Formation of W/O emulsion using hydrophilic nanoparticles by three-phase emulsification and its energetic analysis.

In this study, we investigated the characteristics of water-in-oil (W/O) emulsions formed by hydrophilic nanoparticles in three-phase emulsification and discussed their stability by performing an energy analysis. W/O emulsions prepared using the three-phase emulsification method are stable in several systems, even in those with a high internal-phase ratio of water up to 85 wt%. Hydrophilic nanoparticles can exist in the internal water phase independently, and the emulsifying action does not depend on the concentration of nanoparticles or the state of the internal water phase. The energy analysis of the model, in which nanoparticles partially penetrate from the aqueous phase to the oil phase, suggests that hydrophilic nanoparticles can form W/O emulsions. It was also found that the entropy change based on the hydrophobic hydration around the nanoparticles was the main driving force for the nanoparticles to partially penetrate the oil phase.

Fundamental Differences in Emulsification Principle between Three-phase Emulsification and Conventional Methods.

The present study investigates the principle difference between three-phase emulsification and conventional emulsification methods (surfactant emulsification and the Pickering method). Conventional emulsification methods depend on intensive factors such as interfacial tension and wetting. In the proposed three-phase emulsification, soft hydrophilic nanoparticles adhere to the oil-water interface due to the van der Waals attraction and stabilize the emulsion. Therefore, it can be said that three-phase emulsification is "extensive emulsification" based on the mass of the hydrophilic nanoparticles and oil droplets. Extensive emulsification is irreversible because the van der Waals attraction acts between the particles unless the mass of the soft hydrophilic nanoparticles and oil droplets changes. The differences between three-phase emulsification and conventional emulsification methods were experimentally verified by comparing the difference in the stability of the emulsions resulting from the change in intensive factors, where the internal phase oil transitioned from solid to liquid. The emulsions prepared using the surfactant and Pickering methods were separated into oil and water by the solid-liquid phase transition of hexadecane in the internal oil phase. However, the emulsion prepared using three-phase emulsification maintained its emulsified state without any oil-water separation even when the internal oil phase underwent solid-liquid phase transition. From the results obtained, it can be concluded that three-phase emulsification is an irreversible method because its mechanism is based on extensive factors. Furthermore, this irreversible method allows the emulsification of various oils that cannot be emulsified by conventional methods, and it is also possible to directly mix emulsions prepared with different oils. The authors also call attention to the possibility of improving emulsion characters and new developments in emulsion science.

Cumulative cigarette tar exposure and lung cancer risk among Japanese smokers.

OBJECTIVE: Tar concentration in cigarette brands is chronologically decreasing in the USA and Japan. However, studies investigating lung cancer risk with cumulative tar exposure in Western and Asian countries are insufficient. To investigate the risk of lung cancer with cumulative cigarette tar exposure, we conducted a case-control study among Japanese current smokers. METHODS: This study used data from the US-Japan lung cancer joint study in 1993-1998. A total of 282 subjects with histologically confirmed lung cancer and 162 hospital and 227 community controls were included in the study, and two control groups were combined. The information regarding tar concentration was obtained from the published documents and additional estimation using the equation of regression. Cumulative tar concentration was calculated by multiplying the annual value of brand-specific tar concentration by years of smoking. The odds ratios and 95% confidence intervals for lung cancer with cumulative tar exposure were estimated using a logistic model. RESULTS: The odds ratios for lung cancer with both lower (1-59.8 × 105 mg) and higher (>59.8 × 105 mg) total cumulative tar exposure were statistically significant (3.81, 2.23-6.50 and 11.64, 6.56-20.67, respectively) with increasing trend (P < 0.001). The stratification analysis showed higher odds ratios in subjects with higher cumulative tar exposure regardless of inhalation, duration of smoking filtered cigarettes and histological type. CONCLUSIONS: This study showed that cumulative tar exposure is a dose-dependent indicator for lung cancer risk, and low-tar exposure was still associated with increased cancer risk.

Neighborhood social capital and sleep duration: a population based cross-sectional study in a rural Japanese town.

