Search

Abstract: The tertiary structure of the Leu308Val mutant of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5-substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (K i = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3α-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC50 value equal to 100 nM. [ABSTRACT FROM AUTHOR]

Objective A possible association between subclinical hypothyroidism and cardiovascular disease (CVD) has been reported. Monitoring of atomic-bomb survivors for late effects of radiation exposure at the Radiation Effects Research Foundation has provided the opportunity to examine associations between subclinical hypothyroidism and metabolic CVD risk factors. The objective of the study was to evaluate associations between subclinical hypothyroidism and metabolic CVD risk factors, and a cluster of these factors. Design and participants This was a cross-sectional study of 3549 subjects (mean age 70 years; 1221 men and 2328 women) between 2000 and 2003 comprising 306 subjects with subclinical hypothyroidism and 3243 control euthyroid subjects in Japan. Measurements We investigated associations between subclinical hypothyroidism and metabolic CVD risk factors such as hypertension, diabetes mellitus, dyslipidaemia and hyperuricaemia, and a cluster of these factors. Results Subclinical hypothyroidism was not significantly associated with either hypertension, diabetes mellitus or hyperuricaemia defined by taking into account the use of medications in both men and women, but in men it was associated with dyslipidaemia ( P = 0·02). We observed a significantly increased odds ratio (OR) for the presence of three or more metabolic CVD risk factors in men with subclinical hypothyroidism after adjusting for age, body mass index (BMI), and smoking status [OR: 1·83, 95% confidence interval (CI): 1·13–2·94, P = 0·01]. The significant associations remained after an additional adjustment for atomic-bomb radiation dose. Conclusions There appears to be a significant increase in a cluster of metabolic CVD risk factors among people with subclinical hypothyroidism. [ABSTRACT FROM AUTHOR]

The article reports on the study that evaluates the presence of genomic instability (GIN) in the epidermis of survivors as a late effect of atomic bomb (A-bomb) radiation. It shows that the incidence rate of basal cell carcinoma (BCC) significantly increase as exposure distance approached the hypocenter. The results demonstrate that endogenous activation of DNA damage response (DDR) in the epidermis surrounding BCC in the proximal growth suggests the presence of a GIN in the survivors.

The article offers information on the results of a study that aims to clarify the association of HER2 and C-MYC oncogene amplification in breast cancer in atomic bomb survivors with radiation exposure. It states that 593 survivors developed breast cancers from 1968 to 1999. It suggests that the development of oncogene amplification may be affected by the radiation by inducing genomic instability (GIN).

Background In utero exposure to radiation is known to increase risks of childhood cancers, and childhood exposure is associated with increased risks of adult-onset cancers. However, little is known about whether in utero exposure to radiation increases risks of adult-onset cancers. Methods Solid cancer incidence rates were examined among survivors of the atomic bombings of Hiroshima and Nagasaki who were in utero (n = 2452) or younger than 6 years (n = 15 388) at the time of the bombings. Poisson regression was used to estimate and compare the levels and temporal patterns of the radiation- associated excess risks of first primary solid cancers among these survivors at ages 12-55. All statistical tests were two-sided. Results There were 94 eligible cancers in the in utero group and 649 in the early childhood group. The excess relative risk (ERR) increased with dose for both in utero (age 50, ERR = 1.0 per Sv, 95% confidence interval [CI] = 0.2 to 2.3 per Sv) and early childhood (age 50, ERR = 1.7 per Sv, 95% Cl = 1.1 to 2.5 Sv) exposures. The ERR declined (P= .046) with increasing attained age in the combined cohort. Excess absolute rates (EARs) increased markedly with attained age among those exposed in early childhood but exhibited little change in the in utero group. At age 50, the estimated EARs per 10000 person-years per Sv were 6.8 (95% Cl = <0 to 49) for those exposed in utero and 56 (95% Cl = 36 to 79) for those exposed as young children. Conclusions Both the in utero and early childhood groups exhibited statistically significant dose-related increases in incidence rates of solid cancers. The apparent difference in EARs between the two groups suggests that lifetime risks following in utero exposure may be considerably lower than for early childhood exposure, but further follow-up is needed. [ABSTRACT FROM AUTHOR]

Abstract.: To determine the possible late health effects of atomic-bomb radiation, Radiation Effects Research Foundation (RERF) has been conducting mortality follow-up on a fixed cohort of 120,000 members (Life Span Study cohort or LSS cohort) since 1950. Through record linkage with local cancer registries in Hiroshima and Nagasaki, RERF has also been conducting cancer incidence studies of atomic bomb survivors since 1958. The central finding of the study is an increase in cancer risk. Besides the increase in leukemia risk, increase in risks of solid cancers such as cancers of the breast, lung and colon have also been demonstrated. Radiation-induced leukemia occurred 2 to 3 years after exposure, reached its peak within 6 to 8 years after the bombing, and has since declined steadily. However, radiation-related solid cancer began to appear at later years and the risk still remains to be present, even today. An increase of solid cancer risk appears to be larger for those exposed as children than those exposed as adults. However, since a majority of those exposed as children are still alive and risk estimates for them are uncertain at this stage, it is essential to continue their follow-up. Recently, the LSS also demonstrates an excess risk of death from non-cancer diseases, largely from cardiovascular, digestive and respiratory diseases. Further investigation is of absolute necessity in order to determine whether or not the excess was caused by atomic bomb radiation. [Copyright &y& Elsevier]

Background: Genetic and environmental factors contribute to the pathogenesis of schizophrenia (SZ) and bipolar disorder (BD). Among genetic risk groups stratified by combinations of Polygenic Risk Score (PRS) deciles for SZ, BD and SZ versus BD, genetic SZ risk groups had high SZ risk and prominent cognitive impairments. Furthermore, epigenetic alterations are implicated in these disorders. However, it was unclear whether DNA Methylation Risk Scores (MRSs) for SZ risk derived from blood and brain tissues were associated with SZ risk, particularly the PRS-stratified genetic SZ risk group., Methods: Epigenome-wide association studies (EWASs) of SZ risk in whole blood were preliminarily conducted between 66 SZ patients and 30 healthy controls (HCs) and among genetic risk groups (individuals with low genetic risk for SZ and BD in HCs (n=30) and in SZ patients (n=11), genetic BD risk in SZ patients (n=25) and genetic SZ risk in SZ patients (n=30)) stratified by combinations of PRSs for SZ, BD and SZ versus BD. Next, differences in MRSs based on independent EWASs of SZ risk in whole blood, postmortem frontal cortex (FC) and superior temporal gyrus (STG) were investigated among our case‒control and PRS-stratified genetic risk status groups., Results: Among case‒control and genetic risk status groups, 33 and 351 genome-wide significant differentially methylated positions (DMPs) associated with SZ were identified, respectively, many of which were hypermethylated. Compared with the low genetic risk in HCs group, the genetic SZ risk in SZ group had 39 genome-wide significant DMPs, while the genetic BD risk in SZ group had only six genome-wide significant DMPs. The MRSs for SZ risk derived from whole blood, FC and STG were higher in our SZ patients than in HCs in whole blood and were particularly higher in the genetic SZ risk in SZ group than in the low genetic risk in HCs and genetic BD risk in SZ groups. Conversely, the MRSs for SZ risk based on our whole-blood EWASs among genetic risk groups were also associated with SZ in the FC and STG. There were no correlations between the MRSs and PRSs., Conclusions: These findings suggest that the MRS is a potential genetic marker in understanding SZ, particularly in patients with a genetic SZ risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. Published by BMJ.)

