Mechanical properties of temperature-responsive gels containing ethylene glycol in their side chains.

The mechanical properties of temperature-responsive and biocompatible poly(oligo-ethylene glycol methyl ether methacrylate)-based gels were investigated using dynamic viscoelasticity measurements so as to find applications in tissue and biomedical engineering. The gels were copolymerized using two ethylene glycol methacrylate monomers with diethylene glycol side chains: diethylene glycol methacrylate (MeO2MA), which contains two ethylene oxide units, and oligo-ethylene glycol methyl ether methacrylate (OEGMA) with either four or five ethylene oxide units. The storage (G') and loss (G'') moduli of these gels exhibit unique temperature-responsive behavior and depend on the copolymerization ratio. In MeO2MA-rich gels, phase separation occurred with increasing temperature, resulting in a significant increase in G' and the disappearance of the frequency dependence of G''. Although phase separation of OEGMA-rich gels was also observed with increasing temperature, it resulted in only a slight increase in the storage modulus due to the steric hindrance of the side chain. The mechanical properties of these gels are thus found to be strongly affected by a slight difference in the number of ethylene oxide groups in their side chains.

Development of an anti-hepatitis B virus (HBV) agent through the structure-activity relationship of the interferon-like small compound CDM-3008.

Hepatitis B, a viral infectious disease caused by hepatitis B virus (HBV), is a life-threatening disease that leads liver cirrhosis and liver cancer. Because the current treatments for HBV, such as an interferon (IFN) formulation or nucleoside/nucleotide analogues, are not sufficient, the development of a more effective agent for HBV is urgent required. CDM-3008 (1, 2-(2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole) (RO8191)) is a small molecule with an imidazo[1,2-a][1,8]naphthyridine scaffold that shows anti-HCV activity with an IFN-like effect. Here, we report that 1 was also effective for HBV, although the solubility and metabolic stability were insufficient for clinical use. Through the structure-activity relationship (SAR), we discovered that CDM-3032 (11, N-(piperidine-4-yl)-2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxamide hydrochloride) was more soluble than 1 (>30 mg/mL for 11 versus 0.92 mg/mL for 1). In addition, the half-life period of 11 was dramatically improved in both mouse and human hepatic microsomes (T1/2, >120 min versus 58.2 min in mouse, and >120 min versus 34.1 min in human, for 11 and 1, respectively).

Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes-resistant human leukocyte antigen DRB1*15:02 treated with nivolumab.

Anti-programmed cell death-1 (PD-1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute-onset insulin-dependent diabetes after anti-PD-1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti-PD-1 therapy. We describe an atypical case of hyperglycemia after anti-PD-1 antibody administration. A 68-year-old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA-A*24:02 and -DRB1*09:01) and resistant (HLA-DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti-PD-1 antibody-induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case.

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease.

CONTEXT: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. OBJECTIVE: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. SUBJECTS AND METHODS: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. RESULTS: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. CONCLUSIONS: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

The Complementary Role of Transcription Factors in the Accurate Diagnosis of Clinically Nonfunctioning Pituitary Adenomas.

Clinically nonfunctioning pituitary adenomas (NFAs) may be hormonally inactive tumors of differentiated cells, mainly not only gonadotroph adenomas (GAs) but also silent corticotroph adenomas (SCAs) and other differentiated silent adenomas. Recently, the use of transcription factors has been recommended to confirm cytodiffererentiation of these neoplasms. Our objective was to assess the clinical significance of the new classification system using transcription factors. Five hundred sixteen consecutive NFAs were studied retrospectively. They were initially classified based on hormone immunohistochemistry as follows: 119 hormone-negative adenomas (23.1 %), 300 GAs (58.1 %), 51 SCAs (9.9 %), and 46 other silent adenomas. The 119 hormone-negative adenomas were further evaluated for expression of transcription factors including steroidogenic factor-1 (SF-1), estrogen receptor-α (ERα), pituitary-specific transcription factor 1 (Pit-1), and t-box transcription factor (Tpit). One hundred thirteen of 119 (95 %) hormone-negative adenomas showed mutually exclusive lineage-specific differentiation as gonadotrophs (SF-1 positive), corticotrophs (Tpit positive), or somatotrophs/mammosomatotrophs/lactotrophs/thyrotrophs (Pit-1 positive) in 79 cases (66.4 %), 32 cases (26.9 %), and 2 cases, respectively. The 32 ACTH-negative and Tpit-positive adenomas had higher pro-opiomelanocortin mRNA expression levels compared with GAs (P = 0.0001) on quantitative real-time PCR. They showed a female preponderance (P < 0.0001) and were more frequently giant adenomas (P = 0.0028) associated with marked cavernous sinus invasion (P < 0.0001) compared with GAs. These clinical features were identical to those of the 51 ACTH-positive SCAs. Our results justify the complementary role of transcription factors in the precise classification of NFAs that can more accurately characterize biological behavior. Our data suggest that more than one quarter of hormone-negative adenomas are SCAs that share distinct clinicopathological features with ACTH-expressing SCAs.