BACKGROUND: Studies on social capital and health outcomes have become common, but the relationship between neighborhood social capital and sleep duration by gender is still unclear. We examined the relationship between neighborhood social capital and sleep duration by gender in adults living in a rural community in Japan. METHOD: We conducted a cross-sectional survey of 12,321 residents aged ≥20 years in a town in Mie Prefecture in January-March 2013. Self-completed questionnaires were collected from the residents (n = 7782; valid participation rate, 63.2%). We used five items to assess the neighborhood social capital (Cronbach's α = 0.86). We summed up the scores of each item, and then divided the participants into four groups by quartile of total scores of neighborhood social capital (lowest, low, high, and highest). Sleep duration of < 7 h/day was defined as insufficient sleep duration according to previous studies. To adjust for potential confounders, we performed a multiple log-binominal regression analysis and estimated the prevalence ratios (PRs) and 95% confidence intervals (CIs) for insufficient sleep. RESULTS: Overall 42% of the men and 45% of the women had insufficient sleep. In the men, the lowest group of neighborhood social capital presented a 22% higher prevalence of insufficient sleep (PR 1.22; 95% CIs 1.08-1.38) compared to the highest group of neighborhood social capital. Similarly the low group of neighborhood social capital and the high group of neighborhood social capital had 20 and 19% higher prevalence of insufficient sleep (PR 1.20; 95% CIs 1.06-1.36; PR 1.19; 95% CIs 1.06-1.34, respectively) compared to the highest group of neighborhood social capital. For women there was no significant association between neighborhood social capital and insufficient sleep after controlling for all potential confounders. CONCLUSION: Having lower neighborhood social capital was associated with insufficient sleep among Japanese adults, particularly in the men. This suggests that the context of neighborhood social capital by gender should be considered to promote healthier behaviors with regard to getting enough sleep.

Adsorption of the Three-phase Emulsion on Various Solid Surfaces.

The present study investigates the adsorption of the three-phase emulsion on various solid/water interfaces. Vesicles can be used as emulsifiers in the three-phase emulsions and act as an independent phase unlike the surfactant used in conventional emulsions; therefore, it is expected that the three-phase emulsion formed by the adhesion of vesicles to the oil/water interface will adsorb on various solid/water interfaces. The cationic three-phase emulsion was prepared to encourage emulsion adsorption on negatively charged solid substrates in water. The emulsifier polyoxyethylene-(10) hydrogenated castor oil was rendered cationic by mixing with the surfactant cetyltrimethylammonium bromide and then used to prepare the cationic three-phase emulsion of hexadecane-in-water. Three solid substrates (silicon, glass, and copper) were dipped in the cationic emulsion and the emulsion was found to adsorb on the solid substrates while maintaining its structure. The amount of hexadecane adsorbed on the various surfaces was investigated by gas chromatography and found to increase with increasing hexadecane concentration in the emulsion and eventually plateaued just like molecular adsorption. The maximum surface coverage of the emulsion on the substrates was approximately 80%. However, even the equivalent nonionic three-phase emulsion was found to adsorb on the three solid surfaces. This was attributed to a novel mechanism of irreversible adhesion via the van der Waals attractive force.

A Preferable Method for the Formation of Vesicles from Lamellar Liquid Crystals Using Chemical Additives.

We present a method for vesicle formation from lamellar liquid crystals (LCs) using a cationic amphiphilic substance, namely 2-hydroxyethyl di(alkanol)oxyethyl methylammonium methylsulfate (DEAE). Vesicle formation from the DEAE lamellar dispersion occurred via a two-step chemical addition. This method required neither additional mechanical energy nor the use of special solvents. The transition was solubilized using an organic substance (e.g., limonene) in the lamellar DEAE LC, after which, a small amount of inorganic salt was added to the solubilized lamellar LC dispersion with gentle stirring. The viscosity of the DEAE dispersion following salt addition decreased sharply from 105 mPa·s to 102 mPa·s, and the DEAE dispersion was converted into a high fluidity liquid. Several organic substances were examined as potential solubilizates to initiate the lamellar-vesicle transition. Inorganic salts were also examined as transition triggers using various types of electrolytes; only neutral salts were effective as trigger additives. Dissociation of inorganic salts yielded anions, which inserted between the DEAE bilayer membranes and induced OH- ion exchange. In addition, a number of cations simultaneously formed ion pairs with the DEAE counter ions (CH3SO4- ions). However, as the amount of solubilized organic substances in the DEAE bilayer membrane decreased over time, the vesicles were transformed into lamellar LCs once again. The DEAE states in each step were measured by monitoring the zeta potential, pH, viscosity, and by examination of scanning electron microscopy and atomic force microscopy images. A possible molecular mechanism for the lamellar-vesicle transition of DEAE was proposed.

