Tetsuji Tonda

Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a BH3-only cell death activator.

Herpes simplex virus thymidine kinase (HSV-tk)/gancyclovir (GCV) therapy has the ability to inhibit tumor formation in animal models but the results of clinical trials have been disappointing. To improve the performance of tk/GCV therapy, we tried combination therapy designed to enhance its cytotoxic effects by introducing genes that induce apoptosis of the tumor cells through different pathways. We concentrated our efforts on the use of Bim, a BH3-only member of death activators in the Bcl-2 superfamily, because Bim is not involved in the pathways through which HSV-tk/GCV therapy induces apoptosis in malignant glioma cells. Among three alternative splicing variants, BimEL, BimL, and BimS, BimS lacks the binding domain for the dynein light chain LC8, which negatively regulates the proapoptotic function of BimEL and BimL. All four malignant glioma cell lines, U251, A172, T-430, and U373 underwent cell death after transfer of BimS using an adenovirus vector (AVC2). Intriguingly, combination of AVC2-BimS with AVC2-tk markedly increased the sensitivity of U251 cells to GCV both in vitro and in vivo. In contrast, AVC2-BimL did not induce significant cell death. These results indicated that BimS had the ability to improve the efficiency of HSV-tk/GCV therapy in the treatment of malignant glioma and suggested that the targeting of different proapoptotic pathways may be a useful strategy for the development of an effective gene therapy approach to treatment.

Effect of Mustard Gas Exposure on Incidence of Lung Cancer: A Longitudinal Study

Sulfur mustard, an agent used in chemical warfare, is an alkylating substance with carcinogenic potential. However, the precise long-term carcinogenic effects of mustard gas are unclear. Since 1952, the authors have conducted health surveys of former workers who were employed from 1929 to 1945 in a poisonous gas factory in Okuno-jima, Hiroshima, Japan. This prospective study was undertaken from 1952 to 2005 to examine the incidence of lung cancer among the workers who were exposed to mustard gas (n=480), lewisite (n=55), and/or diphenylcyanarsine (n=178), as well as the incidence among unexposed workers (n=969). The stochastic relation between exposure and lung cancer was explored on the basis of multistage carcinogenesis by using an accelerated hazard model with a transformed age scale. Mustard gas exposure was found to transform the age scale for developing lung cancer. One year of exposure in subjects ≤18 or >18 years old at first exposure shifted the age scale down by 4.9 years and 3.3 years, respectively. On the basis of the long-term follow-up of former workers in the poisonous gas factory, the authors concluded that sulfur mustard decreased the age at which people were at risk of developing lung cancer and that the effect declined with aging.

Optimal Cardiac Phase for Coronary Artery Calcium Scoring on Single-Source 64-MDCT Scanner : Least Interscan Variability and Least Motion Artifacts

OBJECTIVE The purpose of our study was to investigate the cardiac phase with the least interscan variability and motion artifacts on coronary artery calcium studies using a 64-MDCT scanner. SUBJECTS AND METHODS Ninety-one patients with suspected coronary artery disease were scanned twice on retrospective ECG-gated helical scans. Images with 2.5-mm thickness and 1.25-mm interval at nine cardiac phases (center of cardiac phase: 40-80% in 5% increments) were reconstructed. The interscan variability of coronary artery scores (Agatston, volume, and mass) per patient and motion artifact scores per branch, subjectively assigned by motion artifact grading (1, none; 2, minor; and 3, major), were compared between cardiac phases for all patients, low (< 65 beats per minute [bpm]) and high (>or= 65 bpm) heart rate patient groups. RESULTS For all patients, two-factor factorial analysis of variance revealed that the interscan variability was different between cardiac cycles (p < 0.01); however, this was not statistically significant between scoring algorithms (p = 0.46). The least variability was obtained at 70% on Agatston (8%) and volume (7%) and at 75% on mass (7%). Adjacent categories logit model analysis revealed that the motion artifact score was the least at 75% (left anterior descending coronary artery, 1.3; left circumflex coronary artery, 1.4; and right coronary artery, 1.9 in all patients) and that a smaller difference in calcium scores between the scans led to a smaller motion artifact score (p < 0.05). CONCLUSION Middiastole reconstruction (center of cardiac phase: 70-75%), with the least interscan variability and the least motion artifacts, is recommended on 64-MDCT.

Asymptotic Expansion of the Null Distribution of LR Statistic for Multivariate Linear Hypothesis when the Dimension is Large

Abstract In this paper we derive an asymptotic expansion of the null distribution of likelihood ratio statistic for multivariate linear hypothesis when the dimension is comparable to the sample size. Our asymptotic approximations are numerically compared with some other approximations including the large sample approximation due to Box [Box, G. E. P. (1949). A general distribution theory for a class of likelihood criteria. Biometrika 36:317–346]. It is shown that the approximations proposed in this paper are good when the dimension is large and close to the sample size, and further our approximations are similar to the Boxs approximation even for most of the usual large sample cases.