Background: Metformin-induced lactic acidosis with acute kidney injury is rare but well known. Here we report a case of a Japanese patient taking metformin who experienced severe acute renal failure accompanied with significantly elevated metformin plasma concentrations and signs of lactic acidosis., Case Presentation: A 60-year-old Japanese man with type II diabetes, who was taking metformin (500 mg three times a day) along with several other medications, visited the emergency department with dizziness, malaise, and oliguria. The initial laboratory test results showed elevated levels of serum creatinine and blood urea nitrogen, although his renal function was normal approximately 2 weeks earlier. His lactate level was raised (4.27 mmol/L), and he was diagnosed with lactic acidosis. Considering the low creatinine clearance and elevated urinary albumin/serum creatinine ratio, urinary N-acetyl-β-D-glucosaminidase level, and β2-microglobulin level, the patient was further diagnosed with AKI (in other words, acute tubular necrosis). A renal biopsy performed on day 3 after admission revealed renal tubular epithelium necrosis, supporting this diagnosis. The patient underwent intermittent hemodialysis until he was discharged on day 13. The metformin concentrations on days 3, 5, and 7 were 8.95, 2.58, and 0.16 μg/mL, respectively, which is significantly higher than the maximal steady-state concentration of metformin at the recommended dosage (approximately 1 μg/mL). The calculated pharmacokinetic parameters of metformin suggested poor renal excretion and a low distribution volume at higher metformin levels. Other possible acute kidney injury-causing factors included dehydration, alcohol consumption, and the use of an angiotensin receptor blocker or SGLT2 inhibitor., Conclusions: This is the first reported case of acute kidney injury possibly caused by high levels of metformin with lactic acidosis in a patient treated with the recommended metformin dose. Thus, the development of metformin-induced acute kidney injury should be considered for patients with several acute kidney injury risk factors who are taking metformin., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Stomata open in response to several environmental stimuli, such as light and low CO 2 . Plasma membrane (PM) H + -ATPase in guard cells plays a pivotal role for light-induced stomatal opening. In contrast, stomata close in response to the dark or plant hormone abscisic acid (ABA). However, molecular mechanisms of stomatal movements remain unclear. To elucidate the molecular mechanism of stomatal movements, we performed a genetic screen based on stomatal aperture-dependent weight decrease of detached leaves from EMS-treated Arabidopsis thaliana and isolated a rapid transpiration in detached leaves 2 ( rtl2 ). The rtl2 mutant showed constitutive open-stomata phenotype with lower leaf temperature. ABA had no effect on stomatal aperture in rtl2 . The rtl2 mutant also showed increased stomatal density, severe dwarf phenotype with pale green leaves and dark veins. Map-based analysis of the RTL2 locus revealed that the rtl2 mutant possesses a single nucleotide substitution, which induces amino acid substitution Gly162 to Glu in the tryptophan synthase ß subunit 1 (TSB1). The TSB1 encodes an enzyme in tryptophan (Trp) biosynthetic pathway. Amount of TSB1 protein was drastically reduced in rtl2 mutant. A different allele of tsb1 mutant ( tsb1-1 ) also showed constitutive open-stomata phenotype with reduced TSB1 protein as in rtl2 . Analyses of test-crossed plants of rtl2 and tsb1-1 showed open-stomata and dwarf phenotypes. These results indicate that a responsible gene for rtl2 is TSB1 . We further investigated stomatal phenotype in mutants from Trp biosynthetic pathway, such as wei2-1 wei7-1 , trp3-1 , and tsb2-1 . The trp3-1 mutant showed significant wider stomatal aperture as well as tsb1-1 . Trp biosynthetic pathway closely relates to auxin biosynthesis. Then, we investigated auxin responsible genes and found that an expression of AUR3 was up in rtl2 . In contrast, auxin had no effect on stomatal aperture in Arabidopsis and the phosphorylation status of PM H + -ATPase in guard cell protoplasts from Vicia faba . In addition, auxin antagonist had no effect on stomatal aperture. Interestingly, tsb1-1 grown under hydroponic culture system showed normal stomatal aperture by exogenously application of Trp. These results suggest that open stomata phenotype in tsb1-1 is due to Trp deficiency but not auxin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Soda, Hayashi, Takahashi and Kinoshita.)

Daptomycin is used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Current guidelines recommend higher daptomycin doses (8-10 mg/kg) for severe infections; however, pharmacokinetic (PK) and pharmacodynamic-based dosing strategies are still limited. Therefore, we designed a new optimal daptomycin dosing regimen for patients with MRSA infections using a population PK modeling approach. A total of 110 plasma concentrations from 47 adult patients who received daptomycin in general wards were enrolled for population PK modeling. The target area under the concentration-time curve/minimum inhibitory concentration (MIC) ratio, target peak/MIC ratio, and threshold of the trough concentration for safety were set to >666, >60, and 24.3 mg/L, respectively. Renal function was indicated as a significant covariate for daptomycin clearance. The simulated probability of target attainment was more than 90% at MIC values of 0.25 and 0.5 mg/L in all patients at the standard dose (6 mg/kg). In contrast, comprehensive simulation assessments recommended 10 mg/kg every 24 h in patients with creatinine clearance >60 mL/min for MIC values of 1.0 mg/L. We propose a new simplified daptomycin dosing regimen stratified by renal function and MIC values based on PK model-based simulation analyses. The proposed regimen is expected to maximize clinical efficacy and minimize adverse events., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background/aim: The antiviral agent ritonavir is a substrate for cytochrome P450 3A4 (CYP3A4); therefore, concomitant use of CYP3A4-metabolising drugs might cause adverse reactions to this drug. We investigated the plasma level of calcium channel blockers (CCBs) as CYP3A4 substrates and peripheral edema as a potential adverse drug reaction possibly caused by the anti-hepatitis C virus (HCV) regimen of ombitasvir/paritaprevir/ritonavir (OPR) and CCBs., Patients and Methods: We enrolled Japanese patients prescribed OPR for HCV infection. Peripheral edema was graded according to the Common Terminology Criteria for Adverse Events ver. 4. Plasma samples were collected on days 0, 7, 14, 28, and 42 after antiviral treatment, at the trough level., Results: Out of 52 patients, 64% experienced grade 1 or grade 2 peripheral edema, but not grade 3. Concomitant use of CCBs significantly increased the emergence of grade 2 edema (62%), compared with patients treated solely with OPR (48%). The use of OPR significantly increased the plasma concentration of amlodipine., Conclusion: Peripheral edema in patients treated with OPR and CCBs, although tolerable, should be closely monitored., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Patients with schizophrenia (SCZ) have characteristic personality traits compared with healthy subjects. Genome-wide significant variants for neuroticism have been reported in healthy subjects. However, the associations of these genome-wide neuroticism-associated variants with five-factor personality traits in patients with SCZ are less clear. We investigated the influences of nine independent genome-wide significant variants for neuroticism on five-factor personality traits (neuroticism, extraversion, openness, agreeableness, and conscientiousness) assessed by the NEO Five-Factor Inventory (NEO-FFI) in 107 patients with SCZ and 119 healthy controls (HCs). As expected, patients with SCZ scored significantly higher for neuroticism and lower for extraversion, openness, agreeableness and conscientiousness than HCs (p < 0.05). Of nine neuroticism-associated variants, the T allele at rs4653663 related to lower neuroticism was only significantly associated with lower neuroticism in patients with SCZ (β = -0.27, p = 3.88 × 10 -3 ) and in combined subjects (β = -0.15, p = 0.026). Furthermore, of other personality traits, the genetic variant was significantly associated with higher agreeableness in combined subjects (β = 0.17, p = 9.41×10 -3 ), higher conscientiousness in patients with SCZ (β = 0.21, p = 0.031) and lower conscientiousness in HCs (β = -0.20, p = 0.034), and nominally associated with higher extraversion in patients with SCZ (β = 0.18, p = 0.056) and in combined subjects (β = 0.13, p = 0.051). These outcomes were not affected by clinical variables. We suggest that genome-wide neuroticism-associated variant could be associated with neuroticism as well as other personality traits in schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Background: Intelligence is inversely associated with schizophrenia (SCZ) and bipolar disorder (BD); it remains unclear whether low intelligence is a cause or consequence. We investigated causal associations of intelligence with SCZ or BD risk and a shared risk between SCZ and BD and SCZ-specific risk., Methods: To estimate putative causal associations, we performed multi-single nucleotide polymorphism (SNP) Mendelian randomization (MR) using generalized summary-data-based MR (GSMR). Summary-level datasets from five GWASs (intelligence, SCZ vs. control [CON], BD vs. CON, SCZ + BD vs. CON, and SCZ vs. BD; sample sizes of up to 269,867) were utilized., Results: A strong bidirectional association between risks for SCZ and BD was observed (odds ratio; ORSCZ → BD = 1.47, p = 2.89 × 10-41, ORBD → SCZ = 1.44, p = 1.85 × 10-52). Low intelligence was bidirectionally associated with a high risk for SCZ, with a stronger effect of intelligence on SCZ risk (ORlower intelligence → SCZ = 1.62, p = 3.23 × 10-14) than the reverse (ORSCZ → lower intelligence = 1.06, p = 3.70 × 10-23). Furthermore, low intelligence affected a shared risk between SCZ and BD (OR lower intelligence → SCZ + BD = 1.23, p = 3.41 × 10-5) and SCZ-specific risk (ORlower intelligence → SCZvsBD = 1.64, p = 9.72 × 10-10); the shared risk (ORSCZ + BD → lower intelligence = 1.04, p = 3.09 × 10-14) but not SCZ-specific risk (ORSCZvsBD → lower intelligence = 1.00, p = 0.88) weakly affected low intelligence. Conversely, there was no significant causal association between intelligence and BD risk (p > 0.05)., Conclusions: These findings support observational studies showing that patients with SCZ display impairment in premorbid intelligence and intelligence decline. Moreover, a shared factor between SCZ and BD might contribute to impairment in premorbid intelligence and intelligence decline but SCZ-specific factors might be affected by impairment in premorbid intelligence. We suggest that patients with these genetic factors should be categorized as having a cognitive disorder SCZ or BD subtype.