Prostate cancer risk in relation to insulin-like growth factor (IGF)-I and IGF-binding protein-3: A nested case-control study in large scale cohort study in Japan.

High levels of insulin-like growth factor (IGF)-I are reported to be associated with an increased risk of prostate cancer. On the other hand, the insulin-like growth factor binding protein-3 (IGFBP-3) may decrease the risk. We therefore investigated the influence of serum IGF-I and IGFBP-3 on prostate cancer risk in a case-control study nested within a large-scale cohort in Japan (the Japan Collaborative Cohort Study). Information on lifestyle and sera of the subjects were collected in 1988-90. Serum IGF-I, IGF-II and IGFBP-3 were measured in sera stored at -80 degrees C by immuno-radiometric assay. In 13,508 male subjects of the cohort who donated sera, 40 cases and 120 controls (1:3 matched with age and survey area) were identified. Ages of the cases ranged from 59 to 79 years, with a mean of 69.8. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the highest and middle tertiles compared with the lowest in controls using a conditional logistic model. Non-adjusted ORs for the highest tertiles were 0.99 (95% CI, 0.34-2.91) for IGF-I (trend-P = 0.60), 1.91 (95% CI, 0.68-5.38) for IGFBP-3 (trend-P = 0.23), 1.73 (95% CI, 0.69-3.47) for IGF-II (trend-P = 0.23), and 0.67 (95% CI, 0.26-1.76) for the IGF-I/IGBP-3 ratio (trend-P = 0.83). Serum levels of IGF-I, IGF-II, IGFBP-3, or IGF-I/IGFBP-3 ratio were thus not thought to be associated with risk of prostate cancer.

Diabetes mellitus and kidney cancer risk: the results of Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study).

BACKGROUND: Diabetes mellitus (DM) is reported as being a risk factor associated with kidney cancer in Western countries. The incidence of both kidney cancer and DM is lower in Japan than the other developed countries, albeit on the rise. METHODS: We evaluated the risk factors for kidney cancer mortality using the database of the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) study. The analytic cohort included 46 462 males and 64 326 females aged 40-79 years old. The Cox proportional hazards model was used to determine age- and sex-adjusted relative risk and its 95% confidence intervals. RESULTS: DM showed an increased, age- and sex-adjusted hazard ratio for kidney cancer mortality, but it failed to achieve statistical significance after controlling for other factors. CONCLUSION: The present study showed that DM increased the risk of kidney cancer death among the Japanese population. However, further studies may be needed to confirm the findings in the present study because DM failed to remain as a significant risk factor after controlling for other factors because of the small number of kidney cancer deaths in the present study.

Prospective cohort study of the risk of prostate cancer among rotating-shift workers: findings from the Japan collaborative cohort study.

Shift workers have been reported to have an increased risk of some cancers. However, the risk of prostate cancer in shift workers is not known to have been examined previously. This study prospectively examined the association between shift work and risk of prostate cancer incidence among 14,052 working men in Japan enrolled in a large-scale prospective cohort. A baseline survey was conducted between 1988 and 1990. Subjects were asked to indicate the most regular work schedule they had undertaken previously: day work, rotating-shift work, or fixed-night work. During 111,974 person-years, 31 cases of prostate cancer were recorded. The Cox proportional hazards model was used to estimate the risk, with adjustments for age, family history of prostate cancer, study area surveyed, body mass index, smoking, alcohol drinking, job type, physical activity at work, workplace, perceived stress, educational level, and marriage status. Compared with day workers, rotating-shift workers were significantly at risk for prostate cancer (relative risk = 3.0, 95% confidence interval: 1.2, 7.7), whereas fixed-night work was associated with a small and nonsignificant increase in risk. This report is the first known to reveal a significant relation between rotating-shift work and prostate cancer.

