The Spectrum of Epstein-Barr Virus-Associated Lymphoproliferative Disease in Korea: Incidence of Disease Entities by Age Groups

This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma

Influence of the meridional shifts of the Kuroshio and the Oyashio Extensions on the atmospheric circulation

Author Posting. © American Meteorological Society, 2011. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 24 (2011): 762-777, doi:10.1175/2010JCLI3731.1.The meridional shifts of the Oyashio Extension (OE) and of the Kuroshio Extension (KE), as derived from high-resolution monthly sea surface temperature (SST) anomalies in 1982–2008 and historical temperature profiles in 1979–2007, respectively, are shown based on lagged regression analysis to significantly influence the large-scale atmospheric circulation. The signals are independent from the ENSO teleconnections, which were removed by seasonally varying, asymmetric regression onto the first three principal components of the tropical Pacific SST anomalies. The response to the meridional shifts of the OE front is equivalent barotropic and broadly resembles the North Pacific Oscillation/western Pacific pattern in a positive phase for a northward frontal displacement. The response may reach 35 m at 250 hPa for a typical OE shift, a strong sensitivity since the associated SST anomaly is 0.5 K. However, the amplitude, but not the pattern or statistical significance, strongly depends on the lag and an assumed 2-month atmospheric response time. The response is stronger during fall and winter and when the front is displaced southward. The response to the northward KE shifts primarily consists of a high centered in the northwestern North Pacific and hemispheric teleconnections. The response is also equivalent barotropic, except near Kamchatka, where it tilts slightly westward with height. The typical amplitude is half as large as that associated with OE shifts.This work was supported in part by the L’Institut universitaire de France (CF), the WHOI Heyman fellowship, and the NASAGrant withAwardNNX09AF35G(Y.-O. K), and grants through NOAA’s Climate Variability and Predictability Program (MAA)

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages

PPARγ plays a key role in adipocyte biology, and Rosiglitazone (Rosi), a thiazolidinedione (TZD)/PPARγ agonist, is a potent insulin-sensitizing agent. Recent evidences demonstrate that adipose tissue inflammation links obesity with insulin resistance and that the insulin-sensitizing effects of TZDs result, in part, from their anti-inflammatory properties. However the underlying mechanisms are unclear.In this study, we establish a link between free fatty acids (FFAs) and PPARγ in the context of obesity-associated inflammation. We show that treatment of adipocytes with FFAs, in particular Arachidonic Acid (ARA), downregulates PPARγ protein and mRNA levels. Furthermore, we demonstrate that the downregulation of PPARγ by ARA requires the activation the of Endoplamsic Reticulum (ER) stress by the TLR4 pathway. Knockdown of adipocyte PPARγ resulted in upregulation of MCP1 gene expression and secretion, leading to enhanced macrophage chemotaxis. Rosi inhibited these effects. In a high fat feeding mouse model, we show that Rosi treatment decreases recruitment of proinflammatory macrophages to epididymal fat. This correlates with decreased chemokine and decreased chemokine receptor expression in adipocytes and macrophages, respectively.In summary, we describe a novel link between FAs, the TLR4/ER stress pathway and PPARγ, and adipocyte-driven recruitment of macrophages. We thus both describe an additional potential mechanism for the anti-inflammatory and insulin-sensitizing actions of TZDs and an additional detrimental property associated with the activation of the TLR4 pathway by FA

Alteration of Proteins and Pigments Influence the Function of Photosystem I under Iron Deficiency from Chlamydomonas reinhardtii

BACKGROUND: Iron is an essential micronutrient for all organisms because it is a component of enzyme cofactors that catalyze redox reactions in fundamental metabolic processes. Even though iron is abundant on earth, it is often present in the insoluble ferric [Fe (III)] state, leaving many surface environments Fe-limited. The haploid green alga Chlamydomonas reinhardtii is used as a model organism for studying eukaryotic photosynthesis. This study explores structural and functional changes in PSI-LHCI supercomplexes under Fe deficiency as the eukaryotic photosynthetic apparatus adapts to Fe deficiency. RESULTS: 77K emission spectra and sucrose density gradient data show that PSI and LHCI subunits are affected under iron deficiency conditions. The visible circular dichroism (CD) spectra associated with strongly-coupled chlorophyll dimers increases in intensity. The change in CD signals of pigments originates from the modification of interactions between pigment molecules. Evidence from sucrose gradients and non-denaturing (green) gels indicates that PSI-LHCI levels were reduced after cells were grown for 72 h in Fe-deficient medium. Ultrafast fluorescence spectroscopy suggests that red-shifted pigments in the PSI-LHCI antenna were lost during Fe stress. Further, denaturing gel electrophoresis and immunoblot analysis reveals that levels of the PSI subunits PsaC and PsaD decreased, while PsaE was completely absent after Fe stress. The light harvesting complexes were also susceptible to iron deficiency, with Lhca1 and Lhca9 showing the most dramatic decreases. These changes in the number and composition of PSI-LHCI supercomplexes may be caused by reactive oxygen species, which increase under Fe deficiency conditions. CONCLUSIONS: Fe deficiency induces rapid reduction of the levels of photosynthetic pigments due to a decrease in chlorophyll synthesis. Chlorophyll is important not only as a light-harvesting pigment, but also has a structural role, particularly in the pigment-rich LHCI subunits. The reduced level of chlorophyll molecules inhibits the formation of large PSI-LHCI supercomplexes, further decreasing the photosynthetic efficiency

