BackgroundTo implement personalized medicine, we established a large-scale patient cohort, BioBank Japan, in 2003. BioBank Japan contains DNA, serum, and clinical information derived from approximately 200,000 patients with 47 diseases. Serum and clinical information were collected annually until 2012.MethodsWe analyzed clinical information of participants at enrollment, including age, sex, body mass index, hypertension, and smoking and drinking status, across 47 diseases, and compared the results with the Japanese database on Patient Survey and National Health and Nutrition Survey. We conducted multivariate logistic regression analysis, adjusting for sex and age, to assess the association between family history and disease development.ResultsDistribution of age at enrollment reflected the typical age of disease onset. Analysis of the clinical information revealed strong associations between smoking and chronic obstructive pulmonary disease, drinking and esophageal cancer, high body mass index and metabolic disease, and hypertension and cardiovascular disease. Logistic regression analysis showed that individuals with a family history of keloid exhibited a higher odds ratio than those without a family history, highlighting the strong impact of host genetic factor(s) on disease onset.ConclusionsCross-sectional analysis of the clinical information of participants at enrollment revealed characteristics of the present cohort. Analysis of family history revealed the impact of host genetic factors on each disease. BioBank Japan, by publicly distributing DNA, serum, and clinical information, could be a fundamental infrastructure for the implementation of personalized medicine.
The CTOS method enables us to obtain primary lung tumor cells of high viability and purity. CTOS could be a new platform for studying lung cancer biology.
Purpose: To retrospectively evaluate the relationship between apparent diffusion coefficient (ADC) values and Gleason score (GS) in prostate cancer.Methods: A total of 60 patients who underwent radical prostatectomy for clinically localized prostate cancer were selected for this study. Diffusion-weighted magnetic resonance (MR) images were obtained using a 1.5 T system. ADC values were analyzed between three groups: GS of 6 or less (n ¼ 7); GS of 7 (n ¼ 37); and GS of 8 or higher (n ¼ 16). ADC values of the three GS groups were statistically analyzed in order to determine the relationship with GS. In the 37 patients with GS ¼ 7 the difference in ADC values between GS 3þ4 and GS 4þ3 was analyzed.
Results: Median ADC values (10À3 mm 2 /s) of the three GS groups were 1.04 (GS ¼ 6 or less), 0.867 (GS ¼ 7), and 0.729 (GS ¼ 8 or higher). Although there was considerable overlap among the groups, the differences in ADC were statistically significant (P < 0.0001). There was a significant inverse correlation between GS and ADC values (z ¼ À0.437, P < 0.0005). Median ADC values (10 À3 mm 2 /s) of GS 3þ4 and GS 4þ3 patients were 0.88 and 0.814, respectively (P < 0.05).
Conclusion: ADC values showed a negative correlation with GS. Pathologically, however, there was considerable intrasubject heterogeneity.
The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained. Dormant lung cancer cells were found to be resistant to EGFR tyrosine kinase inhibitor (TKI) treatment. In terms of mechanism, we found that a negative regulator of ERBB signaling, MIG6/ERRFI1/RALT/Gene33, was induced by hypoxia both in vitro and in vivo. MIG6 expression prevented heterodimer formation of ERBB family RTKs, and suppressed their downstream signaling. Knockdown of MIG6 enhanced tumor cell growth under hypoxic conditions, and promoted the phosphorylation of ERK and AKT via increased EGFR-HER3 binding. Critically, sensitivity to an EGFR-TKI, as well as to irradiation under hypoxic conditions, was increased in MIG6 knockdown cells. The expression of MIG6 was partly correlated with a pS6 negative zone in patient tumors. Analyses of tumor sections from 68 patients with activating EGFR mutations showed that patients with high MIG6 expression showed significantly shorter survival after EGFR-TKI treatment than other groups. Collectively, our data suggest that dormant cancer cells with a high MIG6 expression level might be one of the causes of EGFR-TKI resistance in EGFR mutant lung cancer cells.
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