Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: A phase I study.

Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m2 on day 1) and fluorouracil (1000 mg/m2 on days 1-4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum-tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.

An inverse association between serum resistin levels and n-3 polyunsaturated fatty acids intake was strongest in the SNP-420 G/G genotype in the Japanese cohort: The Toon Genome Study.

OBJECTIVE: Resistin is secreted by monocytes/macrophages and is associated with insulin resistance, inflammation and cardiovascular diseases. In the Japanese cohort, serum resistin is tightly associated with a single-nucleotide polymorphism (SNP) at -420 (rs1862513) in the promoter region of the human resistin gene. However, interactions between SNP-420 and environmental factors remain to be elucidated. The aim of this study was to investigate the association between serum resistin levels and nutrient intake, and the effect of SNP-420 on this association. DESIGN, PARTICIPANTS AND MEASUREMENTS: The Toon Genome Study is a cohort study of Japanese community-dwelling subjects. A total of 1981 participants were cross-sectionally analysed. Each nutrient intake was assessed using the semiquantitative food frequency questionnaire and categorized into the quartiles (Q1-Q4). Serum resistin was measured by ELISA. RESULTS: Serum resistin tended to be inversely associated with fish intake and positively associated with meat intake after adjustment for age, sex, BMI and energy intake. Serum resistin was inversely associated with n-3 polyunsaturated fatty acids (PUFA) intake after adjustment for age, sex, BMI and energy intake (Q1 12.5, Q2 12.5, Q3 12.2, Q4 11.5 ng/mL; P for trend = .007). This inverse association was strongest in the G/G genotype of SNP-420, followed by C/G and C/C (G/G, Q1 18.9, Q2 19.5, Q3 18.4, Q4 14.5 ng/mL, P = .001; C/G, 14.4, 13.3, 13.1, 12.9, P = .015; C/C, 9.5, 9.5, 9.2, 8.8, P = .020; P for interaction = .004). CONCLUSIONS: The inverse association between serum resistin and n-3 PUFA intake was strongest in SNP-420 G/G genotype in the Japanese cohort.

Correlation between global methylation level of peripheral blood leukocytes and serum C reactive protein level modified by MTHFR polymorphism: a cross-sectional study.

BACKGROUND: Chronic inflammatory conditions are associated with higher tumor incidence through epigenetic and genetic alterations. Here, we focused on an association between an inflammation marker, C-reactive-protein (CRP), and global DNA methylation levels of peripheral blood leukocytes. METHODS: The subjects were 384 healthy Japanese women enrolled as the control group of a case-control study for breast cancer conducted from 2001 to 2005. Global DNA methylation was quantified by Luminometric Methylation Assay (LUMA). RESULTS: With adjustment for lifestyle-related factors, including folate intake, the global DNA methylation level of peripheral blood leukocytes was significantly but weakly increased by 0.43% per quartile category for CRP (P for trend = 0.010). Estimated methylation levels stratified by CRP quartile were 70.0%, 70.8%, 71.4%, and 71.3%, respectively. In addition, interaction between polymorphism of MTHFR (rs1801133, known as C677T) and CRP was significant (P for interaction = 0.046); the global methylation level was significantly increased by 0.61% per quartile category for CRP in the CT/TT group (those with the minor allele T, P for trend = 0.001), whereas no association was observed in the CC group (wild type). CONCLUSIONS: Our study suggests that CRP concentration is weakly associated with global DNA methylation level. However, this association was observed more clearly in individuals with the minor allele of the MTHFR missense SNP rs1801133. By elucidating the complex mechanism of the regulation of DNA methylation by both acquired and genetic factors, our results may be important for cancer prevention.

Low Heart Rate Variability and Sympathetic Dominance Modifies the Association Between Insulin Resistance and Metabolic Syndrome　- The Toon Health Study.

BACKGROUND: Insulin resistance is strongly associated with metabolic syndrome (MetS), but it is not known how this association is influenced by the autonomic nervous system, which controls insulin secretion.Methods and Results:The subjects were 2,016 individuals aged 30-79 years enrolled between 2009 and 2012. MetS was determined using the harmonized MetS definition, which includes waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2 h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. The 5-min heart rate variability (HRV) was evaluated using time-domain indices of standard deviations of NN intervals (SDNN) and root mean square of successive differences (RMSSD). Power spectral analysis yielded frequency-domain measures for HRV: high-frequency (HF) power, low-frequency (LF) power and LF/HF. Multivariable adjusted logistic models showed that the highest quartiles for SDNN, RMSSD, LF, and HF vs. the lowest quartiles had a significant association with MetS. RMSSD, HF, and LF/HF remained significantly associated with MetS after adjustment for HOMA-IR (or ISI). Additive interactions between the levels of high LF/HF and high HOMA-IR (or low ISI) were significantly positive. CONCLUSIONS: Sympathovagal imbalance as evidenced by low HF and high LF/HF modified the association of insulin resistance or low insulin sensitivity with MetS.