Thermodynamic Analysis of the Transition of Liquid Crystals from Lamellar to Vesicular Phase.

Here, we report the results of thermodynamic analyses on the lamellar-vesicular transition for a cationic amphiphilic species, namely 2-hydroxyethyl di(alkanol)oxyethyl methylammonium methylsulfate (DEAE). Previously, we have shown that spontaneous vesicle formation from a Lα-lamellar liquid crystal (LC) phase only occurs on the addition of a quantitative amount of additives to the DEAE LC at certain temperatures and that this change occurs without the input of any extra mechanical energy. These lamellar-vesicular transitions occur in two steps: the first step is the formation of an excited state, caused by the solubilization of organic substances in the bilayer structure. The second step, induced by the addition of a small amount of inorganic salt to the excited LC state, is the transition from lamellar to vesicular phase. From our experimental data, the change in the Gibbs free energy was estimated by assuming an ideal electrical chemical potential. As a result, the thermodynamic parameters at 303 K for the lamellar-vesicular transition from the initial state (lamellar) to the final state (vesicle) were found to be approximately -2.7 kJ/mol for the Gibbs free energy, -14.6 kJ/mol for the enthalpy change, and -11.9 kJ/mol for the entropy change. Each state change was due to structural changes not only in the LC bilayers but also in the hydration structure of the surrounding water. Moreover, the most significant finding is that the free energy change in lamellar-vesicular transition is negative, which may be explained based on the stabilization of solubilized vesicles with respect to the unsolubilized lamellar phases.

Worker resignation due to patient nuisance in hospitals: Determinants and prevention.

To investigate determinants and protective strategies for the resignation of health care workers resulting from patient-derived nuisance in medical institutions, we conducted a cross-sectional survey in the 57 hospitals in Mie Prefecture, Japan. A random sampling of 775 employees (physicians, nurses, administrators, and other health care workers) was provided self-administered questionnaires. Among 480 participants who experienced patient-derived nuisance, 132 participants considered resignation as a result, giving an estimated prevalence of 17.1% (95% CI: 14.4%-19.8%) of all respondents. Nonphysical nuisances such as "demand for an unwarranted apology" (OR: 2.57; 95% CI: 1.61-4.12) had higher ORs for considering resignation than other kinds of nuisance. By contrast, OR for the provision of human support by medical institutions was 0.49 (95% CI: 0.28-0.86). Human support was associated with alleviation of the intention to resign.

Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk.

BACKGROUND & AIMS: Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. METHODS: This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. RESULTS: We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. CONCLUSIONS: We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Report of the Japan diabetes society/Japanese cancer association joint committee on diabetes and cancer, Second report.

The Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer published its first report in July 2013 on the epidemiological assessment of the associations of diabetes with cancer risk/prognosis, the common risk factors for diabetes and cancer, and cancer risk associated with diabetes treatment. The Joint Committee continued its work to assess the role of glycemic control in the development of cancer in patients with diabetes. This review shows that high-quality evidence examining the association between glycemic control and cancer risk is lacking.

Report of the Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on Diabetes and Cancer, Second Report.

The Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on Diabetes and Cancer published its first report in July 2013 on the epidemiological assessment of the associations of diabetes with cancer risk/prognosis, the common risk factors for diabetes and cancer, and cancer risk associated with diabetes treatment The JDS/JCA Joint Committee continued its work to assess the role of glycemic control in the development of cancer in patients with diabetes. This review shows that high-quality evidence examining the association between glycemic control and cancer risk is lacking.

Declining trends in prevalence of Helicobacter pylori infection by birth-year in a Japanese population.