Investigation on circular asymmetry of geographical distribution in cancer mortality of Hiroshima atomic bomb survivors based on risk maps: analysis of spatial survival data

While there is a considerable number of studies on the relationship between the risk of disease or death and direct exposure from the atomic bomb in Hiroshima, the risk for indirect exposure caused by residual radioactivity has not yet been fully evaluated. One of the reasons is that risk assessments have utilized estimated radiation doses, but that it is difficult to estimate indirect exposure. To evaluate risks for other causes, including indirect radiation exposure, as well as direct exposure, a statistical method is described here that evaluates risk with respect to individual location at the time of atomic bomb exposure instead of radiation dose. In addition, it is also considered to split the risks into separate risks due to direct exposure and other causes using radiation dose. The proposed method is applied to a cohort study of Hiroshima atomic bomb survivors. The resultant contour map suggests that the region west to the hypocenter has a higher risk compared to other areas. This in turn suggests that there exists an impact on risk that cannot be explained by direct exposure.

Workshop report on atomic bomb dosimetry-residual radiation exposure: recent research and suggestions for future studies.

Abstract There is a need for accurate dosimetry for studies of health effects in the Japanese atomic bomb survivors because of the important role that these studies play in worldwide radiation protection standards. International experts have developed dosimetry systems, such as the Dosimetry System 2002 (DS02), which assess the initial radiation exposure to gamma rays and neutrons but only briefly consider the possibility of some minimal contribution to the total body dose by residual radiation exposure. In recognition of the need for an up-to-date review of the topic of residual radiation exposure in Hiroshima and Nagasaki, recently reported studies were reviewed at a technical session at the 57th Annual Meeting of the Health Physics Society in Sacramento, California, 22-26 July 2012. A one-day workshop was also held to provide time for detailed discussion of these newer studies and to evaluate their potential use in clarifying the residual radiation exposures to the atomic-bomb survivors at Hiroshima and Nagasaki. Suggestions for possible future studies are also included in this workshop report.

Estimating Regression Coefficients for Balanced Growth Curve Model When Time Trend of Baseline is Not Specified

SYNOPTIC ABSTRACT This article presents a method for estimating the regression coefficients for a growth curve model when the time trend of the baseline has not been specified. The concept of this method is similar to that of the Cox proportional hazard model. No particular shape is assumed for the baseline time trends, or, alternatively, it can be assumed that they are estimated nonparametrically. Because of these nuisance parameters for the baseline trends, we do not have to pay attention to model those shapes. In addition to the simplicity of modeling baseline curves, we can also nonparametrically describe the baseline trends by using the residuals after the regression coefficients have been estimated.

Detecting a Local Cohort Effect for Cancer Mortality Data Using a Varying Coefficient Model

BACKGROUND Cancer mortality is increasing with the aging of the population in Japan. Cancer information obtained through feasible methods is therefore becoming the basis for planning effective cancer control programs. There are three time-related factors affecting cancer mortality, of which the cohort effect is one. Past descriptive epidemiologic studies suggest that the cohort effect is not negligible in cancer mortality. METHODS In this paper, we develop a statistical method for automatically detecting a cohort effect and assessing its statistical significance for cancer mortality data using a varying coefficient model. RESULTS The proposed method was applied to liver and lung cancer mortality data on Japanese men for illustration. Our method detected significant positive or negative cohort effects. The relative risk was 1.54 for liver cancer mortality in the cohort born around 1934 and 0.83 for lung cancer in the cohort born around 1939. CONCLUSIONS Cohort effects detected using the proposed method agree well with previous descriptive epidemiologic findings. In addition, the proposed method is expected to be sensitive enough to detect smaller, previously undetected birth cohort effects.

Estimating and Visualizing the Time-varying Effects of a Binary Covariate on Longitudinal Big Text Data

We propose a method to estimate and visualize effects of a binary covariate on the longitudinally observed text data. Our method consists of series of analytical methods: extracting keywords through a morphological analysis, estimating the time-varying regression coefficient of a binary covariate for keywords appearance and frequency, classifying summary of estimates, and visualizing the time-varying effects of a binary covariate in animated scatter plots. The procedure is demonstrated with Peace Declaration text data observed for forty years in two cities.

Logistic Regression Model for Survival Time Analysis Using Time-Varying Coefficients

SYNOPTIC ABSTRACT In epidemiological studies, odds ratios are widely used for quantifying the relative risk. The odds ratio can be estimated from background factors, using logistic regression. In this article, a logistic regression model for the survival time, using time-varying coefficients is proposed, and statistical inference is conducted using the Newton–Raphson method and simultaneous confidence intervals. Numerical examples and simulation studies demonstrate that the proposed model can be used to obtain the odds ratio in survival time analysis.