Genome-wide association study of plasma resistin levels identified rs1423096 and rs10401670 as possible functional variants in the Japanese population.

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene (RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP -358 G>A, followed by rs1423096 C>T, SNP -420 C>G, and rs10401670 C>T (P = 5.39×10-47, 1.81×10-22, 2.09×10-16, and 9.25×10-15, respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3'-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.

Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study.

BACKGROUND: Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. METHODS: Between 2009-2012, the Toon Health Study recruited 1899 individuals aged 30-79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF:HF ratio. RESULTS: Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41-3.10). CONCLUSIONS: Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals.

Phase 1 study of efatutazone, a novel oral peroxisome proliferator-activated receptor gamma agonist, in combination with FOLFIRI as second-line therapy in patients with metastatic colorectal cancer.

BACKGROUND: Efatutazone, a novel oral highly-selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has demonstrated some inhibitory effects on disease stabilization in patients with metastatic colorectal cancer (mCRC) enrolled in previous phase I studies. Here, we evaluate the safety and pharmacokinetics of efatutazone combined with FOLFIRI (5-fluorouracil, levo-leucovorin, and irinotecan) as second-line chemotherapy in Japanese patients with mCRC. METHODS: Dose-limiting toxicities (DLTs) were evaluated at 2 efatutazone dose levels of 0.25 and 0.50 mg (the recommended dose [RD] of efatutazone monotherapy) twice daily in combination with FOLFIRI in a 3-9 patient cohort. Furthermore, tolerability at the RD level was assessed in additional patients, up to 12 in total. Blood samples for pharmacokinetics and biomarkers and tumor samples for archival tissues were collected from all patients. RESULTS: Fifteen patients (0.25 mg, 3; 0.5 mg, 12) were enrolled. No DLTs were observed. Most patients experienced weight increase (100 %) and edema (80.0 %), which were manageable with diuretics. Common grade 3/4 toxicities were neutropenia (93.3 %), leukopenia (46.7 %), and anemia (33.3 %). Stable disease was observed in 8 of the 14 patients evaluable for tumor response. The plasma adiponectin levels increased over time and increased dose. No clear relationship was detected between treatment efficacies and plasma levels of adiponectin as well as the expression levels of PPARγ and the retinoid X receptor in tumor tissues. CONCLUSIONS: Efatutazone combined with FOLFIRI demonstrates an acceptable safety profile and evidence of disease stabilization in Japanese patients with mCRC. The RD for efatutazone monotherapy can be used in combination with FOLFIRI.

Green tea consumption and breast cancer risk in Japanese women: a case-control study.

Although many in vitro and animal studies have suggested a protective effect of green tea against breast cancer, only a few epidemiological studies have examined this association, and findings have been inconsistent. We examined the association between green tea consumption and breast cancer risk in consideration of the hormone receptor status of tumors and investigated whether the association was modified by dietary and genetic factors based on a hospital-based case-control study in Nagano, Japan. A total of 369 pairs completed a validated food frequency questionnaire and provided blood samples. Four single nucleotide polymorphisms (SNPs) were genotyped: CYP19A1 (rs10046), COMT (rs4680), MTHFR C677T (rs1801133), and MTHFR A1298C (rs1801131). We found no inverse association between green tea consumption and breast cancer risk. Compared with women who drank less than 120 ml of green tea per day, the adjusted odds ratio for women who drank more than 600 ml was 1.27 (95% confidence interval = 0.75-2.14; P for trend = 0.20). We also found no inverse association for either tumor subtype. No substantial effect modification was observed for menopausal status, 4 SNPs, or dietary intake of folate or isoflavone. This study provides additional evidence that green tea consumption is not associated with a decreased risk.

Fulminant type 1 diabetes caused by DIHS could be affected by the reactivation of HHV-6.

