HapMap scanning of novel human minor histocompatibility antigens

Minor histocompatibility antigens (mHags) are molecular targets of allo-immunity associated with hematopoietic stem cell transplantation (HSCT) and involved in graft-versus-host disease, but they also have beneficial antitumor activity. mHags are typically defined by host SNPs that are not shared by the donor and are immunologically recognized by cytotoxic T cells isolated from post-HSCT patients. However, the number of molecularly identified mHags is still too small to allow prospective studies of their clinical importance in transplantation medicine, mostly due to the lack of an efficient method for isolation. Here we show that when combined with conventional immunologic assays, the large data set from the International HapMap Project can be directly used for genetic mapping of novel mHags. Based on the immunologically determined mHag status in HapMap panels, a target mHag locus can be uniquely mapped through whole genome association scanning taking advantage of the unprecedented resolution and power obtained with more than 3 000 000 markers. The feasibility of our approach could be supported by extensive simulations and further confirmed by actually isolating 2 novel mHags as well as 1 previously identified example. The HapMap data set represents an invaluable resource for investigating human variation, with obvious applications in genetic mapping of clinically relevant human traits.     

Successful treatment of young-onset adult T cell leukemia/lymphoma and preceding chronic refractory eczema and corneal injury by allogeneic hematopoietic stem cell transplantation

Only some carriers of human T cell lymphotropic virus type I (HTLV-1) develop adult T cell leukemia/lymphoma (ATLL) after a long latency period, and an association has been reported between chronic refractory eczema, known as infective dermatitis, and young-onset ATLL. A 25-year-old female developed ATLL and underwent allogeneic hematopoietic stem cell transplantation (HSCT) in non-remission. She had chronic refractory eczema and corneal injury at the onset of ATLL. Remission of ATLL was achieved, and the HTLV-1 proviral load decreased after HSCT. In addition, her pre-existing eczema and corneal injuries almost disappeared. More than a year has passed since the transplantation was performed, and she has had no recurrence of either ATLL or lesions in the skin and eye. Her clinical course suggests a possible association between skin and eye lesions and HTLV-1 infection. Changes in the immunological condition after HSCT might play a key role. Special attention is needed when HTLV-1 carriers develop eye or skin lesions.     

Repeated social defeat stress induces chronic hyperthermia in rats

Psychological stressors are known to increase core body temperature (T_c) in laboratory animals. Such single stress-induced hyperthermic responses are typically monophasic, as T_c returns to baseline within several hours. However, studies on the effects of repeated psychological stress on T_c are limited. Therefore, we measured T_c changes in male Wistar rats after they were subjected to 4 social defeat periods (each period consisting of 7 daily 1 h stress exposures during the light cycle followed by a stress-free day). We also assessed affective-like behavioral changes by elevated plus maze and forced swim tests.In the stressed rats, the first social defeat experience induced a robust increase in T_c (+ 1.3 °C). However, the T_c of these rats was not different from control animals during the subsequent dark period. In comparison, after 4 periods of social defeat, stressed rats showed a small but significantly higher (+ 0.2-0.3 °C) T_c versus control rats during both light and dark periods. Stressed rats did not show increased anxiety-like behavior versus control rats as assessed by the elevated plus maze test. However, in the forced swim test, the immobility time of stressed rats was significantly longer versus control rats, suggesting an increase in depression-like behavior. Furthermore, hyperthermia and depression-like behavior were still observed 8 days after cessation of the final social defeat session. These results suggest that repeated social defeat stress induces a chronic hyperthermia in rats that is associated with behavior resembling depression but not anxiety.     

Cleaning efficacy and dentin micro-hardness after root canal irrigation with a strong acid electrolytic water

The purpose of this study was to evaluate the cleaning effect of root canal walls using strong acid electrolytic water (SAEW) as a root canal irrigant, and to investigate the influence of SAEW on the root canal dentin by micro-hardness test. Forty-three single-rooted, single-canaled teeth were instrumented using standard step-back technique with K-files. Irrigation was performed using distilled water, 5.25% NaOCl and 3% H(2)O(2), SAEW, or 15% EDTA solution in five groups. Samples were prepared to be examined under a scanning electron microscope (SEM) and micro Vickers hardness (H(V)) test machine. Our results showed that the root cleaning effects of the combined use of SAEW and NaOCl solution as root canal irrigants were equivalent to those in the group with NaOCl and 15% EDTA. When SAEW was used for 1 min under ultrasonic vibration, no decreases in the hardness of dentin inside the root canal were detected.     

Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein

BACKGROUND & AIMS: Despite the evidence of hepatic iron overload in patients with chronic hepatitis C, it remains unknown if iron overload is related to hepatocarcinogenesis in this condition. The aim of this study was to determine whether iron overload contributes to development of hepatocellular carcinoma (HCC) in transgenic mice expressing the hepatitis C virus (HCV) polyprotein. METHODS: Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or control diet. Mice in each group were assessed for altered liver morphology and function and the development of liver tumors. RESULTS: Hepatic iron concentrations in mice fed the excess-iron diet were comparable to those of patients with chronic hepatitis C. There was no inflammation in transgenic and nontransgenic livers. Compared with mice in 3 other groups, transgenic mice fed the excess-iron diet showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, and greater hepatic content of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine at 12 months after initiation of feeding. The number of proliferating hepatocytes was significantly increased in mice fed the excess-iron diet but was not different between transgenic and nontransgenic mice. Hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet but not in mice in other groups at 12 months after initiation of feeding. CONCLUSIONS: Iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein.     

Tareciliosides N–S: further cycloartane saponins from the leaves of Tarenna gracilipes, and cytotoxicity of saponins and triterpenes

Six cycloartane glycosides, named tareciliosides N–S, and a known iridoid glucoside, ixoroside, were isolated in further extensive studies on the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Tarenna gracilipes. From the EtOAc-soluble fraction, three known triterpenes were isolated. Their toxicities toward A549 and Leishmania major trypanosome protozoa were assayed. Triterpenes were selectively active in the two organisms.     

Low response to a monovalent inactivated unadjuvanted influenza A (H1N1) pdm09 vaccine in pediatricians of a general hospital in Japan

Immunization of health care personnel (HCP) is critically important to reduce healthcare-associated influenza infections substantially. During 2009-2010, 74% of all HCP at Kitano Hospital, Osaka, Japan, including 94% of pediatricians, received the monovalent unadjuvanted influenza A (H1N1) pdm09 vaccine. We evaluated the vaccine's immunogenicity. Sixteen pediatricians received 15 μg hemagglutinin antigen subcutaneously. Antibody titer assays were conducted using hemagglutination-inhibition antibody assay on days 0 and 21, and at 5 mo after vaccination. Seroprotection rates, seroconversion rates, and geometric mean titer folds at 21 d were, respectively, 43.8%, 43.8%, and 5.4 in all subjects, 70.0%, 70.0%, and 8.0 in subjects aged 27-34 y, and 0.0%, 0.0%, and 8.0 in subjects aged ≥ 35 y. None of the latter group met the European Medicines Agency criteria. We hope to adopt intradermal routes and further the development of the influenza vaccine using new technology to improve immunogenicity in Japan.     

Weight gain during adulthood and body weight at age 20 are associated with the risk of endometrial cancer in Japanese women

Background

Current obesity is an established risk factor for endometrial cancer; however, the roles of weight gain during adulthood and obesity in early adulthood on endometrial cancer have not been elucidated. Here, we conducted a case-control study comprising 222 histologically diagnosed incident endometrial cancer cases and 2162 age- and menstrual-status matched non-cancer controls.

Methods

Information on current body weight, weight and height at age 20 years, and lifestyle/environmental factors was obtained from a self-administered questionnaire. Subjects were classified into 3 groups according to change in body mass index (BMI, kg/m²) from age 20 years to enrollment (≤0 [reference], 0–3, and >3 kg/m²). The effects of adult BMI change and obesity in early adulthood were evaluated using an unconditional logistic regression model adjusted for potential confounders.

Results

A high BMI at age 20 (BMI ≥25, BMI <25 as reference) was significantly positively associated with endometrial cancer risk (P = 0.005), as was a BMI increase during adulthood (0–3 BMI change, multivariate odds ratio [OR] = 1.28, 95% confidence interval [CI] = 0.88–1.87; >3 BMI change, OR = 2.02, 95% CI = 1.38–2.96; P-trend < 0.001). Parity and BMI at age 20 appeared to modify the effect of weight gain on cancer risk, albeit without statistical significance. This positive association of weight gain with risk was observed only for endometrioid adenocarcinoma.

Conclusions

The results show that endometrial cancer is positively associated with obesity at age 20 and weight gain during adulthood among Japanese women.Key words: endometrial cancer, weight gain, case-control study     

Profile of participants and genotype distributions of 108 polymorphisms in a cross-sectional study of associations of genotypes with lifestyle and clinical factors: a project in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

Background

Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene–environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005.

Methods

We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay.

Results

The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35–69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001).

Conclusions

This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene–environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.Key words: allele frequency, cross-sectional studies, gene–environment interactions, Japan Multi-institutional Collaborative Cohort Study, polymorphism