Genotype-Dependent Tumor Regression in Marek’s Disease Mediated at the Level of Tumor Immunity

Marek’s disease (MD) of chickens is a unique natural model of Hodgkin’s and Non Hodgkin’s lymphomas in which the neoplastically-transformed cells over-express CD30 (CD30hi) antigen. All chicken genotypes can be infected with MD virus and develop microscopic lymphomas. From 21 days post infection (dpi) microscopic lymphomas regress in resistant chickens but, in contrast, they progress to gross lymphomas in susceptible chickens. Here we test our hypothesis that in resistant chickens at 21 dpi the tissue microenvironment is pro T-helper (Th)-1 and compatible with cytotoxic T lymphocyte (CTL) immunity but in susceptible lines it is pro Th-2 or pro T-regulatory (T-reg) and antagonistic to CTL immunity. We used the B2, non-MHC-associated, MD resistance/susceptibility system (line [L]61/line [L]72) and quantified the levels of key mRNAs that can be used to define Th-1 (IL-2, IL-12, IL-18, IFNγ), Th-2 (IL-4, IL-10) and T-reg (TGFβ, GPR-83, CTLA-4, SMAD-7) lymphocyte phenotypes. We measured gene expression in both whole tissues (represents tissue microenvironment and tumor microenvironment) and in the lymphoma lesions (tumor microenvironment) themselves. Gene ontology-based modeling of our results shows that the dominant phenotype in whole tissue as well as in microscopic lymphoma lesions, is pro T-reg in both L61 and L72 but a minor pro Th-1 and anti Th-2 tissue microenvironment exists in L61 whereas there is an anti Th-1 and pro Th-2 tissue microenvironment in L72. The tumor microenvironment per se is pro T-reg, anti Th-1 and pro Th-2 in both L61 and L72. Together our data suggests that the neoplastic transformation is essentially the same in both L61 and L72 and that resistance/susceptibility is mediated at the level of tumor immunity in the tissues

TGF-β induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid β plaques in Alzheimer's disease

The role of a small transforming growth factor beta (TGF-β)-induced TIAF1 (TGF-β1-induced antiapoptotic factor) in the pathogenesis of Alzheimer's disease (AD) was investigated. TIAF1 physically interacts with mothers against DPP homolog 4 (Smad4), and blocks SMAD-dependent promoter activation when overexpressed. Accordingly, knockdown of TIAF1 by small interfering RNA resulted in spontaneous accumulation of Smad proteins in the nucleus and activation of the promoter governed by the SMAD complex. TGF-β1 and environmental stress (e.g., alterations in pericellular environment) may induce TIAF1 self-aggregation in a type II TGF-β receptor-independent manner in cells, and Smad4 interrupts the aggregation. Aggregated TIAF1 induces apoptosis in a caspase-dependent manner. By filter retardation assay, TIAF1 aggregates were found in the hippocampi of nondemented humans and AD patients. Total TIAF1-positive samples containing amyloid β (Aβ) aggregates are 17 and 48%, respectively, in the nondemented and AD groups, suggesting that TIAF1 aggregation occurs preceding formation of Aβ. To test this hypothesis, in vitro analysis showed that TGF-β-regulated TIAF1 aggregation leads to dephosphorylation of amyloid precursor protein (APP) at Thr668, followed by degradation and generation of APP intracellular domain (AICD), Aβ and amyloid fibrils. Polymerized TIAF1 physically interacts with amyloid fibrils, which would favorably support plaque formation in vivo

Implementation of exon arrays: alternative splicing during T-cell proliferation as determined by whole genome analysis

<p>Abstract</p> <p>Background</p> <p>The contribution of alternative splicing and isoform expression to cellular response is emerging as an area of considerable interest, and the newly developed exon arrays allow for systematic study of these processes. We use this pilot study to report on the feasibility of exon array implementation looking to replace the 3' <it>in vitro </it>transcription expression arrays in our laboratory.</p> <p>One of the most widely studied models of cellular response is T-cell activation from exogenous stimulation. Microarray studies have contributed to our understanding of key pathways activated during T-cell stimulation. We use this system to examine whole genome transcription and alternate exon usage events that are regulated during lymphocyte proliferation in an attempt to evaluate the exon arrays.</p> <p>Results</p> <p>Peripheral blood mononuclear cells form healthy donors were activated using phytohemagglutinin, IL2 and ionomycin and harvested at 5 points over a 7 day period. Flow cytometry measured cell cycle events and the Affymetrix exon array platform was used to identify the gene expression and alternate exon usage changes. Gene expression changes were noted in a total of 2105 transcripts, and alternate exon usage identified in 472 transcript clusters. There was an overlap of 263 transcripts which showed both differential expression and alternate exon usage over time. Gene ontology enrichment analysis showed a broader range of biological changes in biological processes for the differentially expressed genes, which include cell cycle, cell division, cell proliferation, chromosome segregation, cell death, component organization and biogenesis and metabolic process ontologies. The alternate exon usage ontological enrichments are in metabolism and component organization and biogenesis. We focus on alternate exon usage changes in the transcripts of the spliceosome complex. The real-time PCR validation rates were 86% for transcript expression and 71% for alternate exon usage.</p> <p>Conclusions</p> <p>This study illustrates that the Exon array technology has the potential to provide information on both transcript expression and isoform usage, with very little increase in expense.</p

Nutritional, Health, and Technological Functionality of Lupin Flour Addition to Bread and Other Baked Products: Benefits and Challenges