CONTEXT: In the previous issue of this journal, we reported that the incidence of fulminant type 1 diabetes (FT1D) due to the drug-induced hypersensitivity syndrome (DIHS) in Japan is higher than that in the general population and is associated with HLAB62. On the other hand, the reactivation of human herpesvirus 6 (HHV-6), which has been reported to be associated with DIHS, was observed at a higher frequency, but its association with the development of FT1D was unclear. OBJECTIVE: We aimed to clarify the relationship between the onset of FT1D and the reactivation of HHV-6. METHODS: We conducted a literature search for cases of DIHS-induced FT1D in addition to previously reported cases, and investigated the changes in the HHV-6 antibody titer before and after the onset of FT1D. RESULTS: The HHV-6 antibody titer was increased just before or after the onset of FT1D in all 8 cases. In one case, HHV-6 DNA was also identified shortly before the onset of FT1D. CONCLUSION: These results indicate for the first time that the reactivation of HHV-6 is associated with the onset of FT1D caused by DIHS.　.

Association between serum concentrations of perfluoroalkyl substances and global DNA methylation levels in peripheral blood leukocytes of Japanese women: A cross-sectional study.

Global DNA methylation levels in peripheral blood leukocytes can be a biomarker for cancer risk; however, levels can be changed by various factors such as environmental pollutants. We investigated the association between serum concentrations of perfluoroalkyl substances (PFASs) and global DNA methylation levels of leukocytes in a cross-sectional study using the control group of a Japanese breast cancer case-control study [397 women with a mean age of 54.1 (SD 10.1) years]. Importantly, our analysis distinguished branched PFAS isomers as different from linear isomers. The serum concentrations of 20 PFASs were measured by in-port arylation gas-chromatography negative chemical ionization mass spectrometry. Global DNA methylation levels in peripheral blood leukocytes were measured using a luminometric methylation assay. Associations between log10-transformed serum PFAS concentrations and global DNA methylation levels were evaluated by regression coefficients in multivariable robust linear regression analyses. Serum concentrations of 13 PFASs were significantly associated with increased global DNA methylation levels in leukocytes. Global DNA methylation was significantly increased by 1.45 %-3.96 % per log10-unit increase of serum PFAS concentration. Our results indicate that exposure to PFASs may increase global DNA methylation levels in peripheral blood leukocytes of Japanese women.

Association of dietary and genetic factors related to one-carbon metabolism with global methylation level of leukocyte DNA.

Global hypomethylation of leukocyte DNA has been associated with an increased risk of cancer. As dietary and genetic factors related to one-carbon metabolism may influence both the methylation and synthesis of DNA, we investigated associations between these factors and the global methylation level of peripheral blood leukocyte DNA based on a cross-sectional study of 384 Japanese women. Dietary intake of folate and vitamins B2, B6, and B12 was assessed with a validated semiquantitative food frequency questionnaire. Five polymorphisms in methylenetetrahydrofolate reductase (MTHFR) (rs1801133 and rs1801131), methionine synthase (MTR) (rs1805087), and methionine synthase reductase (MTRR) (rs10380 and rs162049) were genotyped. Global DNA methylation of leukocyte DNA was quantified using Luminometric Methylation Assay. A linear trend of association between methylation and dietary and genetic factors was evaluated by regression coefficients in a multivariable linear regression model. Mean global methylation level (standard deviation) was 70.2% (3.4) and range was from 59.0% to 81.2%. Global methylation level significantly decreased by 0.36% (95% confidence interval, 0.03-0.69) per quartile category for folate level. Subgroup analysis suggested that alcohol drinking modified the association between folate intake and global methylation level (P(interaction)  = 0.01). However, no statistically significant association was observed for intake of vitamins B2, B6, and B12, alcohol consumption, or five single nucleotide polymorphisms of MTHFR, MTR, and MTRR. We found that higher folate intake was significantly associated with a lower level of global methylation of leukocyte DNA in a group of healthy Japanese females.

Association of postmenopausal endogenous sex hormones with global methylation level of leukocyte DNA among Japanese women.