Gastric cancer incidence and mortality have been decreasing in Japan. These decreases are likely due to a decrease in prevalence of Helicobacter pylori infection. Our aim was to characterize the trends in prevalence of H. pylori infection focused on birth-year. We carried out a cross-sectional study that included 4285 subjects who were born from 1926 to 1989. We defined H. pylori infection by the serum H. pylori antibody titer. Individuals having H. pylori infection and those with negative H. pylori antibody titer and positive pepsinogen test were defined as high-risk individuals for gastric cancer. We estimated the birth-year percent change (BPC) of the prevalence by Joinpoint regression analysis. The prevalence of H. pylori infection among the subjects born from 1927 to 1949 decreased from 54.0% to 42.0% with a BPC of -1.2%. It was followed by a rapid decline in those born between 1949 (42.0%) and 1961 (24.0%) with a BPC of -4.5%, which was followed by those born between 1961 (24.0%) and 1988 (14.0%) with a BPC of -2.1%. The proportion of high-risk individuals for gastric cancer among the subjects born from 1927 to 1942 decreased from 62.0% to 55.0% with a BPC of -0.8%. A subsequent rapid declining trend was observed in those born between 1942 (55.0%) and 1972 (18.0%) with a BPC of -3.6%, and then it became stable. These remarkable declining trends in the prevalence of H. pylori infection by birth-year would be useful to predict the future trend in gastric cancer incidence in Japan.

Growth Hormone 1 T1663A Polymorphism, Recreational Physical Activity and BMI, and Breast Cancer Risk in Chinese Women.

To evaluate the relationship between the growth hormone 1 (GH1) T1663A polymorphism, recreational physical activity and body mass index (BMI) with reference to breast cancer, we conducted a case-control study with 669 cases of breast cancer and 682 population-based controls in Jiangsu Province, China. A structured questionnaire was used to elicit detailed information. All subjects completed an in-person interview. GH1 genotypes were identified using PCR-RFLP methods. Odds ratios (ORs) were estimated with an unconditional logistic model. The distribution of GH1 genotypes was not significantly different between controls and cases (χ2=2.576, P=0.276). Results of stratified analysis by the participation status of the recreational physical activity showed that the persons with GH1 A allele were at a decreased risk of breast cancer (adjusted-OR=0.66; 95% CI, 0.50-0.87) only among inactive individuals. Stratified analysis by BMI showed that the genotype A/A was associated with a decreased risk of breast cancer only among individuals of the BMI<25 (adjusted-OR=0.80; 95% CI, 0.66-0.98). The findings of this study suggest that recreational physical activity and BMI may modify any association between the GH1 T1663A polymorphism and breast cancer risk.

Protective roles of aldo-keto reductase 1B10 and autophagy against toxicity induced by p-quinone metabolites of tert-butylhydroquinone in lung cancer A549 cells.

tert-Butylhydroquinone (BHQ), an antioxidant used as a food additive, exhibits an anticancer effect at low doses, but is carcinogenic in rodents at high doses. BHQ is metabolized into cytotoxic tert-butylquinone (TBQ), which is further converted to 6-tert-butyl-2,3-epoxy-4-hydroxy-5-cyclohexen-1-one (TBEH) through 6-tert-butyl-2,3-epoxy-4-benzoquinone (TBE). Both TBQ and TBE are cytotoxic, but their toxic mechanisms have not been fully characterized. In this study, we have investigated the toxic mechanisms of TBQ and TBE, and the defense system against the two p-quinones using lung cancer A549 cells. TBQ and TBE, but not BHQ and TBEH, showed cytotoxicity to A549 cells. Neither caspase-3 activation nor an increase in the expression of endoplasmic reticulum stress-associating target genes was observed. TBQ and TBE reacted with reduced glutathione, and significantly decreased the glutathione level in A549 cells, suggesting that the cytotoxicity of the p-quinones is caused by their high electrophilicity reacting with biomolecules. The A549 cells treated with the p-quinones also showed increased levels of autophagic vacuoles and LC3-II protein, which are specific autophagy markers. An autophagy inhibitor, 3-methyladenine (3MA), decreased the LC3-II production by the p-quinones, but enhanced the cytotoxicity induced by TBQ and TBE, suggesting that autophagy contributes to alleviating the p-quinone-triggered cytotoxicity. In addition, the TBE-induced cytotoxicity and autophagy activation in the cells were significantly suppressed by overexpression of aldo-keto reductase (AKR)1B10 that efficiently reduces TBE into TBEH, and were augmented by pretreatment with a potent AKR1B10 inhibitor, C1. The effects of 3MA and C1 on the TBE-induced cytotoxicity were additive. The data provides evidence for the first time that autophagy and AKR1B10 contribute to the defense system against the cytotoxicity caused by the electrophilic p-quinone metabolites of BHQ.

