An ex vivo readout for evaluation of dendritic cell-induced autologous cytotoxic T lymphocyte responses against esophageal cancer

Esophageal cancer is a highly malignant disease that despite surgery and adjuvant therapies has an extremely poor outcome. Dendritic cell (DC) immunotherapy as a novel promising strategy could be an alternative for treating this malignancy. Effective DC-mediated immune responses can be achieved by raising cytotoxic T lymphocyte (CTL) response against multiple antigens through loading DCs with total tumor RNA. However, the efficacy of this strategy first needs to be evaluated in a pre-clinical setting. The aim of the study was to set up an ex vivo autologous human readout assay for assessing the effects of DC-mediated cytotoxic responses, using total tumor RNA as an antigen load. Biopsy specimens of seven esophageal cancer patients were used to establish primary cultures of normal and cancer cells and to obtain autologous RNA for loading DCs. Mature DCs loaded with either normal or tumor RNA were obtained and subsequently used to raise various lymphocytes populations. Apoptosis levels of the autologous cultures were measured before and after incubating the cultures with the different lymphocytes populations. The mean apoptosis levels in the tumor cell cultures, induced by lymphocytes instructed by DCs loaded with tumor RNA, significantly increased with 15.6% ±2.9 SEM (range 3.4–24.5%, t-test, P < 0.05). Incubation of the normal cultures with the lymphocytes populations showed a mean non-significant increase in apoptosis of 0.4% ±3.4 SEM (range −13.9 to 9.8%, t-test, P = 0.7). Here, we introduce a practical, patient-specific autologous readout assay for pre-clinical testing of DC-mediated cytotoxic responses. Additionally, we demonstrated that the use of autologous tumor RNA as a strategy for raising cytotoxic responses against multiple tumor antigens could be effective for treating esophageal cancer. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A religious upbringing reduces the influence of genetic factors on disinhibition: evidence for interaction between genotype and environment on personality.

Information on personality, on anxiety and depression and on several aspects of religion was collected in 1974 Dutch families consisting of adolescent and young adult twins and their parents. Analyses of these data showed that differences between individuals in religious upbringing, in religious affiliation and in participation in church activities are not influenced by genetic factors. The familial resemblance for different aspects of religion is high, but can be explained entirely by environmental influences common to family members. Shared genes do not contribute to familial resemblances in religion. The absence of genetic influences on variation in several dimensions of religion is in contrast to findings of genetic influences on a large number of other traits that were studied in these twin families. Differences in religious background are associated with differences in personality, especially in Sensation Seeking. Subjects with a religious upbringing, who are currently religious and who engage in church activities score lower on the scales of the Sensation Seeking Questionnaire. The most pronounced effect is on the Disinhibition scale. The resemblances between twins for the Disinhibition scale differ according to their religious upbringing. Receiving a religious upbringing seems to reduce the influence of genetic factors on Disinhibition, especially in males.     

Potential bias regarding birth weight in historical and contemporary twin data bases.

In this study we examine the hypothesis that monozygotic (MZ) twins in historical databases are less discordant for birth weight due to negative selection of severely discordant MZ twins. Furthermore, we test the hypothesis that MZ twins are less discordant for birth weight when comparing a volunteer based twin registry with a population based twin registry, due to selective registration. Data were available on 3927 twin pairs from the volunteer Australian Twin Registry born before 1964, 3059 volunteer twin pairs from the Netherlands Twin Register born 1987-1989 and 454 Belgian twin pairs from The East Flanders Prospective Twin Survey born 1987-1989. Intrapair relative birth weight differences (RBWD) were computed for MZ and dizygotic (DZ) twins from each twin registry. Comparing birth weight differences between MZ and DZ twins provides support for the hypothesis that MZ twins are subject to a negative selection in historical databases. Furthermore, Australian MZ twins have a lower RBWD compared to Dutch MZ twins when corrected for the RBWD of Australian and Dutch DZ twins, indicating circumstances which only affect MZ twins. Our hypothesis that MZ twins are less discordant for birth weight in a volunteer based twin registry compared to a population based twin registry had to be rejected. We suggest that investigators using historical databases to test the fetal origins hypothesis should be aware of this increased likelihood of selective exclusion of individuals with extreme morphometric parameters at time of birth.     