BACKGROUND: Although global hypomethylation of leukocyte DNA has been associated with an increased risk of several sites of cancer, including breast cancer, determinants of global methylation level among healthy individuals remain largely unexplored. Here, we examined whether postmenopausal endogenous sex hormones were associated with the global methylation level of leukocyte DNA. METHODS: A cross-sectional study was conducted using the control group of a breast cancer case-control study in Nagano, Japan. Subjects were postmenopausal women aged 55 years or over who provided blood samples. We measured global methylation level of peripheral blood leukocyte DNA by luminometric methylation assay; estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate, testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex-hormone binding globulin by immunoradiometric assay. A linear trend of association between methylation and hormone levels was evaluated by regression coefficients in a multivariable liner regression model. A total of 185 women were included in the analyses. RESULTS: Mean global methylation level (standard deviation) was 70.3% (3.1) and range was from 60.3% to 79.2%. Global methylation level decreased 0.27% per quartile category for estradiol and 0.39% per quartile category for estrone while it increased 0.41% per quartile category for bioavailable estradiol. However, we found no statistically significant association of any sex hormone level measured in the present study with global methylation level of leukocyte DNA. CONCLUSIONS: Our findings suggest that endogenous sex hormones are not major determinants of the global methylation level of leukocyte DNA.

Recurrent Hypoglycemia Due to a High Titer of Insulin Antibody in Response to Exogenous Insulin Administration in Two Cases of Type 1 Diabetes.

In the first case, a 60-year-old man who was using continuous subcutaneous insulin infusion (CSII), developed recurrent hypoglycemia due to insulin antibodies. This is the first report of such a case using CSII. In the second case, a 70-year-old man was follow-up case who developed hypoglycemia while using human insulin. In both cases, the hypoglycemia subsided after switching to multiple daily insulin injection and/or insulin preparation. The results of Scatchard analyses of the two cases were similar to those of cases of insulin autoimmune syndrome (IAS) that improved after recovery from hypoglycemia.The clinical characteristics and Scatchard analysis data were essentially the same as those for IAS, except for the presence of insulin administration.

Fragment c gamma receptor gene polymorphisms and breast cancer risk in case-control studies in Japanese, Japanese Brazilians, and non-Japanese Brazilians.

Previous studies showing the presence of antibodies against tumor-associated antigens in healthy individuals suggest that antibody-dependent cell cytotoxicity (ADCC) might play a role in the development of breast cancer. We hypothesized that functional polymorphisms in fragment c gamma receptor (FcgR) genes were associated with breast cancer risk. We conducted hospital-based case-control studies of patients aged 20-74 years with invasive breast cancer, and matched controls from medical checkup examinees in Nagano, Japan and from cancer-free patients in São Paulo, Brazil. A total of 869 pairs (403 Japanese, 80 Japanese Brazilians and 386 non-Japanese Brazilians) were genotyped for two single nucleotide polymorphisms (SNPs): a histidine (H)/arginine (R) polymorphism at position 131 of FcgRIIa (FcgRIIa H131R) and a valine (V)/phenylalanine (F) polymorphism at position 158 of FcgRIIIa (FcgRIIIa F158V). We found no statistically significant association between either of the two SNPs and breast cancer risk regardless of population. In analyses of the three populations combined, adjusted odds ratio (OR) was 0.93 [95% confidence interval (CI) 0.66-1.32] for women with the R/R versus H/H genotype of the FcgRIIa H131R polymorphism and 1.04 (95% CI 0.69-1.57) for the V/V versus F/F genotype of the FcgRIIIa F158V polymorphism. On combination of the two SNPs, compared to women with both the R/R genotype of the FcgRIIa H131R polymorphism and F/F genotype of the FcgRIIIa F158V polymorphism, the adjusted OR for women with both the H/H and V/V genotype was 0.68 (95% CI 0.37-1.27). In conclusion, our findings suggest that ADCC might not play a major role in the etiology of breast cancer.

Comparison of postmenopausal endogenous sex hormones among Japanese, Japanese Brazilians, and non-Japanese Brazilians.

BACKGROUND: Differences in sex hormone levels among populations might contribute to the variation in breast cancer incidence across countries. Previous studies have shown higher breast cancer incidence and mortality among Japanese Brazilians than among Japanese. To clarify the difference in hormone levels among populations, we compared postmenopausal endogenous sex hormone levels among Japanese living in Japan, Japanese Brazilians living in the state of São Paulo, and non-Japanese Brazilians living in the state of São Paulo. METHODS: A cross-sectional study was conducted using a control group of case-control studies in Nagano, Japan, and São Paulo, Brazil. Participants were postmenopausal women older than 55 years of age who provided blood samples. We measured estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex hormone-binding globulin (SHBG) by immunoradiometric assay. A total of 363 women were included for the present analyses, comprising 185 Japanese, 44 Japanese Brazilians and 134 non-Japanese Brazilians. RESULTS: Japanese Brazilians had significantly higher levels of estradiol, bioavailable estradiol, estrone, testosterone and free testosterone levels, and lower SHBG levels, than Japanese. Japanese Brazilians also had significantly higher levels of bioavailable estradiol, estrone and DHEAS and lower levels of SHBG and androstenedione than non-Japanese Brazilians. Levels of estradiol, testosterone and free testosterone, however, did not differ between Japanese Brazilians and non-Japanese Brazilians. These differences were observed even after adjustment for known breast cancer risk factors. We also found an increase in estrogen and androgen levels with increasing body mass index, but no association for most of the other known risk factors. CONCLUSIONS: We found higher levels of estrogens and androgens in Japanese Brazilians than in Japanese and levels similar to or higher than in non-Japanese Brazilians. Our findings may help explain the increase in the incidence and mortality rate of breast cancer among Japanese Brazilians.