Dietary habits and risk of urothelial cancer incidence in the JACC Study.

BACKGROUND: The relationships between dietary habits and urothelial cancer have been discussed in many epidemiologic studies, however, they have not been sufficiently elucidated. In the present study, the associations of dietary habits with the risk of urothelial cancer incidence were evaluated taking into consideration sex, age, and smoking habits. METHODS: The Japan Collaborative Cohort Study (JACC Study) was planned in the late 1980s as a large-scale cohort study surveying people comprehensively and detailing their lifestyles, and the study subjects were followed up until the end of 1997. Among the total of 110,792 participants, 26,464 men and 38,720 women were in areas where incident cases with cancer were identified. During the observation period, 95 men and 28 women suffered from urothelial cancer. Hazard ratios for dietary factors were calculated by Cox's proportional hazards model. RESULTS: Increasing age, male gender, and smoking history were all significantly associated with the risk of urothelial cancer. High consumption of pork was significantly associated with the risk. In contrast, high intakes of milk and fresh fish were significantly inversely associated with the risk. High intakes of Chinese cabbage and fruits were also significantly inversely associated with the risk of urothelial cancer. CONCLUSIONS: It is suggested that high intakes of milk, fresh fish, Chinese cabbage, and fruits have preventive effects against urothelial cancer.

Association of serum phytoestrogen concentration and dietary habits in a sample set of the JACC Study.

BACKGROUND: Phytoestrogens may be associated with a reduced risk of hormone dependent neoplasms such as prostate and breast cancers. We tried to determine the validity of the association between serum phytoestrogen concentrations and dietary habits obtained from a food frequency questionnaire used in the Japan Collaborative Cohort Study (JACC Study) for Evaluation of Cancer Risk sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho). METHODS: The subjects were 151 male controls who were selected for a nested case-control study for evaluating prostate cancer risk as part of the JACC Study. Dietary habits were determined using a food frequency questionnaire at baseline, and the concentrations of genistein, daidzein, and equol in frozenstored serum samples assayed in 2002 were compared. RESULTS: Tofu intake showed a significant association with the serum concentrations of genistein and daidzein (Spearman's correlation coefficients (rs)=0.30 and 0.27, respectively), and miso soup showed a slight association with serum concentrations of these phytoestrogens. In contrast, serum concentrations of equol were not associated with dietary intake of tofu and miso soup. After adjustment for serum daidzein concentration, serum equol concentration was associated with the intake of foods containing fat, meat, and coffee, but not green tea. CONCLUSIONS: Serum genistein and daidzein concentrations were significantly associated with dietary intake of tofu, and slightly with intake of miso soup. Consumption of fat, meat, and coffee may be associated with equol production by intestinal microflora in this sample set.

Risk factors for kidney cancer in a Japanese population: findings from the JACC Study.

BACKGROUND: The incidence of kidney cancer is high in Western and Northern Europe and North America, and low in Asia. Although the incidence of kidney cancer in Japan is lower than the rates in the other industrialized countries, there is no doubt that it is increasing. METHODS: We evaluated the risk factors for kidney cancer death using the database of the Japan Collaborative Cohort (JACC) Study (i.e., medical history, anthropometry, and lifestyle including dietary habits). The analytic cohort included 47,997 males and 66,520 females aged 40 years and older. The Cox proportional hazards model was used to determine adjusted relative risks. RESULTS: A total of 36 males and 12 females died from kidney cancer during the follow-up of 9.6+/-2.6 years and 9.9+/-2.2 years, respectively. A medical history of hypertension, a fondness for fatty food, and consumption of black tea were associated with an increased risk of kidney cancer death while an intake of taro, sweet potato and potato was associated with a decreased risk. CONCLUSIONS: The present study showed four factors to be related to kidney cancer death. However, further studies may be needed to evaluate risk factors for kidney cancer death in Japan because the number of kidney cancer death in the present study was small.