Background: Impairments in intelligence are more severe in patients with schizophrenia (SCZ) than in patients with bipolar disorder (BD) despite clinical and genetic similarities between the disorders. Genetic loci differentiating SCZ from BD, that is, SCZ-specific risk, have been identified. Polygenetic [risk] scores (PGSs) for SCZ-specific risk are higher in SCZ patients than in healthy controls (HCs). However, the influence of genetic risk on impaired intelligence is poorly understood. Here, we investigated whether SCZ-specific risk could predict impairments in intelligence in SCZ patients and HCs., Methods: Large-scale genome-wide association study datasets related to SCZ vs BD, childhood intelligence (CHI), and adulthood intelligence (n = 12 441-282 014) were utilized to compute PGSs. PGSs derived from the genome-wide association studies were calculated for 130 patients with SCZ and 146 HCs. Premorbid and current intelligence and the decline were measured in SCZ patients and HCs. Correlations between PGSs and intelligence functions were investigated., Results: High PGSs for SCZ-specific risk were correlated with low premorbid intelligence in SCZ patients and HCs (β = -0.17, P = 4.12 × 10-3). The correlation was still significant after adjusting for diagnostic status (β = -0.13, P = .024). There were no significant correlations between PGSs for SCZ-specific risk and current intelligence or intelligence decline (P > .05). PGSs for CHI were lower in SCZ patients than in HCs (R2 = 0.025, P = .025), while the PGSs for CHI were not significantly correlated with premorbid and current intelligence, the decline, or the PGSs for SCZ-specific risk (P > .05)., Conclusions: These findings suggest that genetic factors differentiating SCZ from BD might affect the pathogenesis of SCZ and/or pathological differences between SCZ and BD via the impairment of premorbid intelligence, that is, crystallized intelligence, while genetic factors for CHI might affect the pathogenesis of SCZ but not via impairments in intelligence., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Background: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with impaired intelligence that predicts poor functional outcomes. However, little is known regarding the extent and severity of intelligence decline, that is, decreased present intelligence quotient (IQ) relative to premorbid levels, across psychiatric disorders and which clinical characteristics affect the decline., Methods: Premorbid IQ, present IQ, and intelligence decline were compared across patients with MDD (n = 45), BD (n = 30), and SCZ (n = 139), and healthy controls (HCs; n = 135). Furthermore, we investigated which factors contribute to the intelligence decline in each diagnostic group., Results: Significant differences were observed in premorbid IQ, present IQ, and intelligence decline across the diagnostic groups. Patients with each psychiatric disorder displayed lower premorbid and present IQ and more intelligence decline than HCs. Patients with SCZ displayed lower premorbid and present IQ and more intelligence decline than patients with MDD and BD, while there were no significant differences between patients with MDD and BD. When patients with BD were divided based on bipolar I disorder (BD-I) and bipolar II disorder (BD-II), degrees of intelligence decline were similar between MDD and BD-II and between BD-I and SCZ. Lower educational attainment was correlated with a greater degree of intelligence decline in patients with SCZ and BD but not MDD., Conclusions: These findings confirm that although all psychiatric disorders display intelligence decline, the severity of intelligence decline differs across psychiatric disorders (SCZ, BD-I > BD-II, MDD > HCs). Higher educational attainment as cognitive reserve contributes to protection against intelligence decline in BD and SCZ.

Ferulic Acid (FA) is a highly abundant phenolic phytochemical which is present in plant tissues. FA has biological effects on physiological and pathological processes due to its anti-apoptotic and anti-oxidative properties, however, the detailed mechanism(s) of function is poorly understood. We have identified FA as a molecule that inhibits apoptosis induced by hydrogen peroxide (H 2 O 2 ) or actinomycin D (ActD) in rat pheochromocytoma, PC12 cell. We also found that FA reduces H 2 O 2 -induced reactive oxygen species (ROS) production in PC12 cell, thereby acting as an anti-oxidant. Then, we analyzed FA-mediated signaling responses in rat pheochromocytoma, PC12 cells using antibody arrays for phosphokinase and apoptosis related proteins. This FA signaling pathway in PC12 cells includes inactivation of pro-apoptotic proteins, SMAC/Diablo and Bad. In addition, FA attenuates the cell injury by H 2 O 2 through the inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK). Importantly, we find that FA restores expression levels of brain-derived neurotrophic factor (BDNF), a key neuroprotective effector, in H 2 O 2 -treated PC12 cells. As a possible mechanism, FA increases BDNF by regulating microRNA-10b expression following H 2 O 2 stimulation. Taken together, FA has broad biological effects as a neuroprotective modulator to regulate the expression of phosphokinases, apoptosis-related proteins and microRNAs against oxidative stress in PC12 cells.