Serum perfluoroalkyl substances and breast cancer risk in Japanese women: A case-control study.

BACKGROUND: Perfluoroalkyl substances (PFASs) may contribute to causing breast cancer; however, associations between exposure to PFASs and risk of breast cancer are controversial. OBJECTIVES: In the present study, we newly distinguished branched isomers of PFASs from their linear isomers and aimed to investigate the association between serum PFAS concentrations and breast cancer risk in Japanese women. METHODS: We used a case-control design to study 405 eligible matched pairs attending four hospitals in Nagano Prefecture, Japan from May 2001 to September 2005. We used in-port arylation gas-chromatography mass spectrometry with negative chemical ionization to measure serum concentrations of 20 PFAS congeners. We calculated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer and its hormone-receptor subtypes by quartiles or tertiles of serum PFASs. RESULTS: After multivariable adjustment for breast cancer risk factors, we found that serum concentrations of 20 PFAS congeners were significantly inversely associated with risk of breast cancer. Comparing the extreme quartiles of linear isomers of perfluorooctane sulfonate or perfluorooctanoic acid, ORs were 0.15 (95% CI: 0.07, 0.33 P for trend <0.0001) and 0.21 95% CI: 0.10, 0.44 P for trend <0.0001). Among postmenopausal women, whereas we found the linear isomer of perfluorotridecanoic acid to be inversely associated with breast cancer risk, a medium degree of exposure to the branched isomer of perfluorotridecanoic acid was associated with a marginally increased risk of breast cancer (OR [95% CI] = 1.74 [0.98, 3.09]). DISCUSSION: In our case-control study, we found overall no association between serum PFAS concentrations and increased risk of breast cancer. Many inverse associations between serum PFAS concentrations and breast cancer risk were found.

Leisure-time physical activity and breast cancer risk by hormone receptor status: effective life periods and exercise intensity.

OBJECTIVE: Physical activity may decrease breast cancer risk. However, it is unclear what intensity of exercise and during which life periods this effect on decreasing risk is efficiently expressed, and whether the associations differ by the estrogen-/progesterone- receptor (ER/PR) status of tumors. We investigated associations between age- and intensity-specific leisure-time physical activity and ER/PR-defined breast cancer risk. METHODS: We conducted a hospital-based case-control study in Nagano, Japan. Subjects were 405 cases newly diagnosed (>99% known ER/PR) from 2001 to 2005, who were age-/area-matched with 405 controls. Activity was assessed with a self-reported questionnaire which considered intensity level (moderate and/or strenuous) at different ages (at 12 and 20 years, and in the previous 5 years). Odds ratios (ORs) and 95% confidence intervals were calculated using logistic regression. RESULTS: Strenuous but not moderate physical activity at age 12 was inversely associated with pre- and postmenopausal breast cancer risk across ER/PR subtypes [overall OR(≥ 5 days/week vs. none) = 0.24 (0.14-0.43)]. Moderate physical activity in the previous 5 years was significantly associated with a decrease in risk for postmenopausal ER + PR + tumors only [OR(≥ 1 day/week vs. none) = 0.35 (0.18-0.67)]. CONCLUSION: Strenuous activity in teens and moderate activity after menopause may contribute to a reduction in breast cancer risk.

The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population.