Mortality in the JACC study till 1999.

BACKGROUND: We have been conducting a cohort study named "the Japan Collaborative Cohort Study (JACC Study) for Evaluation of Cancer Risk sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho)" since 1988. The aim of this paper is to describe the mortality of our JACC cohort in the follow-up period from 1988 through 1999, to compare it with the mortality, especially cancer deaths, of the Japanese population in the same period and to compare the causes of mortality by district among the cohort. METHODS: We conducted a follow-up study of 110,792 Japanese inhabitants aged 40-79 years in 1988--1990 for about 10 years to the end of 1999. RESULTS: Of 46,465 males, 37,750 (81.2%) were alive, 7,238 (15.6%) were dead and 1,477 (3.2%) had moved out of the study areas. The figures were 57,016 (88.6%), 4,940 (7.7%) and 2,371 (3.7%) among 64,327 females, respectively. The mean follow-up period was 9.9 years. The proportion of cancer deaths by site in our cohort members was almost same as the Japanese population aged 40-79 years old in 1995. Sex-specific standardized mortality ratios of total deaths, all cancer deaths, and most cancers in our cohort were less than 100 in both males and females for total cohort and the cohort by district. CONCLUSION: Our cohort members appeared to be almost the same or slightly healthier and less likely to die from total causes and cancers than the general population.

Serum carotenoids and other antioxidative substances associated with urothelial cancer risk in a nested case-control study in Japanese men.

PURPOSE: We assayed whether high serum carotenoids and antioxidative substances decrease the risk of urothelial cancer in a case-control study nested in a community based cohort in Japan, that is the Japan Collaborative Cohort Study. MATERIALS AND METHODS: Information on subject life-styles and serum were collected in 1988 to 1990 and subjects were followed as late as 1999. Individuals who had or died of urothelial cancer and controls were matched for study area, sex and age. Serum was stored at -80C and analyzed in 2003. Of 14,097 male and 25,662 female subjects 40 to 79 years old there were 42 cases, which were matched to 124 controls. RESULTS: The OR for the highest to lowest tertile of serum concentration was 0.28 (95% CI 0.07 to 1.15, trend p = 0.08) for beta-carotene, 0.36 (95% CI 0.10 to 1.27, trend p = 0.10) for total carotenes and 0.31 (95% CI 0.09 to -1.09, trend p = 0.09) for total carotenoids after adjustment for smoking in addition to matching variables. High concentrations of tocopherols and xanthophylls slightly tended to decrease the risk of urothelial cancer. In contrast, serum retinol, oxidized low density lipoprotein and Cu/Zn-superoxide dismutase were not associated with urothelial cancer risk. CONCLUSIONS: Our results suggest that high serum carotenoids may decrease the risk of urothelial cancer with carotenes more effective than xanthophylls.

Dietary habits and risk of urothelial cancer death in a large-scale cohort study (JACC Study) in Japan.

In the present study, the associations of dietary habits with the risk of urothelial cancer death were evaluated taking into consideration sex, age, and smoking habits. The Japan Collaborative Cohort Study was established in 1988-1990 and consisted of 47,997 men and 66,520 women observed until the end of 1999. A self-administered food-frequency questionnaire was used as a baseline survey. Hazard ratios for dietary factors were calculated by Cox's proportional hazards model. During the observation period, 63 men and 25 women died of urothelial cancer. Increasing age, male gender, and history of smoking were all significantly associated with increased risk of urothelial cancer death. A high intake of milk and fruits other than oranges reduced the risk significantly and dose dependently, in particular among subjects with smoking history. However, consumption of butter and yogurt had no associations with the risk. Intakes of cabbage, lettuce, green leafy vegetables, carrots, squash, tomatoes, and oranges were not significantly associated with the risk. It was suggested that urothelial cancer death could be potentially preventable by smoking cessation and regular intake of milk and fruit.

Relationship between abdominal visceral fat and lacunar infarcts in Japanese men.