Background/aim: It has been reported that some adverse events (AEs) of enzalutamide (ENZ) occur more frequently in Japanese patients with castration-resistant prostate cancer (CRPC) due to higher steady-state trough plasma concentrations of ENZ (C SS, ENZ ) and its active metabolite (NDE), (C SS, NDE ). Thus, we investigated the efficacy, safety, and pharmacokinetics of ENZ in Japanese patients with CRPC., Patients and Methods: Fourteen patients were administered ENZ at a standard dose (160 mg/day) or reduced doses (80 or 120 mg/day). Prostate-specific antigen (PSA), AEs, C SS, ENZ , and C SS, NDE were examined., Results: A maximum PSA decrement of ≥50% from baseline was achieved in 92% of patients. AEs were few (>20%) and mild. No differences in C SS, ENZ and C SS, NDE between other ethnic groups in previous literature and our subjects was observed., Conclusion: ENZ shows adequate efficacy and safety in Japanese patients with CRPC, even if administered at reduced doses in real-world conditions., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Patients with schizophrenia display characteristic smoking-related behaviors and genetic correlations between smoking behaviors and schizophrenia have been identified in European individuals. However, the genetic etiology of the association remains to be clarified. The present study investigated transethnic genetic overlaps between European-based smoking behaviors and the risk of Japanese schizophrenia by conducting polygenic risk score (PRS) analyses. Large-scale European genome-wide association study (GWAS) datasets (n = 24,114-74,035) related to four smoking-related intermediate phenotypes [(i) smoking initiation, (ii) age at smoking initiation, (iii) smoking quantity, and (iv) smoking cessation] were utilized as discovery samples. PRSs derived from these discovery GWASs were calculated for 332 Japanese subjects [schizophrenia patients, their unaffected first-degree relatives (FRs), and healthy controls (HCs)] as a target sample. Based on GWASs of European smoking phenotypes, we investigated the effects of PRSs on smoking phenotypes and the risk of schizophrenia in the Japanese population. Of the four smoking-related behaviors, the PRSs for age at smoking initiation in Europeans significantly predicted the age at smoking initiation (R 2  = 0.049, p = 0.026) and the PRSs for smoking cessation significantly predicted the smoking cessation (R 2  = 0.092, p = 0.027) in Japanese ever-smokers. Furthermore, the PRSs related to age at smoking initiation in Europeans were higher in Japanese schizophrenia patients than in the HCs and those of the FRs were intermediate between those of patients with schizophrenia and those of the HCs (R 2  = 0.015, p = 0.015). In our target subjects, patients with schizophrenia had a higher mean age at smoking initiation (p = 0.018) and rate of daily smoking initiation after age 20 years (p = 0.023) compared with the HCs. A total of 60.6% of the patients started to smoke before the onset of schizophrenia. These findings suggest that genetic factors affecting late smoking initiation are associated with the risk of schizophrenia.

Four human hydroxysteroid dehydrogenases in the aldo-keto reductase (AKR) superfamily, AKR1C1-AKR1C4, are involved in the metabolism of steroids and other carbonyl compounds including drugs, and altered expression of AKRs (1C1, 1C2 and/or 1C3) is related to the pathogenesis of several extrahepatic cancers. Here, we report that unsaturated fatty acids (FAs) are potent competitive inhibitors of the AKR enzymes. The sensitivities to the FAs were different among the enzymes, especially between AKR1C1 and AKR1C2. The most potent inhibitors for AKR1C1, AKR1C2 and AKR1C4 were docosahexaenoic acid (Ki 0.77 µM), palmitoleic acid (Ki 0.41 µM) and linoleic acid (Ki 0.33 µM), respectively. AKR1C3 was the most sensitive to FA inhibition, showing low Ki values (0.23-0.29 µM) for oleic, linoleic, eicosapentaenoic and docosahexaenoic acids. Linoleic and oleic acids also inhibited AKR1C3-mediated metabolism of 9,10-phenanthrenequinone in colon DLD1 cells. Molecular docking and site-directed mutagenesis studies suggested upon FA binding to AKR1C1 and AKR1C3: (i) the carboxyl group of the FA binds to the oxyanion-binding site in the active site; (ii) the difference in FA sensitivity between AKR1C1 and AKR1C2 is due to their residue difference at position 54; (iii) Ser118, Phe306 and Phe311 of AKR1C3 are important for determining the inhibitory potency of FAs., (© The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

This is the third analysis of solid cancer incidence among the Life Span Study (LSS) cohort of atomic bomb survivors in Hiroshima and Nagasaki, adding eleven years of follow-up data since the previously reported analysis. For this analysis, several changes and improvements were implemented, including updated dose estimates (DS02R1) and adjustment for smoking. Here, we focus on all solid cancers in aggregate. The eligible cohort included 105,444 subjects who were alive and had no known history of cancer at the start of follow-up. A total of 80,205 subjects had individual dose estimates and 25,239 were not in either city at the time of the bombings. The follow-up period was 1958-2009, providing 3,079,484 person-years of follow-up. Cases were identified by linkage with population-based Hiroshima and Nagasaki Cancer Registries. Poisson regression methods were used to elucidate the nature of the radiation-associated risks per Gy of weighted absorbed colon dose using both excess relative risk (ERR) and excess absolute risk (EAR) models adjusted for smoking. Risk estimates were reported for a person exposed at age 30 years with attained age of 70 years. In this study, 22,538 incident first primary solid cancer cases were identified, of which 992 were associated with radiation exposure. There were 5,918 cases (26%) that occurred in the 11 years (1999-2009) since the previously reported study. For females, the dose response was consistent with linearity with an estimated ERR of 0.64 per Gy (95% CI: 0.52 to 0.77). For males, significant upward curvature over the full dose range as well as restricted dose ranges was observed and therefore, a linear-quadratic model was used, which resulted in an ERR of 0.20 (95% CI: 0.12 to 0.28) at 1 Gy and an ERR of 0.010 (95% CI: -0.0003 to 0.021) at 0.1 Gy. The shape of the ERR dose response was significantly different among males and females (P = 0.02). While there was a significant decrease in the ERR with increasing attained age, this decrease was more rapid in males compared to females. The lowest dose range that showed a statistically significant dose response using the sex-averaged, linear ERR model was 0-100 mGy (P = 0.038). In conclusion, this analysis demonstrates that solid cancer risks remain elevated more than 60 years after exposure. Sex-averaged upward curvature was observed in the dose response independent of adjustment for smoking. Findings from the current analysis regarding the dose-response shape were not fully consistent with those previously reported, raising unresolved questions. At this time, uncertainties in the shape of the dose response preclude definitive conclusions to confidently guide radiation protection policies. Upcoming results from a series of analyses focusing on the radiation risks for specific organs or organ families, as well as continued follow-up are needed to fully understand the nature of radiation-related cancer risk and its public health significance. Data and analysis scripts are available for download at: http://www.rerf.or.jp .

Background and Purpose: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive hematological malignancy caused by human T-cell leukemia virus type-1 (HTLV-1); no effective methods have yet been identified to prevent development of ATLL in carriers of HTLV-1. This study investigated the association between cigarette smoking and the risk of ATLL development among Japanese carriers of HTLV-1., Methods: This study examined the association between smoking and development of ATLL in a cohort of 1,332 Japanese HTLV-1 carriers aged 40-69 years free of ATLL at baseline from two different HTLV-1-endemic areas of Japan. Cox proportional hazards models adjusted for sex, geographic area, age at baseline, and alcohol drinking were used to estimate the effect of cigarette smoking on ATLL development., Results: Between 1993 and 2012, 25 new ATLL cases were identified among these subjects. The overall crude incidence rate for ATLL was 1.08 per 1,000 person-years among HTLV-1 carriers and was higher among male carriers than among female carriers (2.21 vs. 0.74). The risk of ATLL development increased significantly with increasing numbers of cigarettes smoked per day (hazard ratio for every increment of 20 cigarettes, 2.03; 95 % confidence interval (CI) 1.13-3.66 overall, 2.07 (95 % CI 1.13-3.73) in male carriers)., Conclusions: Cigarette smoking may influence ATLL development among HTLV-1 carriers in Japan.