Cigarette smoke inhalation and risk of lung cancer: a case-control study in a large Japanese population.

Several studies have shown that cigarette smoke inhalation is associated with an increased risk of lung cancer (LC) in European populations. The aim of our study was to clarify the relationship between cigarette smoke inhalation and the risk of LC in a Japanese population. We carried out a large case-control study of cigarette smoking and the risk of LC in Japan. Cases were newly diagnosed patients with histologically confirmed LC (n=653). Controls (n=1281) included hospital controls (n=453) and community-based controls (n=828). Odds ratios (OR) and 95% confidence intervals (CI) were derived from unconditional logistic regression analysis, adjusted for basic confounding variables including age, sex, drinking status, fruit and vegetable intake, family history of LC, occupation, and years of education. Compared with never smokers, ORs for ever smokers who do not inhale cigarette smoke (noninhalation) and ever smokers who inhale cigarette smoke (inhalation) were 1.72 (95% CI: 1.15-2.59) and 3.28 (95% CI: 2.38-4.53), respectively, when adjusted for basic confounding variables. When the analysis was restricted to ever smokers, the OR adjusted for basic confounding factors and pack-year of the risk of LC in the inhalation group was significantly higher than that in the noninhalation group. OR for the inhalation group compared with the noninhalation group was 1.52 (95% CI: 1.06-2.18, P=0.021). A similar pattern was observed in subcategory analyses for adenocarcinoma, squamous cell carcinoma and small cell carcinoma, and other histological types, although without statistical significance. Our case-control study showed that inhalation of cigarette smoke is a significant risk for LC independent from pack-years in a Japanese population.

Associations between variants on ADIPOQ and ADIPOR1 with colorectal cancer risk: a Chinese case-control study and updated meta-analysis.

BACKGROUND: Epidemiological studies have suggested that variants on adiponectin (ADIPOQ) and its receptor ADIPOR1 (adiponectin receptor 1) are associated with colorectal cancer (CRC) risk; however, the results were inconclusive. The aim of the study was to evaluate the associations between the variants on ADIPOQ and ADIPOR1 and the CRC risk with a hospital-based case-control study in the Chinese population along with meta-analysis of available epidemiological studies. METHODS: With a hospital-based case-control study of 341 cases and 727 controls, the associations between the common variants on ADIPOQ (rs266729, rs822395, rs2241766 and rs1501299) and ADIPOR1 (rs1342387 and rs12733285) and CRC susceptibility were evaluated. Meta-analysis of the published epidemiological studies was performed to investigate the associations between the variants and CRC risk. RESULTS: For the population study, we found that variant rs1342387 of ADIPOR1 was associated with a reduced risk for CRC [adjusted odds ratio (OR) = 0.74, 95% confidential intervals (95% CI) = 0.57-0.97; CT/TT vs. CC]. The meta-analysis also suggested a significant association for rs1342387 and CRC risk; the pooled OR was 0.79 (95% CI = 0.66-0.95) for the CT/TT carriers compared to CC homozygotes under the random-effects model (Q = 8.06, df = 4, P = 0.089; I(2) = 50.4%). The case-control study found no significant association for variants rs266729, rs822395, rs2241766, and rs1501299 on ADIPOQ or variant rs12733285 on ADIPOR1 and CRC susceptibility, which were consistent with results from the meta-analysis studies. CONCLUSIONS: These data suggested that variant rs1342387 on ADIPOR1 may be a novel CRC susceptibility factor.

Intake of freshwater fish and associated fatty acids and risk of breast cancer.