Bridging health technology assessment (HTA) with multicriteria decision analyses (MCDA): field testing of the EVIDEM framework for coverage decisions by a public payer in Canada

<p>Abstract</p> <p>Background</p> <p>Consistent healthcare decisionmaking requires systematic consideration of decision criteria and evidence available to inform them. This can be tackled by combining multicriteria decision analysis (MCDA) and Health Technology Assessment (HTA). The objective of this study was to field-test a decision support framework (EVIDEM), explore its utility to a drug advisory committee and test its reliability over time.</p> <p>Methods</p> <p>Tramadol for chronic non-cancer pain was selected by the health plan as a case study relevant to their context. Based on extensive literature review, a by-criterion HTA report was developed to provide synthesized evidence for each criterion of the framework (14 criteria for the MCDA Core Model and 6 qualitative criteria for the Contextual Tool). During workshop sessions, committee members tested the framework in three steps by assigning: 1) weights to each criterion of the MCDA Core Model representing individual perspective; 2) scores for tramadol for each criterion of the MCDA Core Model using synthesized data; and 3) qualitative impacts of criteria of the Contextual Tool on the appraisal. Utility and reliability of the approach were explored through discussion, survey and test-retest. Agreement between test and retest data was analyzed by calculating intra-rater correlation coefficients (ICCs) for weights, scores and MCDA value estimates.</p> <p>Results</p> <p>The framework was found useful by the drug advisory committee in supporting systematic consideration of a broad range of criteria to promote a consistent approach to appraising healthcare interventions. Directly integrated in the framework as a "by-criterion" HTA report, synthesized evidence for each criterion facilitated its consideration, although this was sometimes limited by lack of relevant data. Test-retest analysis showed fair to good consistency of weights, scores and MCDA value estimates at the individual level (ICC ranging from 0.676 to 0.698), thus lending some support for the reliability of the approach. Overall, committee members endorsed the inclusion of most framework criteria and revealed important areas of discussion, clarification and adaptation of the framework to the needs of the committee.</p> <p>Conclusions</p> <p>By promoting systematic consideration of all decision criteria and the underlying evidence, the framework allows a consistent approach to appraising healthcare interventions. Further testing and validation are needed to advance MCDA approaches in healthcare decisionmaking.</p

Analysis of single nucleotide polymorphisms in the FAS and CTLA-4 genes of peripheral T-cell lymphomas

Angioimmunoblastic T-cell lymphoma (AILT) represents a subset of T-cell lymphomas but resembles an autoimmune disease in many of its clinical aspects. Despite the phenotype of effector T-cells and high expression of FAS and CTLA-4 receptor molecules, tumor cells fail to undergo apoptosis. We investigated single nucleotide polymorphisms (SNPs) of the FAS and CTLA-4 genes in 94 peripheral T-cell lymphomas. Although allelic frequencies of some FAS SNPs were enriched in AILT cases, none of these occurred at a different frequency compared to healthy individuals. Therefore, SNPs in these genes are not associated with the apoptotic defect and autoimmune phenomena in AILT

Cell signalling by reactive lipid species: new concepts and molecular mechanisms

The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway

Community Violence and Youth: Affect, Behavior, Substance Use, and Academics

Community violence is recognized as a major public health problem (WHO, World Report on Violence and Health,2002) that Americans increasingly understand has adverse implications beyond inner-cities. However, the majority of research on chronic community violence exposure focuses on ethnic minority, impoverished, and/or crime-ridden communities while treatment and prevention focuses on the perpetrators of the violence, not on the youth who are its direct or indirect victims. School-based treatment and preventive interventions are needed for children at elevated risk for exposure to community violence. In preparation, a longitudinal, community epidemiological study, The Multiple Opportunities to Reach Excellence (MORE) Project, is being fielded to address some of the methodological weaknesses presented in previous studies. This study was designed to better understand the impact of children’s chronic exposure to community violence on their emotional, behavioral, substance use, and academic functioning with an overarching goal to identify malleable risk and protective factors which can be targeted in preventive and intervention programs. This paper describes the MORE Project, its conceptual underpinnings, goals, and methodology, as well as implications for treatment and preventive interventions and future research