The analysis of cancer trends in Japan requires periodic updating. Herein, we present a comprehensive report on the trends in cancer incidence and mortality in Japan using recent population-based data. National cancer mortality data between 1958 and 2013 were obtained from published vital statistics. Cancer incidence data between 1985 and 2010 were obtained from high-quality population-based cancer registries of three prefectures (Yamagata, Fukui and Nagasaki). Joinpoint regression analysis was performed to examine the trends in age-standardized rates of cancer incidence and mortality. All-cancer mortality decreased from the mid-1990s, with an annual percent change of -1.3% (95% confidence interval [CI]: -1.4, -1.3). During the most recent 10 years, over 60% of the decrease in cancer mortality was accounted for by a decrease in stomach and liver cancers (63% for males and 66% for females). The long-term increase in female breast cancer mortality, beginning in the 1960s, plateaued in 2008. All-cancer incidence continuously increased, with annual percent changes of 0.6% (95% CI: 0.5, 0.8) between 1985 and 2005, and 1.8% (95% CI: 0.6, 2.9) between 2005 and 2010. During the most recent 10 years, almost half of the increase in cancer incidence was accounted for by an increase in prostate cancer (60%) in males and breast cancer (46%) in females. The cancer registry quality indices also began to increase from ∼2005. Decreases in stomach and liver cancers observed for incidence and mortality reflect the reduced attribution of infection-related factors (i.e. Helicobacter pylori and hepatitis virus). However, it should be noted that cervical cancer incidence and mortality rates began to increase from ∼1990., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In this retrospective study, we aimed to clarify the risk of developing a second primary cancer and to determine the periods of high risk of second primary cancers. Subjects were all patients who had been diagnosed with a first primary cancer and registered with the Nagasaki Prefecture Cancer Registry between 1985 and 2007. We calculated the standardized incidence ratio (SIR) of second primary cancer according to site and years after diagnosis of the first primary cancer. A second primary cancer developed in 14 167 of 174 477 subjects (8.1%) during a median follow-up of 1.8 years. The SIR of all cancer was 1.10 (95% confidence interval, 1.08-1.11). Some specific relationships were observed between sites with risk factors in common, such as smoking, drinking, and hormone status. The SIRs were relatively high after approximately 10 years for all sites, and trends differ among cancer sites. We showed that cancer patients are at higher risk of a second primary cancer than the general population. In respect of the risk of a second primary cancer, physicians should be alert for cancers that have risk factors in common with the first primary cancer., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Few studies have investigated the incidence rate of lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM) in Asian populations. We assessed the incidence of LPL/WM using data from 13 population-based cancer registries in Japan and data from the Taiwan National Cancer registry. During 1996-2003, a total of 280 new cases of LPL/WM were recorded in Japan and 56 were recorded in Taiwan, with the median age at diagnosis being 73 and 67 years, respectively. The incidence of LPL/WM showed male predominance in both countries. Crude age-specific incidence rates increased sharply with age in both countries, especially in people >65 years. Age-standardized (to the World standard population) incidence rates per 100,000 person-years were 0.043 (0.071 for men and 0.023 for women) and 0.031 (0.041 for men and 0.020 for women) in Japan and Taiwan, respectively. Age-standardized (to the 2,000 US standard population) incidence rates in Japan and Taiwan were lower than rates reported in the literature for Asians living in the United State. A significant increasing trend was observed in the incidence over the period from 1996 to 2003 in Japan alone. This report suggests that both environmental and/or genetic factors may be involved in LPL/WM development., (© 2013 UICC.)

Objective: In Japan, population-based cancer incidence data are reported several years behind the latest year of cancer mortality data. To bridge this gap, we aimed to determine a short-term projection method for cancer incidence., Methods: Data between 1985 and 2007 were obtained from the population-based cancer registries in four prefectures (Miyagi, Yamagata, Fukui and Nagasaki). Three projection models were examined: generalized linear model with age and period (A + P linear); generalized linear model with age, period and their interactions (A*P linear); and generalized additive model with age, period and their interactions smoothed by spline (A*P spline). We performed a 5-year projection for the years 2000 and 2005, based on the data of 1985-95 and 1985-2000, respectively. Seven cancer sites (stomach, liver, colorectal, lung, female breast, cervix uteri and prostate) and all cancers combined were analyzed. The accuracy of projection was evaluated by whether each observed number fell within the 95% confidence interval of the projected number., Results: The A*P spline model accurately projected 8 of 13 cancer site-sex combinations, whereas the number of site-sex combinations of accurate projection was 2 and 6 for A + P linear and A*P linear models, respectively. For liver and colorectal cancers, the A*P spline model alone performed accurate projections; the relative differences between projected and observed numbers of cancer incidence ranged between -0.4 and +10.9% for the A*P spline, and between +7.4 and +37.6% for the other two models. All three models failed to project sudden increases in prostate cancer between 2000 and 2005., Conclusions: The A*P spline model is a candidate method for the projection of cancer incidence in Japan. However, we need a continuous validation for prostate cancer.

Atomic bomb survivors have been reported to have an increased risk of some cancers, especially leukemia. However, the risk of prostate cancer in atomic bomb survivors is not known to have been examined previously. This study examined the association between atomic bomb radiation and the incidence of prostate cancer among male Nagasaki atomic bomb survivors. The subjects were classified by distance from the hypocenter into a proximal group (<2 km), a distal group (≥2 km), and an early entrance group (those who entered the region <2 km from the hypocenter within 2 weeks after the explosion). Between 1996 and 2009, 631 new cases of prostate cancer were identified among approximately 18 400 male Nagasaki atomic bomb survivors who were alive in 1996. The Cox proportional hazard model was used to estimate the risk of prostate cancer development, with adjustment for age at atomic bomb explosion, attained age, smoking status, and alcohol consumption. Compared with the distal group, the proximal group had significant increased risks of total, localized, and high-grade prostate cancer (relative risk and 95% confidence interval: 1.51 [1.21-1.89]; 1.80 [1.26-2.57]; and 1.88 [1.20-2.94], respectively). This report is the first known to reveal a significant relationship between atomic bomb radiation and prostate cancer., (© 2013 Japanese Cancer Association.)

Objective: The analysis of cancer trends in Japan has only been sporadically reported. We present a comprehensive report on the trends in cancer incidence and mortality in Japan using the most recent population-based data., Methods: National cancer mortality data between 1958 and 2011 were obtained from published vital statistics. Cancer incidence data between 1985 and 2007 were obtained from high-quality population-based cancer registries of four prefectures (Miyagi, Yamagata, Fukui and Nagasaki). Joinpoint regression analysis was performed to examine the trends in age-standardized rates of cancer incidence and mortality., Results: All-cancer mortality decreased from the mid-1990s, with an annual percent change of -1.3% (95% confidence interval: -1.4, -1.3), while all-cancer incidence continually increased from 1985, with an annual percent change of 0.7% (95% confidence interval: 0.6, 0.8). Major cancer sites, particularly the liver, colorectum and lung (males), showed a pattern of increasing incidence and mortality rates until the mid-1990s, stabilizing or decreasing thereafter. Stomach cancer showed a long-term decreasing trend for both incidence and mortality, while female breast cancer showed a continuously increasing trend. The incidence of prostate cancer, particularly at the localized stage, increased rapidly between 2000 and 2003, while that of mortality decreased from 2004. No changes were detected in the incidence or mortality for colorectal, female breast or cervical cancers after the establishment of national screening programs for these cancers., Conclusions: The analysis of cancer trends in Japan revealed a recent decrease in mortality and a continuous increase in incidence, which are considered to reflect changes in the underlying risk factors such as tobacco smoking and infection, and are partially explained by early detection and improved treatment.