To investigate the association between intake of freshwater fish and their fatty acids and the risk of breast cancer in Chinese women, we conducted a case-control study with 669 cases and 682 population-based controls in Jiangsu Province of China. A structured questionnaire was used to elicit detailed information. Unconditional logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Total freshwater fish intake was linked to decrease in the adjusted OR for breast cancer, but without dose-dependence. Analyses by freshwater fish species showed that consumption of black carp and silver carp was inversely related to breast cancer risk, with adjusted-ORs for the highest intake category of black carp (≥500g/month) of 0.54 (95%CI=0.33-0.92; P trend<0.002) and for silver carp (≥1000g/month) of 0.19 (95%CI=0.11-0.33; P trend<0.001). In contrast, consumption of crucian carp was positively related to breast cancer risk, with an adjusted OR for the highest intake category (≥1000g/month) of 6.09 (95%CI=3.04-12.2; P trend<0.001). Moderate intakes of SFA, PUFA, n3-PUFA and n6-PUFA from freshwater fish may decrease the risk of breast cancer among premenopausal women. The findings of this study suggest that intake of freshwater fish and their fatty acids may modify risk of breast cancer, and that different species of freshwater fish could have a different actions on breast cancer risk. Future epidemiologic studies are needed to know the effects of freshwater fish intake on breast cancer risk and the cause of these effects.

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10.

Inhalation of 9,10-phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust, exerts fatal damage against a variety of cells involved in respiratory function. Here, we show that treatment with high concentrations of 9,10-PQ evokes apoptosis of lung cancer A549 cells through production of reactive oxygen species (ROS). In contrast, 9,10-PQ at its concentrations of 2 and 5 µM elevated the potentials for proliferation, invasion, metastasis and tumorigenesis, all of which were almost completely inhibited by addition of an antioxidant N-acetyl-l-cysteine, inferring a crucial role of ROS in the overgrowth and malignant progression of lung cancer cells. Comparison of mRNA expression levels of six aldo-keto reductases (AKRs) in the 9,10-PQ-treated cells advocated up-regulation of AKR1B10 as a major cause contributing to the lung cancer malignancy. In support of this, the elevation of invasive, metastatic and tumorigenic activities in the 9,10-PQ-treated cells was significantly abolished by the addition of a selective AKR1B10 inhibitor oleanolic acid. Intriguingly, zymographic and real-time PCR analyses revealed remarkable increases in secretion and expression, respectively, of matrix metalloproteinase 2 during the 9,10-PQ treatment, and suggested that the AKR1B10 up-regulation and resultant activation of mitogen-activated protein kinase cascade are predominant mechanisms underlying the metalloproteinase induction. In addition, HPLC analysis and cytochrome c reduction assay in in vitro 9,10-PQ reduction by AKR1B10 demonstrated that the enzyme catalyzes redox-cycling of this quinone, by which ROS are produced. Collectively, these results suggest that AKR1B10 is a key regulator involved in overgrowth and malignant progression of the lung cancer cells through ROS production due to 9,10-PQ redox-cycling.

Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells.

Continuous exposure to daunorubicin (DNR) confers resistance against the drug-elicited lethality of leukemic cells and then reduces the remission rate. However, the detailed mechanisms involved in resistance development of leukemic cells to DNR remain unclear. Upregulation of aldo-keto reductases (AKRs) in human leukemic U937 cells was evaluated by gene-specific PCR and western blot analyses, and the contribution of AKRs toward the DNR sensitivity was assessed using gene expression and RNA-interference techniques and specific inhibitors. In addition, DNR reduction and cell differentiation were analyzed by fluorescence high-performance liquid chromatography and flow cytometry, respectively. Treatment with high doses of DNR triggered apoptotic induction of U937 cells through the production of reactive oxygen species (ROS) and a ROS-dependent mechanism. In contrast, DNR, at its sublethal doses, induced the expression of AKR1C1 and AKR1C3, both of which reduced the DNR sensitivity of the cells. The enzymes did not interfere with the cell differentiation caused by DNR, whereas their upregulation facilitated reduction of the anticancer drug and a ROS-derived lipid aldehyde 4-hydroxy-2-nonenal. These results suggest crucial roles of AKR1C1 and AKR1C3 in the acquisition of DNR resistance of leukemic cells by metabolizing both DNR and cytotoxic aldehydes derived from ROS-linked lipid peroxidation.