisms through which the use of hair dye could be associated with human metabolism and cancer risk.

Studies on the associations between persistent organic pollutants (POPs) and smoking according to gender and smoking amount (cigarettes/day) are limited, and the results regarding the relationship between POPs and smoking are not completely consistent across studies. The smoking rate in Korea is one of the highest among the Organization for Economic Cooperation and Development (OECD) countries. We investigated the association between serum concentrations of POPs and cigarette smoking in Koreans by smoking status (never-smoker/ever-smoker) and smoking amount (cigarettes/day) according to gender. Serum concentrations of 32 polychlorinated biphenyls (PCBs) and 19 organochlorine pesticides (OCPs) were measured in 401 participants (232 men and 169 women) who received health examinations during the Korean Cancer Prevention Study-II. We compared POP levels in ever-smokers and never-smokers and conducted multivariate logistic regression analyses to identify associations between POPs and smoking. Among women, the concentrations of PCB 156, PCB 167, and PCB 180 were significantly higher in ever-smokers than in never-smokers. After adjustments for age, body mass index, gamma-glutamyl transpeptidase, and alcohol intake, serum PCB 157 concentration was positively associated with male ever-smokers (OR 2.26; 95% CI, 1.01–5.04). In addition, trans-nonachlordane in OCPs as well as PCBs was significantly positively related with female ever-smokers (OR 3.21; 95% CI, 1.04–9.86). We found that subjects who smoked fewer than 15 cigarettes/day had a higher risk of having high POP concentrations than never-smokers. These results indicate that smoking may be associated with human serum POPs levels. •For women, serum PCB levels were higher in ever-smokers than in never-smokers.•The risk of high level of POPs was higher in ever-smokers than in never-smokers.•Subjects who smoked <15 cigarettes/day had a high risk of having high POP levels.

Previous studies of urinary bisphenol A (BPA), phthalate metabolites, and obesity risk have shown inconsistent results. Menopausal status is one of the main factors that affect hormone secretion change in women. In this study, we examined whether urinary BPA and phthalate metabolite levels are associated with obesity and whether the associations differ by sex and menopausal status in a sample of Korean adult populations. We recruited participants at three branches (Yeouido, Gangnam, and Gwanghwamun) of the Korea Medical Institute, a nationwide health check-up center, from 2015 to 2016. Urinary BPA level was measured by high-performance liquid chromatography–tandem mass spectrometry (Agilent 6490 Triple Quad LC-MS/MS; Agilent Technologies, CA, USA). Urinary six phthalate metabolites were analyzed with ultra-high-performance liquid chromatography–tandem mass spectrometry (TSQ Quantum Access Mass; Thermo Fisher Scientific, MA, USA). Participants with body mass index ≥ 25 kg/m 2 were defined as general obesity group. Men with waist circumference (WC) ≥ 90 cm and women with WC ≥ 85 cm were defined as abdominal obesity group. Age, sex, alcohol intake, smoking, and exercise were considered in multivariate logistic regression models. Among the total of 702 participants, 211 participants were classified into the general obesity group, and 131 participants were classified into the abdominal obesity group. Urinary phthalate metabolite levels were not associated with general and abdominal obesity in men and women. However, in women, urinary BPA concentration was positively associated with abdominal obesity (OR = 1.50, 95% CI 1.00–2.26). Also, the association was stronger in postmenopausal women (OR = 2.23, 1.01–4.92), while it was weak in premenopausal women (OR = 1.31, 0.78–2.20). In this study, urinary BPA concentration was associated with abdominal obesity in women, especially postmenopausal women. Future studies should consider sex and menopausal status when investigating associations between urinary BPA, phthalate metabolites levels, and obesity.

Smoking is a major risk factor for lung cancer. Bilirubin, an antioxidant, is inversely associated with the risk of diseases related to oxidative stress. This study was conducted to determine the influence of smoking and bilirubin levels on the risk of lung cancer in the Severance cohort study. This study included 68,676 Korean who received a health examination at Severance Health Promotion Center from 1994 to 2004. Serum bilirubin measurements within normal range were divided into tertiles whereas smoking states were divided as never-smokers, former smokers and current smokers. A diagnosis of lung cancer was coded as occurring based on the report from the National Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using Cox proportional hazards model. At the end of the study period, 240 patients (men: 181, women: 59) developed lung cancer. Compared to those with bilirubin levels ≥ 1.0 mg/dL, HRs (95% CI) for lung cancer were 2.8 (1.8-4.2) for subjects having bilirubin levels from 0.2 to 0.7 mg/dL in men. When we stratified our analysis by smoking status, bilirubin consistently showed a protective effect on the risk of lung cancer on both never- and current smokers. Current smokers having bilirubin levels from 0.2 to 0.7 mg/dL had a risk of lung cancer by 6.0-fold higher than never-smokers with bilirubin levels ≥ 1.0 mg/dL in men. In this large prospective study, higher baseline bilirubin level in the normal range was associated with low risk of lung cancer. Smoking and low bilirubin levels were cumulatively associated with a higher risk of lung cancer.