Thyroid cancer risk following exposure to ionizing radiation in childhood and adolescence is a topic of public concern. To characterize the long-term temporal trend and age-at-exposure variation in the radiation-induced risk of thyroid cancer, we analyzed thyroid cancer incidence data for the period from 1958 through 2005 among 105,401 members of the Life Span Study cohort of Japanese atomic-bomb survivors. During the follow-up period, 371 thyroid cancer cases (excluding those with microcarcinoma with a diameter <10 mm) were identified as a first primary among the eligible subjects. Using a linear dose-response model, the excess relative risk of thyroid cancer at 1 Gy of radiation exposure was estimated as 1.28 (95% confidence interval: 0.59-2.70) at age 60 after acute exposure at age 10. The risk decreased sharply with increasing age-at-exposure and there was little evidence of increased thyroid cancer rates for those exposed after age 20. About 36% of the thyroid cancer cases among those exposed before age 20 were estimated to be attributable to radiation exposure. While the magnitude of the excess risk has decreased with increasing attained age or time since exposure, the excess thyroid cancer risk associated with childhood exposure has persisted for >50 years after exposure., (Copyright © 2012 UICC.)

Purpose: We examined colon cancer risk in atomic bomb survivors to investigate whether excess body weight after the bombings alters sensitivity to radiation effects., Methods: Of the 56,064 Japanese atomic bomb survivors with follow-up through 2002 with self-reported anthropometric data obtained from periodic mail surveys, 1,142 were diagnosed with colon cancer. We evaluated the influence of body mass index (BMI) and height on radiation-associated colon cancer risk using Poisson regression., Results: We observed a similar linear dose-response relationship for the 56,064 subjects included in our analysis and the entire cohort of Japanese atomic bomb survivors [excess relative risk (ERR) per Gray (Gy) = 0.53, 95 % confidence interval (CI) 0.25-0.86]. Elevation in earliest reported BMI, BMI reported closest to colon cancer diagnosis, and time-varying BMI were associated with an elevated risk of colon cancer [relative risk (RR) per 5 kg/m(2) increase in BMI = 1.14, 95 % CI 1.03-1.26; RR = 1.16, 95 % CI 1.05-1.27; and RR = 1.15, 95 % CI 1.04-1.27, respectively]. Height was not significantly related to colon cancer risk. Inclusion of anthropometric variables in models had little impact on radiation risk estimates, and there was no evidence that sensitivity to the effect of radiation on colon cancer risk depended on BMI., Conclusions: Radiation exposure and BMI are both risk factors for colon cancer. BMI at various times after exposure to the atomic bombings does not significantly influence the relationship between radiation dose and colon cancer risk, suggesting that BMI and radiation impact colon cancer risk independently of each other.

Inhibitors of a human aldo-keto reductase, AKR1B10, are regarded as promising therapeutics for the treatment of cancer, but those with both high potency and selectivity compared to the structurally similar aldose reductase (AKR1B1) have not been reported. In this study, we have found that, among honeybee propolis products, caffeic acid phenethyl ester (CAPE) inhibited AKR1B10 (IC(50) = 80 nM) with 7-fold selectivity over AKR1B1. Based on a model of docked CAPE in AKR1B10, its derivatives were designed, synthesized and evaluated for inhibitory potency. Among them, 3-(4-hydroxy-2-methoxyphenyl)acrylic acid 3-(3-hydroxyphenyl)propyl ester (10c) was the most potent competitive inhibitor (K(i) = 2.6 nM) with 790-fold selectivity for AKR1B10 over AKR1B1. Molecular docking of 10c and site-directed mutagenesis of AKR1B10 residues suggested that the interactions between the 2-methoxy and 3-hydroxy groups of 10c and the enzyme's Val301 and Gln114, respectively, are important for the inhibitor's selectivity. Additionally, the sub-μM concentration of 10c significantly suppressed the farnesal metabolism and cellular proliferation in AKR1B10-overexpressing cells., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Population-based cancer registries are operated by over 80% of prefectures in Japan. However, only a limited proportion of the registries can provide long-term incidence data. Here, we aimed to establish a method for monitoring cancer incidence trends in Japan using data from selected prefectures. Based on the availability of long-term (≥ 20 years) high-quality data, we collected incidence data from five prefectures (Miyagi, Yamagata, Fukui, Osaka, and Nagasaki), which included an annual average of 54,539 primary cancer cases diagnosed between 1985 and 2004. Cancer mortality data for 1995-2004 were obtained from the vital statistics. Representativeness and homogeneity of the trends were examined by funnel plot analysis of log-linear regression coefficients calculated for the most recent 10 years of data (1995-2004) of age-standardized rates (ASR). The ASR of incidence for five prefectures in total (5-pref total) showed a significant decrease, with an annual percent change (APC) of -1.0 (95% confidence interval [CI] -1.4: -0.6) for males and -0.4 (95% CI -0.8: -0.1) for females. Excluding data from Osaka (4-pref total) reversed the decreasing trend; the corresponding APC was +0.4 (95% CI -0.2: +1.0) for males and +0.7 (95% CI +0.5: +0.9) for females. The APCs for the ASR of mortality for the 4-pref total (males, -1.5; females, -1.3) were more representative of nationwide data (males, -1.4 [95% CI -1.7: -1.2]; females, -1.1 [95% CI -1.4: -0.9]) than those for the 5-pref total (males, -1.7; females, -1.4). We conclude that using data from Miyagi, Yamagata, Fukui, and Nagasaki prefectures, with continuous monitoring of the representativeness of the data, is a provisionally relevant way to evaluate cancer incidence trends in Japan., (© 2011 Japanese Cancer Association.)

In a nationwide survey of ATL in Japan, a total of 910 cases of ATL and 7,164 cases of B-NHL as a control disease, newly diagnosed from January 2006 to December 2007 (2 years), were enrolled from 156 hospitals. Male-female ratios were 1.16 for ATL and 1.22 for B-NHL. Among all ATL cases registered, 59.8% were from an HTLV-1 endemic area in Kyushu, and the ratio of ATL to B-NHL in this area was 1 to 3, while that in a non-endemic area in Tokyo was 1 to 40. Compared to previous nationwide studies, the age of ATL patients shifted toward older ages and the mean age gradually increased from 52.7 years in the first survey (cases before 1980) to 61.1 years in the ninth survey (1996-1997) and, finally, to 66.0 years in the present study (range: 19 to 94, median: 67). On subtype classification, 46.7% were classified as the acute type, 34.8% the lymphoma type, 10.3% the smoldering type, and 8.2% the chronic type, and the rate of the acute type decreased with an increase in the lymphoma type compared to that in previous studies. An increase in the mean age is explained by the high HTLV-1 prevalence in elderly people over 64 years old in endemic areas (20%), and by the continual development of ATL from this large pool of HTLV-1 carriers. According to mortality statistics from the Ministry of Health, Labor and Welfare in Japan, approximately 1,000 people die annually from ATL, a statistic that has not changed at least for the past decade.