It was recently reported that GCKR rs780094 was associated with fasting plasma glucose (FPG) and triglyceride (TG) levels in various ethnic populations (A allele for low FPG and high TG). An association between GCKR rs780094 and type 2 diabetes mellitus (T2DM) (A allele for low risk) has also been reported. We examined the association between GCKR rs780094 and T2DM in Japanese subjects by analyzing 488 cases and 398 controls. A meta-analysis was performed involving two previous association studies. We also analyzed the association between the single-nucleotide polymorphism and clinical parameters in the general Japanese population (n=1854). In the case-control study, the A allele of GCKR rs780094 was associated with a reduced risk of T2DM (odds ratio=0.711 (95% confidence interval=0.589-0.859), P=4.2 × 10(-4)). A meta-analysis confirmed the association of GCKR rs780094 with T2DM susceptibility. In the general Japanese population, subjects with the A/A genotype had lower levels of FPG, fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the G/G genotype. Conversely, subjects with the A/A genotype had higher levels of TG than those with the G/G genotype. We replicated GCKR rs780094 as a marker of T2DM susceptibility in Japanese subjects. This suggests that GCKR rs780094 is a common variant for T2DM susceptibility in various ethnic groups.

Dietary isoflavone intake, polymorphisms in the CYP17, CYP19, 17beta-HSD1, and SHBG genes, and risk of breast cancer in case-control studies in Japanese, Japanese Brazilians, and non-Japanese Brazilians.

We tested the hypothesis that polymorphisms in cytochrome P450c17alpha (CYP17), aromatase (CYP19), 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD1) and sex hormone-binding globulin (SHBG) genes may modify the association between isoflavone intake and breast cancer risk. We conducted hospital-based, case-control studies in Nagano, Japan and Sao Paulo, Brazil. A total of 846 pairs (388 Japanese, 79 Japanese Brazilians, and 379 non-Japanese Brazilians) completed validated food frequency questionnaires. Four single nucleotide polymorphisms (SNPs) in CYP17 (rs743572), CYP19 (rs10046), 17beta-HSD1 (rs605059), and SHBG (rs6259) genes were genotyped. We found no association between the 4 SNPs and breast cancer risk. In combination analyses of isoflavone intake and SNPs, an inverse association between intake and risk was limited to women with at least one A allele of the rs605059 polymorphism for all 3 populations, albeit without statistical significance. For the rs6259 polymorphism, the inverse association was limited to postmenopausal Japanese with the GG genotype (odds ratio [OR] for highest vs. lowest tertile = 0.50, 95% confidence interval [CI] = 0.29-0.87; P for trend < 0.01), and to non-Japanese Brazilians with at least one A allele (OR for consumers vs. nonconsumer = 0.21, 95% CI = 0.06-0.77). We found no remarkable difference for the rs743572 and rs10046 polymorphisms. Our findings suggest that polymorphisms in the 17beta-HSD1 and SHBG genes may modify the association between isoflavone intake and breast cancer risk.

Insulin and epidermal growth factor suppress basal glucose-6-phosphatase catalytic subunit gene transcription through overlapping but distinct mechanisms.

The G6Pase (glucose-6-phosphatase catalytic subunit) catalyses the final step in the gluconeogenic and glycogenolytic pathways, the hydrolysis of glucose-6-phosphate to glucose. We show here that, in HepG2 hepatoma cells, EGF (epidermal growth factor) inhibits basal mouse G6Pase fusion gene transcription. Several studies have shown that insulin represses basal mouse G6Pase fusion gene transcription through FOXO1 (forkhead box O1), but Stoffel and colleagues have recently suggested that insulin can also regulate gene transcription through FOXA2 (forkhead box A2) [Wolfrum, Asilmaz, Luca, Friedman and Stoffel (2003) Proc. Natl. Acad. Sci. 100, 11624-11629]. A combined GR (glucocorticoid receptor)-FOXA2 binding site is located between -185 and -174 in the mouse G6Pase promoter overlapping two FOXO1 binding sites located between (-188 and -182) and (-174 and -168). Selective mutation of the FOXO1 binding sites reduced the effect of insulin, whereas mutation of the GR/FOXA2 binding site had no effect on the insulin response. In contrast, selective mutation of the FOXO1 and GR/FOXA2 binding sites both reduced the effect of EGF. The effect of these mutations was additive, since the combined mutation of both FOXO1 and GR/FOXA2 binding sites reduced the effect of EGF to a greater extent than the individual mutations. These results suggest that, in HepG2 cells, GR and/or FOXA2 are required for the inhibition of basal G6Pase gene transcription by EGF but not insulin. EGF also inhibits hepatic G6Pase gene expression in vivo, but in cultured hepatocytes EGF has the opposite effect of stimulating expression, an observation that may be explained by a switch in ErbB receptor sub-type expression following hepatocyte isolation.