Prediction of peritoneal metastasis in advanced gastric cancer by gene expression profiling of the primary site

Peritoneal metastasis is the most common cause of tumour progression in advanced gastric cancer. Clinicopathological findings including cytologic examination of peritoneal lavage have been applied to assess the risk of peritoneal metastasis, but are sometimes inadequate for predicting peritoneal metastasis in individuals. Hence, we tried to construct a new prediction system for peritoneal metastasis by using a PCR-based high throughput array with 2304 genes. The prediction system, constructed from the learning set comprised of 30 patients with the most informative 18 genes, classified each case into a 'good signature group' or 'poor signature group'. Then, we confirmed the predictive performance in an additional validation set comprised of 24 patients, and the prediction accuracy for peritoneal metastasis was 75%. Kaplan-Meier analysis with peritoneal metastasis revealed significant difference between these two groups (P=0.0225). By combining our system with conventional clinicopathological factors, we can identify high risk cases for peritoneal metastasis more accurately.     

Lysocellin, a metabolite of the novel drug 'alopestatin', induces G1 arrest and prevents cytotoxicity induced by etoposide

We report here that lysocellin, a polyether antibiotic from a streptomycete, induces G1 phase arrest in human osteosarcoma MG63 cells. Lysocellin up-regulates p21WAF1/Cip1 and down-regulates cyclin D1 at the mRNA level. In addition, cyclin D1 is down-regulated by the proteasome-dependent signal pathway in MG63 cells. In drug combination studies, we found that lysocellin treatment weakened the cytotoxic activity of etoposide in MG63 cells using a colony-formation assay. To study the in vivo efficacy of lysocellin, we isolated a novel compound related to lysocellin from the same streptomycete, and found that the novel drug is converted to lysocellin in vivo and decreases etoposide-induced alopecia in a neonatal rat model. We raise the possibility that this novel drug, named 'alopestatin', may be a promising agent against alopecia.     

The combination effect of amrubicin with cisplatin or irinotecan for small-cell lung cancer cells

The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.     

Association of the OGG1-Ser326Cys polymorphism with lung adenocarcinoma risk

Adenocarcinoma (ADC) is the most frequent histological type of lung cancer and comprises the majority of lung cancers in non-smokers. Thus, genetic factors responsible for ADC susceptibility need to be determined to establish efficient ways of preventing the disease. The OGG1 gene, encoding a glycosylase for 8-hydroxyguanine, an oxidatively damaged promutagenic base, has the polymorphism Ser326Cys, and OGG1-326Cys protein was indicated to have a lower ability to prevent mutagenesis than the OGG1-326Ser protein. Case-control studies to date suggest that the OGG1-326Cys allele is associated with a higher risk for several types of cancers, including overall lung cancer. However, the contribution of this polymorphism to lung ADC risk is unclear. In the present study, the OGG1-Ser326Cys polymorphism was assessed for association with lung ADC risk using a case-control study of a Japanese population consisting of 1097 cases and 394 controls. Odds ratios (OR) of the 326Cys allele carriers increased in a dose-dependent manner with allele number (P for the trend test = 0.04). The OR of homozygotes for the 326Cys allele was increased significantly when homozygotes for the 326Ser allele were used as a reference (OR = 1.5, 95% confidence interval [CI] = 1.0-2.1, P = 0.04). Furthermore, the overall OR for lung ADC of the Cys/Cys homozygotes out of a total of 1925 ADC patients and 3449 controls from six case-control studies reported up to the present were 1.43 (95% CI = 1.11-1.84, P = 0.0045). These results indicate that OGG1-326Cys functions as a risk allele for lung ADC development.     

Usefulness of contrast enhanced-MRI in the diagnosis of unicystic ameloblastoma

The radiographic features of unicystic ameloblastoma (UA) are typically unilocular and round area of radiolucency. Therefore, this type of lesion is often misdiagnosed as an odontogenic keratocyst or a dentigerous cyst. UA should be differentiated from odontogenic cysts because the former have a higher rate of recurrence than the latter. In the present study, we performed contrast enhanced-MRI (CE-MRI) to diagnose 13 cases of unilocular, round radiolucent lesions visualized on panoramic radiograph and/or CT. In the cases of UA, low signal intensity was observed on T1-weighted images (WIs), and a markedly high signal intensity was observed on T2-WIs; moreover, relatively thick rim-enhancement with/without small intraluminal nodules was observed upon CE-T1WIs. CE-MRI was considered useful in the diagnosis of UA, as characteristic features of this type of lesion i.e., thick enhancement of the tumor wall and small intraluminal nodules were detected only by CE-MRI in the present study.     

Inhibition of scratching behavior associated with allergic dermatitis in mice by tacrolimus, but not by dexamethasone

Itching is the most important problem in many allergic and inflammatory skin diseases especially in atopic dermatitis. However, animal models for allergic dermatitis useful for the study of itching have rarely been established. We established a mouse allergic dermatitis model involving frequent scratching behavior by repeated painting with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse skin, and comparatively examined the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior. Repeated DNFB painting caused typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behavior. An apparent thickening of the epidermis and dermis, and the significant accumulation of inflammatory cells were observed. Increased interferon (IFN)-gamma mRNA expression and the induction of interleukin (IL)-4 and IL-5 mRNA expression were also observed in the skin lesion. The scratching behavior was inhibited by dibucaine and naloxone. Although tacrolimus reduced the increased expression of IFN-gamma and IL-4 mRNA, dexamethasone potently depressed that of IFN-gamma, IL-4 and IL-5 mRNA. Dexamethasone inhibited the accumulation of lymphocytes and eosinophils, although tacrolimus did not. Both drugs failed to inhibit the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior that was associated with the inhibition of nerve fiber extension into the epidermis, whereas dexamethasone failed to have any effect. The mouse dermatitis model seems to be beneficial for the study of itching associated with allergic dermatitis, such as atopic dermatitis, and tacrolimus seems to exhibit an anti-itch effect through the inhibition of nerve fiber extension at least in part.     

Do adolescent leisure-time physical activities foster health and well-being in adulthood? Evidence from two British birth cohorts

BACKGROUND: Calls for public health initiatives to increase adolescent leisure-time physical activity suggest that increasing activity in this age group will reduce social inequalities in health. While the public health benefits of exercise are undisputed, there is little evidence on its role in reducing health inequalities. The paper examines the extent to which adolescent leisure-time physical activity promotes adult health and well-being and explores whether adolescent leisure-time physical activity can act to reduce health inequalities arising from material deprivation during childhood. METHODS: This is a longitudinal study of the 1958 British birth cohort followed from age 16 to age 33 years (N = 15,452) and the 1970 British birth cohort followed to age 30 years (N = 14,018). Adult self-rated general health and Malaise Inventory scores are regressed on self-reports of leisure time physical activity. Analyses are conducted separately for men and women controlling for adolescent body mass index (BMI) and psychosocial problems. RESULTS: There was a consistent relationship between leisure-time physical activity in adolescence and psychological well-being approximately 15 years later for both the cohorts. This relationship was independent of adolescent BMI and psychosocial problems. More physical activity in adolescence predicted better adult self-assessed health in the 1958 cohort only. Leisure-time physical activity did not affect inequalities in health. CONCLUSIONS: Policies aimed at increasing participation in leisure-time physical activities in youth may improve population health but are unlikely to prevent the development of social inequalities in health.