Shifts in the histologic type of lung cancer accompanying changes in lung cancer incidence have been observed in Japan and the United States. We examined the association between the shift in tobacco design from nonfilter to filter cigarettes with changes in the incidence of adenocarcinoma (AD) and squamous cell carcinoma (SQ) of the lung. We compiled population-based incidence data from the Surveillance, Epidemiology and End Results in the United States (1973-2005) and from selected Japanese cancer registries (1975-2003). Trends in age-standardized rates of lung cancer incidence by histologic type were characterized using joinpoint analyses. A multiple regression framework was used to examine the relationship between tobacco use and incidence by histologic type. We observed that AD has replaced SQ as the most frequent histologic type in males and females in both Japan and the United States. Filter cigarette consumption was positively associated with the incidence of AD, with time lags of 25 and 15 years in Japan and the United States, respectively ( beta(2)(AD)): 1.946 × 10(-3) , p < 0.001 and 3.142 × 10(-3) , p < 0.001). In contrast, nonfilter cigarette consumption was positively associated with the incidence of SQ, with time lags of 30 and 20 years in Japan and the United States, respectively (beta (SQ)(2) ): 0.464 × 10(-3) , p = 0.006 and 0.364 × 10(-3) , p = 0.008). In conclusion, the shift from nonfilter to filter cigarettes appears to have merely altered the most frequent type of lung cancer, from SQ to AD., (Copyright © 2010 UICC.)

Objective: In Japan, biological safety cabinets (BSCs) are normally used by medical staff while handling antineoplastic agents. We have also set up a class II B2 BSC at the Division of Chemotherapy for Outpatients. The air temperature inside this BSC, however, decreases in winter. We assumed that this decrease is caused by the intake of open-air. Therefore, we investigated the effects of low open-air temperature on the BSC temperature and the time of admixtures of antineoplastic agents., Methods: The studies were conducted from January 1 to March 31, 2008. The outdoor air temperature was measured in the shade near the intake nozzle of the BSC and was compared with the BSC temperature. The correlation between the outdoor air temperature and the BSC temperature, the dissolution time of cyclophosphamide (CPA) and gemcitabine (GEM), and accurate weight measurement of epirubicin (EPI) solution were investigated for low and normal BSC temperatures., Result: The BSC temperature was correlated with the open-air temperature for open-air temperatures of 5-20°C (p < 0.0001). The dissolution of CPA and GEM at these temperatures was significantly delayed as compared to that at 25°C (p < 0.01 and p < 0.0001, respectively). The weight measurement of EPI solution using a syringe method lacks accuracy because of its high coefficient of viscosity at low temperatures (p < 0.01)., Conclusion: These results suggest that the BSC temperature decreases below room temperature in winter when air is drawn from outdoors. We showed that the BSC temperature affects the dissolution rate of antineoplastic agents. Further, we suggested that the BSC temperature drop might delay the affair of the admixtures of antineoplastic agents and increase the waiting time of outpatients for chemotherapy.

Objective: To investigate the degree to which ionising radiation confers risk of mortality from heart disease and stroke., Design: Prospective cohort study with more than 50 years of follow-up., Setting: Atomic bomb survivors in Hiroshima and Nagasaki, Japan., Participants: 86 611 Life Span Study cohort members with individually estimated radiation doses from 0 to >3 Gy (86% received <0.2 Gy)., Main Outcome Measures: Mortality from stroke or heart disease as the underlying cause of death and dose-response relations with atomic bomb radiation., Results: About 9600 participants died of stroke and 8400 died of heart disease between 1950 and 2003. For stroke, the estimated excess relative risk per gray was 9% (95% confidence interval 1% to 17%, P=0.02) on the basis of a linear dose-response model, but an indication of possible upward curvature suggested relatively little risk at low doses. For heart disease, the estimated excess relative risk per gray was 14% (6% to 23%, P<0.001); a linear model provided the best fit, suggesting excess risk even at lower doses. However, the dose-response effect over the restricted dose range of 0 to 0.5 Gy was not significant. Prospective data on smoking, alcohol intake, education, occupation, obesity, and diabetes had almost no impact on the radiation risk estimates for either stroke or heart disease, and misdiagnosis of cancers as circulatory diseases could not account for the associations seen., Conclusion: Doses above 0.5 Gy are associated with an elevated risk of both stroke and heart disease, but the degree of risk at lower doses is unclear. Stroke and heart disease together account for about one third as many radiation associated excess deaths as do cancers among atomic bomb survivors.

Cancer has been the primary cause of death in Japan for many years and accurate cancer incidence data are necessary in order to make plans for cancer control. Although population-based cancer registries are the best answer, regrettably there are still many regions with low accuracy registries. In an alternative estimation, cancer incidences have been analyzed by age-period-cohort (APC) models, allowing future prediction of cancer incidences in 2004. Considering the unexpectedly rapid aging of the Japanese population after this figure was reported, it would be worthwhile to examine more recent data. In this study, we therefore projected major cancer incidences based on the earlier results leaving estimated values for the age and cohort effects. Relating to the period effect, the most adequate scenario was selected from 12 projection methods. Furthermore, incidences when registration rates varied between 70 and 100% were calculated. As a result, different trends from reported incidences were observed for liver cancer in males, and trends of registration rates differed by sites. Until stable accurate registration data become available, it is difficult to judge whether predicted increase is real or only looks so because the registration rate is not 100%. However, it is clearly necessary to continuously observe variation in cancer incidences.

In medical care systems for cancer, it is important to consider the issues of standardization and centralization. In this study, we employed the Nagasaki Cancer Registry, which has a high registry rate, to investigate standardization and centralization for five major cancers, in addition to childhood malignancies (which are often rare types). Subjects were patients diagnosed with cancer and registered in the Nagasaki Cancer Registry between 1985 and 2004. For standardization, we calculated a Preference Index and five-year survival rate, and for centralization we investigated Pareto curves and Gini coefficients as well as the annual average number of cases per hospital. Results suggested that patients migrate to medical service areas different from where they reside in order to receive treatment at facilities thought to have a better record of treatment. In addition, while the number of patients and treatment facilities for childhood cancer was decreasing due to a decline in the number of children, the centralized tendency differed for the 12 diagnoses assessed. By conducting analyses based on population-based cancer registries using the evaluation methods employed in this study, it should be possible to investigate patients' migrant patterns, as well as to develop systems for providing medical care in secondary medical service areas.

The authors investigated the relation between ionizing radiation and lymphoma mortality in 2 cohorts: 1) 20,940 men in the Life Span Study, a study of Japanese atomic bomb survivors who were aged 15-64 years at the time of the bombings of Hiroshima and Nagasaki, and 2) 15,264 male nuclear weapons workers who were hired at the Savannah River Site in South Carolina between 1950 and 1986. Radiation dose-mortality trends were evaluated for all malignant lymphomas and for non-Hodgkin's lymphoma. Positive associations between lymphoma mortality and radiation dose under a 5-year lag assumption were observed in both cohorts (excess relative rates per sievert were 0.79 (90% confidence interval: 0.10, 1.88) and 6.99 (90% confidence interval: 0.96, 18.39), respectively). Exclusion of deaths due to Hodgkin's disease led to small changes in the estimates of association. In each cohort, evidence of a dose-response association was primarily observed more than 35 years after irradiation. These findings suggest a protracted induction and latency period for radiation-induced lymphoma mortality.