Background The biological function of mesenchymal stem‐like cells (MSLCs), a type of stromal cells, in the regulation of the tumour microenvironment is unclear. Here, we investigated the molecular mechanisms underlying extracellular matrix (ECM) remodelling and crosstalk between MSLCs and glioblastomas (GBMs) in tumour progression. Methods In vitro and in vivo co‐culture systems were used to analyze ECM remodelling and GBM infiltration. In addition, clinical databases, samples from patients with GBM and a xenografted mouse model of GBM were used. Results Previous studies have shown that the survival of patients with GBM from whom MSLCs could be isolated is substantially shorter than that of patients from whom MSLCs could not be isolated. Therefore, we determined the correlation between changes in ECM‐related gene expression in MSLC‐isolatable patients with that in MSLC non‐isolatable patients using gene set enrichment analysis (GSEA). We found that lysyl oxidase (LOX) and COL1A1 expressions increased in MSLCs via GBM‐derived clusters of differentiation 40 ligand (CD40L). Mechanistically, MSLCs are reprogrammed by the CD40L/CD40/NFκB2 signalling axis to build a tumour infiltrative microenvironment involving collagen crosslinking. Importantly, blocking of CD40L by a neutralizing antibody‐suppressed LOX expression and ECM remodelling, decreasing GBM infiltration in mouse xenograft models. Clinically, high expression of CD40L, clusters of differentiation 40 (CD40) and LOX correlated with poor survival in patients with glioma. This indicated that GBM‐educated MSLCs promote GBM infiltration via ECM remodelling in the tumour microenvironment. Conclusion Our findings provide mechanistic insights into the pro‐infiltrative tumour microenvironment produced by GBM‐educated MSLCs and highlight a potential therapeutic target that can be used for suppressing GBM infiltration. In GBM patients, the survival rate of MSLC isolatable patients is lower than MSLC non‐isolatable patients, and ECM remodeling is more active. GBM‐secreted CD40L educates MSLCs, and educated‐MSLCs promote ECM remodeling for GBM infiltration via CD40/NFκB2/LOX signaling axis. When MSLCs are present in the GBM microenvironment, which could inhibition of GBM infiltration by treatment with CD40L blockade.

Glioblastoma remains an incurable brain disease due to the prevalence of its recurrence. Considerable evidence suggests that glioma stem‐like cells are responsible for glioma relapse after treatment, which commonly involves ionizing radiation. Here, we found that fractionated ionizing radiation (2 Gy/day for 3 days) induced glioma stem‐like cell expansion and resistance to anticancer treatment such as cisplatin (50 μM) or taxol (500 nM), or by ionizing radiation (10 Gy) in both glioma cell lines (U87, U373) and patient‐derived glioma cells. Of note, concomitant increase of nitric oxide production occurred with the radiation‐induced increase of the glioma stem‐like cell population through upregulation of inducible nitric oxide synthase (iNOS). In line with this observation, downregulation of iNOS effectively reduced the glioma stem‐like cell population and decreased resistance to anticancer treatment. Collectively, our results suggest that targeting iNOS in combination with ionizing radiation might increase the efficacy of radiotherapy for glioma treatment.

Study designA pilot randomized controlled trial.ObjectivesTo evaluate the clinical efficacy of upper limb robotic therapy in people with tetraplegia.SettingInpatient rehabilitation hospital in Seoul, Korea.MethodsParticipants were randomly allocated to a robotic therapy (RT) or occupational therapy (OT) group. Both groups received usual care plus 30 min of additional therapy per day for 4 weeks. The additional therapy provided to the OT group was OT, and the additional therapy provided to RT group was RT using the Armeo Power. Primary outcomes were the Medical Research Council scale of each key muscle and Upper Extremity Motor Score (UEMS) for the trained arm. Secondary outcomes were the Spinal Cord Independence Measurement version III (SCIM-III) subscale and total score. Evaluations were performed at baseline and 4 weeks.ResultsA total of 34 individuals with tetraplegia were included; 17 in each group. At 4 weeks, the median (IQR) change in UEMS in the RT group was 1/25 (0 to 3) points compared with 0/25 (−1 to 1) points in the OT group (p = 0.03). The median (IQR) change in total SCIM-III score in the RT group was 7/100 (1.5 to 11) points compared with 0/100 (−8 to 4) points in the OT group (p < 0.01).ConclusionsThere were small improvements in motor strength and SCIM-III scores in the RT group, but there were no statistically significant differences between the groups. Further studies are required for a better understanding of the effects of RT for people with tetraplegia.

Titanium dioxide (TiO(2)) has been widely used in many areas, including biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some TiO(2) particles have a considerable cytotoxic effect in normal human cells. However, the molecular basis for the cytotoxicity of TiO(2) has yet to be defined. In this study, we demonstrated that combined treatment with TiO(2) nanoparticles sized less than 100 nm and ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-dependent upregulation of Fas and conformational activation of Bax in normal human cells. Treatment with P25 TiO(2) nanoparticles with a hydrodynamic size distribution centered around 70 nm (TiO(2) (P25-70)) together with ultraviolet A irradiation-induced caspase-dependent apoptotic cell death, accompanied by transcriptional upregulation of the death receptor, Fas, and conformational activation of Bax. In line with these results, knockdown of either Fas or Bax with specific siRNA significantly inhibited TiO(2)-induced apoptotic cell death. Moreover, inhibition of reactive oxygen species with an antioxidant, N-acetyl-L-cysteine, clearly suppressed upregulation of Fas, conformational activation of Bax, and subsequent apoptotic cell death in response to combination treatment using TiO(2) (P25-70) and ultraviolet A irradiation. These results indicate that sub-100 nm sized TiO(2) treatment under ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-mediated upregulation of the death receptor, Fas, and activation of the preapoptotic protein, Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.