BACKGROUND: The relationship between abdominal visceral fat accumulation and lacunar infarcts has not been previously investigated in Japanese men. METHODS AND RESULTS: The subjects were 637 middle-aged (40-64 years) and 222 elderly (65-79 years) men who participated in a health checkup program from 1999 to 2003. The association between lacunar infarcts identified by magnetic resonance imaging and cardiovascular risk factors, including abdominal visceral fat accumulation evaluated by computed tomography, was examined. The prevalence of lacunar infarcts was 4.9%. Hypertension was associated with lacunar infarcts among both the middle-aged men [age-adjusted odds ratio (OR)=2.9 (95% confidence interval (CI): 1.1-7.8)] and the elderly men [OR=5.1 (95%CI: 1.4-19.0)]. Abdominal visceral fat accumulation was slightly associated with lacunar infarcts among middle-aged men, but not among elderly men: OR in the highest (>or=117 cm(2)) vs lowest (or=143 cm(2)) was still slightly associated with lacunar infarcts after adjustment for age, hypertension, drinking and smoking among middle-aged men [OR=2.7 (95%CI: 0.8-9.1)]. CONCLUSIONS: This cross-sectional study suggests that abdominal visceral fat accumulation is a possible risk factor of lacunar infarcts, in addition to hypertension, in middle-aged Japanese men.

Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men.

The purpose of this study was to examine whether a high serum concentration of phytoestrogens reduces the risk of prostate cancer in a case-control study nested in a community-based cohort in Japan (Japan Collaborative Cohort (JACC) Study). Information on lifestyles and sera of the subjects were collected in 1988-90, and they were followed up to 1999. Incident and dead cases of prostate cancer and controls were matched for study area and age. Phytoestrogens and sex hormones in sera stored at - 80 degrees C were measured in 2002. Of 14,105 male subjects of the cohort who donated their sera, 52 cases and 151 controls were identified. Three datasets were analyzed; 1) all subjects, 2) 40 cases and 101 controls after excluding subjects with low testosterone levels who were suspected of having had medical intervention, and 3) 28 cases and 69 controls with prostate specific antigen level of

Validity of sonographic screening for the detection of abdominal cancers.

PURPOSE: This study assessed the prevalence of abdominal cancers and the validity of sonographic screening for abdominal cancers in an asymptomatic population. METHODS: We investigated the findings of the first sonographic screening of 16,024 residents of Osaka Prefecture. A comparison of records was carried out between the list of those screened and the Osaka Cancer Registry to identify false-negative results of our screening. RESULTS: The rate of subjects who required further testing after screening was 4.76% (762/16,024). Eleven of the 762 subjects with a positive sonographic screening study had abdominal cancers detected on further testing. Three subjects had false-negative screening results. The positive predictive value of sonographic screening was 1.4% (11/762), and the rate of screening-detected cancers was 0.069% (11/16,024). The prevalence of abdominal cancers was 0.087% (14/16,024), the sensitivity of screening sonography for the detection of abdominal cancers was 78.6% (11/14), and the specificity was 95.3% (15,259/16,010). Seven of 11 screening-detected cancers were resected curatively, and 6 of these patients are still alive. Five of these 6 cancers were renal cell carcinomas. CONCLUSIONS: The sensitivity of screening sonography was relatively high and the specificity was sufficient among our asymptomatic population. The present study suggests that the target organ for sonographic screening to detect curable cancers should be the kidneys.

Various S-GOT/S-GPT ratios in nonviral liver disorders and related physical conditions and life-style.

The relationship between the GOT/GPT ratio in nonviral liver disorders and underlying physical condition and life-style were evaluated. The subjects were 12,808 male railway company workers who underwent an annual health checkup. Nonviral liver disorders were defined as elevated transaminases (GOT > 76 IU/liter or GPT > 86 IU/liter, while negative for hepatitis B and C markers (282 cases). Controls were 9,783 males with normal findings for GOT, GPT, and y-GTP. By logistic regression analysis, GOT-dominant liver disorders were significantly related to alcohol consumption, hypertriglyceridemia, and diabetes mellitus. They were still significant on multivariate analysis. GPT-dominant liver disorders were significantly related to obesity, less exercise, hypercholesterolemia, and hypertriglyceridemia. Obesity and hypercholesterolemia were significant on multivariate analysis. In conclusion, the relationship between hypertriglyceridemia or diabetes mellitus and GOT-dominant disorders, which was not explained empirically, could indicate another pathogenesis for nonviral liver disorders, such as underlying insulin resistance.