Reliable population-based cancer survival data are essential for assessment of the effectiveness of cancer screening programs, distribution of cancer therapy and prevalent cancer cases. International comparisons are useful to allow societies, mass media and health authorities to gain a real appreciation of the cancer problem in their own country and provide an impetus to improve registration and cancer control planning. Since directly comparable survival data among East Asian countries are presently very limited, a comparative study on population-based cancer survival involving China, Indonesia, Japan, Korea, the Philippines and Taiwan, with Nepal as an observer, was proposed. At the 1st Working Group meeting in Tokyo on March 18th, 2009, it was decided to publish the present Commentary as a step towards realization of truly comparable cancer survival statistics in the region. Included are general information and quality of data of cancer registration at each participating registry and five-year relative survival rates of cancer of the stomach, colo-rectum, liver, lung, breast and cervix.

Objective: The objective of the study was to evaluate the association of thyroid disease with radiation dose in atomic bomb survivors exposed in utero., Design: This was a cross-sectional study., Setting: The study was conducted in atomic bomb survivors in Hiroshima and Nagasaki, Japan., Participants: Participants included 328 atomic bomb survivors exposed in utero (mean age 55.2 yr, 162 males) who participated in the thyroid study at the Radiation Effects Research Foundation. Examinations were conducted between March 2000 and February 2003., Main Outcome Measures: The relationships of various thyroid conditions to atomic bomb radiation dose were measured., Results: Among the 319 participants excluding nine participants whose exposure radiation dose was not estimated, the mean maternal uterine radiation dose was 0.256 Gy. We observed no significant dose-response relationship for the prevalence of solid thyroid nodules (odds ratio at 1 Gy, 2.78; 95% confidence interval 0.50-11.80, P = 0.22), but the risk estimate was similar to the estimate for childhood exposures. The prevalence of cysts and autoimmune thyroid diseases was not associated with radiation dose (P > 0.30). We could not evaluate the dose response for malignant tumors or benign nodules due to the small number of cases., Conclusions: We did not observe a statistically significant linear dose response to radiation for thyroid nodules or autoimmune thyroid diseases 55-58 yr after participants' in utero exposure. However, the risk estimate for solid thyroid nodules was similar for those exposed in utero and those exposed in childhood. Because the study had limited statistical power to detect moderately sized effects, further studies are needed for a definitive conclusion.

Few epidemiological studies have been conducted on the prevalence, blood pressure trends by age, and basic characteristics of chronic hypotension. Among 13,370 subjects (5,094 men and 8,276 women) examined from 1958 to 1999 in Japan, 92 were identified as chronic hypotensives (11 men and 81 women) whose systolic blood pressure (SBP, mmHg) was lower than 100 mmHg for 8 or more years. Trends of SBP and body mass index (BMI, kg/m2) were determined over a 16-year period in this group of chronic hypotensives and 276 age- and sex-matched controls (33 men and 243 women); during this 16-year period, the chronic hypotensives and controls ranged in age from 19 to 75 years. BMI, heart rate (HR, bpm), body temperature (degrees C), Hb (g/dl), and creatinine (Cre, mg/dl) were compared between the chronic hypotensives and the controls at the last examination. The chronic hypotensives had a female preponderance (0.2% in men and 1.0% in women, p=0.001), and their SBP and BMI increased little with increasing age. BMI (20.2+/-3.4), BMI-adjusted SBP (101+/-19), HR (63+/-10), body temperature (36.7+/-0.3), Hb (12.5+/-1.1), and Cre (0.81+/-0.13) were lower in the chronic hypotensives than those (22.9+/-3.4, 126+/-20, 68+/-10, 36.8+/-0.3, 12.9+/-1.1, and 0.86+/-0.12, respectively) in controls (p<0.05). The present results clearly show that chronic hypotensives have a female preponderance and low BMI, HR, body temperature, Hb, and Cre in addition to low SBP that does not increase with age.

Objective: To examine the association between the incidence of gastric cancer and lifestyle factors such as cigarette smoking, alcohol drinking, and diet as well as atomic bomb radiation exposure., Methods: Longitudinal study including 38,576 atomic-bomb survivors in Hiroshima and Nagasaki, Japan, followed-up between 1980 and 1999. Individual radiation dose was estimated according to the Dosimetry System 1986 (DS86). Lifestyle determinants were based on the responses to a mail survey sent at baseline. 1270 incident carcinomas of gastric cancer were identified during the 485,575 person-years of follow-up. Poisson regression was used to estimate incidence rate ratios., Results: Ionizing radiation exposure, male gender, age, and smoking were significantly associated with an increased risk of stomach cancer. No association was suggested between the frequency of consumption of fruit, vegetables, green tea, and soy products and gastric cancer., Conclusions: In this Japanese population, although radiation and smoking were strong determinants of stomach cancer, no supportive evidence could be shown for the effect of dietary factors.

Objectives: This study prospectively evaluated the associations of human T-lymphotropic virus type-I (HTLV-I) infection with survival and cancer incidence., Methods: The study base comprised 4297 adults (aged 40-69 years in 1993) who had either visited the outpatient clinic or who had received annual health check-ups at the A Hospital, Nagasaki, Japan, between 1985 and 1992 (HTLV-I seropositivity = 24.7%). During the follow-up period (1993-1999 or 2000), 290 deaths and 261 cases of malignant neoplasms occurred, including ten deaths and six incident cases of adult T-cell leukemia/lymphoma (ATL)., Results: After adjustment for gender, age and other covariates, HTLV-I seropositivity was associated with an increased mortality from all-causes excluding ATL (rate ratio, RR = 1.3, 95% confidence interval, CI = 1.0-1.7), all non-neoplastic diseases (RR = 1.5, 95% CI = 1.0-2.3) and heart diseases. HTLV-I infection was not found to be associated with an increased risk of developing total cancers other than ATL (RR = 0.98, 95% CI = 0.74-1.3), colorectal cancers, liver cancer or lung cancer, but was associated with a reduced risk of gastric cancer (RR = 0.42, 95% CI = 0.17-0.99)., Conclusions: HTLV-I infection is associated with increased mortality from all-causes excluding ATL and all non-neoplastic diseases. HTLV-I carriers may not be at increased general cancer risk, but at reduced risk of gastric cancer.

Objectives: The purpose of this study was to investigate the serological risk factors for development of adult T-cell leukemia/lymphoma (ATL) among human T-cell lymphotropic virus type-I (HTLV-I) carriers., Methods: A nested case-control study was performed. The source population comprised 23,922 subjects who had either visited the outpatient clinic or who had received annual health check-ups at the K Hospital, Nagasaki, Japan, at least once during 1985-1996 (HTLV-I seroprevalence = 16.1%). Markers of HTLV-I infection were examined in stored sera from 29 incident cases of ATL diagnosed during 1985-1997, and 158 controls matched for sex, birth year, date of sample collection, and HTLV-I seropositivity (median follow-up = 6.4 years)., Results: In exact conditional logistic regression analysis, high levels of soluble interleukin-2 receptor (> or = 500 U/ml) and high HTLV-I antibody titers (> or = 1,024) were independently associated with an increased risk of developing ATL (Odds ratio 20.5. 95% confidence interval (CI) 4.5-194 and 2.9, 95% CI 0.98-9.5, respectively). The results remained essentially unchanged when the subjects were restricted to those whose histories were followed for two years or longer., Conclusions: These findings indicate that high soluble interleukin-2 receptor levels and high HTLV-I antibody titers are strong predictors of ATL among carriers of HTLV-I.