Genetic and environmental influences on self-reported and parent-reported behavior problems in young adult adoptees

The aim of the present study was to estimate the genetic, shared and nonshared environmental contributions to self-reported and parent-reported internalizing and externalizing problems in a follow-up study of intercountry adopted young adults. Young Adult Self-Report ratings were obtained from 1475 adoptees aged 22–32 years and Young Adult Behavior Checklist ratings from 1115 adoptive parents. For the genetic analyses, a subset of 143 adopted biologically related and 295 unrelated siblings was used. The data were subjected to model fitting decomposing three sources of variance: genetic factors (A) shared environment (C) and nonshared environment (E). Genetic factors were of more importance in both self-reported ( A ²= 54%, C ²= 0, and E ²= 46%) and parent-reported ( A ²= 76%, C ²= 15% and E ²= 9%) internalizing problems. Environmental factors were of more importance in both self-reported ( A ²= 33%, C ²= 17% and E ²= 50%) and parent-reported ( A ²= 28%, C ²= 27% and E ²= 45%) externalizing problems. This was in contrast with findings from the first and second assessments in the same sample during adolescence when genetic factors were more important in explaining externalizing problems compared with internalizing problems. Our results suggest a developmental reversal in genetic and environmental influences on behavior problems from early adolescence into adulthood, which could be related to different underlying developmental trajectories.     

Lifetime medical costs of obesity: prevention no cure for increasing health expenditure

Background

Obesity is a major cause of morbidity and mortality and is associated with high medical expenditures. It has been suggested that obesity prevention could result in cost savings. The objective of this study was to estimate the annual and lifetime medical costs attributable to obesity, to compare those to similar costs attributable to smoking, and to discuss the implications for prevention.

Methods and Findings

With a simulation model, lifetime health-care costs were estimated for a cohort of obese people aged 20 y at baseline. To assess the impact of obesity, comparisons were made with similar cohorts of smokers and “healthy-living” persons (defined as nonsmokers with a body mass index between 18.5 and 25). Except for relative risk values, all input parameters of the simulation model were based on data from The Netherlands. In sensitivity analyses the effects of epidemiologic parameters and cost definitions were assessed. Until age 56 y, annual health expenditure was highest for obese people. At older ages, smokers incurred higher costs. Because of differences in life expectancy, however, lifetime health expenditure was highest among healthy-living people and lowest for smokers. Obese individuals held an intermediate position. Alternative values of epidemiologic parameters and cost definitions did not alter these conclusions.

Conclusions

Although effective obesity prevention leads to a decrease in costs of obesity-related diseases, this decrease is offset by cost increases due to diseases unrelated to obesity in life-years gained. Obesity prevention may be an important and cost-effective way of improving public health, but it is not a cure for increasing health expenditures.     

Netherlands Twin Register: a focus on longitudinal research.

In 1986 we began The Netherlands Twin Register (NTR) by recruiting young twins and multiples a few weeks or months after birth. Currently we register around 50% of all newborn multiples in The Netherlands. Their parents receive a questionnaire at registration and afterwards when the children are 2, 3, 5, 7, 10 and 12 years of age. Teachers are asked to rate the behavior of the children at ages 7, 10 and 12 years. Adolescent and young-adult twins were recruited through City Councils in the early 1990s. These twins, their parents and siblings participate in longitudinal survey studies that include items about health, fertility, lifestyle, addiction, personality and psychopathology, religion, socioeconomic status, and educational attainment. The total number of twins and multiples registered with the NTR is currently over 60,000. Subgroups of twins and siblings take part in studies of cognitive development, brain function and neuropsychological indices of attention processes, and molecular genetic studies of classical and behavioral cardiovascular risk factors. DNA samples are currently collected in selected twin families for two large linkage studies, which aim to find QTLs for anxious depression and for nicotine addiction. Sisters who are mothers of DZ twins contribute DNA samples for a linkage study of DZ twinning. Large cohorts of phenotyped family members from the general population are very valuable for genetic epidemiological studies and permit selection of informative families for gene finding studies.     

CoPub Mapper: mining MEDLINE based on search term co-publication

Background  

High throughput microarray analyses result in many differentially expressed genes that are potentially responsible for the biological process of interest. In order to identify biological similarities between genes, publications from MEDLINE were identified in which pairs of gene names and combinations of gene name with specific keywords were co-mentioned.     

Large gryphaeid oysters as habitats for numerous sclerobionts: a case study from the northern Red Sea

The shell of a living specimen of the Indo-Pacific gryphaeid giant oyster Hyotissa hyotis was colonized by numerous encrusting, boring, nestling and baffling taxa which show characteristic distribution patterns. On the upper valve, sponge-induced bioerosion predominates. On the lower valve intergrowth of chamid bivalves and thick encrusting associations—consisting mostly of squamariacean and corallinacean red algae, acervulinid foraminifera, and scleractinian corals—provides numerous microhabitats for nestling arcid and mytilid bivalves as well as for encrusting bryozoans and serpulids. Such differences between exposed and cryptic surfaces are typical for many marine hard substrata and result from the long-term stable position of the oyster on the seafloor. The cryptic habitats support a species assemblage of crustose algae and foraminifera that, on exposed surfaces, would occur in much deeper water.