Lupin is an undervalued legume despite its high protein and dietary fiber content and potential health benefits. This review focuses on the nutritional value, health benefits, and technological effects of incorporating lupin flour into wheat-based bread. Results of clinical studies suggest that consuming lupin compared to wheat bread and other baked products reduce chronic disease risk markers; possibly due to increased protein and dietary fiber and bioactive compounds. However, lupin protein allergy has also been recorded. Bread quality has been improved when 10% lupin flour is substituted for refined wheat flour; possibly due to lupin-wheat protein cross-linking assisting bread volume and the high water-binding capacity (WBC) of lupin fiber delaying staling. Above 10% substitution appears to reduce bread quality due to lupin proteins low elasticity and the high WBC of its dietary fiber interrupting gluten network development. Gaps in understanding of the role of lupin flour in bread quality include the optimal formulation and processing conditions to maximize lupin incorporation, role of protein cross-linking, antistaling functionality, and bioactivity of its γ-conglutin protein

Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation

Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3' untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T(reg) cell functionality.Marc Beyer... Timothy Sadlon...Simon C Barry... et al

Poverty and Health: The Living Standard Approach as a Supplementary Concept to Measure Relative Poverty. Results from the German Socio-Economic Panel (GSOEP 2011)

Background: A common indicator of the measurement of relative poverty is the disposable income of a household. Current research introduces the living standard approach as an alternative concept for describing and measuring relative poverty. This study compares both approaches with regard to subjective health status of the German population, and provides theoretical implications for the utilisation of the income and living standard approach in health research. Methods: Analyses are based on the German Socio-Economic Panel (GSOEP) from the year 2011 that includes 12 290 private households and 21106 survey members. Self-rated health was based on a subjective assessment of general health status. Income poverty is based on the equalised disposable income and is applied to a threshold of 60 % of the median-based average income. A person will be denoted as deprived (inadequate living standard) if 3 or more out of 11 living standard items are lacking due to financial reasons. To calculate the discriminate power of both poverty indicators, descriptive analyses and stepwise logistic regression models were applied separately for men and women adjusted for age, residence, nationality, educational level, occupational status and marital status. Results: The results of the stepwise regression revealed a stronger poverty-health relationship for the living standard indicator. After adjusting for all control variables and the respective poverty indicator, income poverty was statistically not significantly associated with a poor subjective health status among men (OR Men: 1.33; 95 % CI: 1.00-1.77) and women (OR Women: 0.98; 95 % CI: 0.78-1.22). In contrast, the association between deprivation and subjective health status was statistically significant for men (OR Men: 2.00; 95 % CI: 1.57-2.52) and women (OR Women: 2.11; 95 % CI: 1.76-2.64). Conclusions: The results of the present study indicate that the income and standard of living approach measure different dimensions of poverty. In comparison to the income approach, the living standard approach measures stronger shortages of wealth and is relatively robust towards gender differences. This study expands the current debate about complementary research on the association between poverty and health

Poverty, public transfers and health: An analysis on self-rated health of social benefit recipients in Germany.

Background: Prevention and reduction of poverty are key elements of social welfare policy in Germany. This study is the first analysis of self-rated health of individuals that escape poverty by benefiting form public transfers. Methods: Analyses are based on the German Socio-economic Panel (GSOEP) of 2010. Self-rated health was based on subjective assessment of general health status. Subjects were directly asked about receipt of public transfers. Income poverty was based on the equalized disposable income and is applied to a threshold of 60 % of the median-based average income. We analyzed the association between self-rated health and pre- and post-transfer poverty by means of descriptive analyses and binary logistic regression. Results: After adjusting for age, we found a significantly higher risk of poor self-rated health among those who escaped income poverty due to the receipt of social transfers compared to others (ORWomen: 1.85; 95 %-CI: 1.27-2.69; ORMen: 2.57; 95 %-CI: 1.63-4.05), in particular to those at risk of post-transfer poverty. These poverty-related inequalities in health were predominantly explained by nationality, occupational status, household type and long-term care within the household. Conclusion: This study provides first evidence that the receipt of public transfers is associated with increased risk of poor health in the light of impending income-poverty. This study adds to the current debate about the social and health implications of public transfers in the relationship between poverty and health

Contribution of Health Care Research to Establishing Social Equality in Health and Health Care Opportunities

Social inequalities in health and health care services represent issues of major concern. Findings in this area reveal inequalities in health and health care indicating disadvantages for individuals with a low socioeconomic background. Although the health care system plays a marginal role in the explanation of inequalities in health, health services research can be an important part in the development of equal health opportunities. The current article describes the causal associations between social inequalities, health inequalities and the health care service. Health services research can make a contribution to increasing equal opportunities in health and health care service. Against this background, we discuss the existing potential and need of research in the area of health services

Health inequalities in old age: the relative contribution of material, behavioral and psychosocial factors in a German sample

Background Whereas the association between education and health in later life is well described, investigations about the underlying mechanisms of these health inequalities are scarce. This study examines the relative contribution of material, behavioral and psychosocial factors to health inequalities in older Germans. Methods Data were drawn from the fifth wave of the Survey of Health, Ageing and Retirement in Europe (SHARE). The analytic sample included 3246 participants aged 60-85 years. We examined the independent and indirect contribution of material, behavioral and psychosocial factors to the association between education and self-rated health based on logistic regression models. Results Material factors were most important as they were additionally working through behavioral and psychosocial factors whereas the independent contribution of behavioral and psychosocial factors was much lower than suggested in the separate analyses of the three explanatory pathways. Conclusions Policy interventions that focus on the improvement of material living conditions might reduce health inequalities in old age. In studies on the underlying mechanisms of health inequalities, material, behavioral and psychosocial factors should be modeled as inter-related predictors as the separate analysis does not reveal their actual contribution so that the relevance of single explanatory pathways might be overestimated