Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments

Platform for Plasmodium vivax vaccine discovery and development

Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80-100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development

Ambulatory blood pressure monitoring in elderly patients with chronic atrial fibrillation: is it absolutely contraindicated or a useful tool in clinical practice and research?

The aim of this study was to test whether ambulatory blood pressure monitoring (ABPM) in elderly patients with atrial fibrillation (AF) is as feasible and reliable as ABPM is in patients with normal sinus rhythm (SR). Studies of ABPM in the elderly remain limited, and the use of this method in patients with AF remains controversial. The Italian SIIA 2008 guidelines consider ABPM 'absolutely contraindicated' for AF patients. This study was conducted on 200 hospitalized patients aged 65 65 years (68% females; mean age 82.4 \ub1 6.3 years): 100 patients with SR and 100 patients with permanent AF. Each patient completed serial blood pressure (BP) measurements with a clinical sphygmomanometer (Sphyg) and ABPM. Differences in mean heart rate (HR) between patient groups were not statistically significant. A total of 99.5% of patients were hypertensive. There were no significant differences between SR and AF patients in mean systolic BP (SBP) and diastolic BP (DBP) values, as measured with the Sphyg or by ABPM. Compared with the Sphyg, errors associated with BP measurements obtained by ABPM did not significantly differ between the two groups. ABPM proved to be as feasible as Sphyg measurements in both AF patients (intraclass correlation coefficients=0.73, 0.67 and 0.74 for SBP, DBP and HR, respectively) and SR patients (intraclass correlation coefficients=0.74, 0.58 and 0.67 for SBP, DBP and HR, respectively). A Bland-Altman plot analysis confirmed that there was good agreement between the two methods. Stable AF (HR 60-100 b.p.m.) should not be considered as an absolute contraindication for the use of ABPM, even in the elderly; it could be a 'relative' contraindication for very unstable AF patient

CSP-A Model for In Vivo Presentation of Plasmodium berghei Sporozoite Antigens by Hepatocytes.

One target of protective immunity against the Plasmodium liver stage in BALB/c mice is represented by the circumsporozoite protein (CSP), and mainly involves its recognition by IFN-γ producing specific CD8+T-cells. In a previous in vitro study we showed that primary hepatocytes from BALB/c mice process Plasmodium berghei (Pb) CSP (PbCSP) and present CSP-derived peptides to specific H-2k(d) restricted CD8+T-cells with subsequent killing of the presenting cells. We now extend these observations to an in vivo infection model in which infected hepatocytes and antigen specific T-cell clones are transferred into recipient mice inducing protection from sporozoite (SPZ) challenge. In addition, using a similar protocol, we suggest the capacity of hepatocytes in priming of naïve T-cells to provide protection, as further confirmed by induction of protection after depletion of cross-presenting dendritic cells (DCs) by cytochrome c (cyt c) treatment or using traversal deficient parasites. Our results clearly show that hepatocytes present Plasmodium CSP to specific-primed CD8+T-cells, and could also prime naïve T-cells, leading to protection from infection. These results could contribute to a better understanding of liver stage immune response and design of malaria vaccines

Ambulatory blood pressure monitoring in elderly patients with chronic atrial fibrillation: is it absolutely contraindicated or a useful tool in clinical practice and research?

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The European vaseline series in 10 European Countries, 2005/2006 – Results of the European Surveillance System on contact Allergies (ESSCA). Contct Dermatitis 61:31-38, 2009

BACKGROUND: Continual surveillance based on patch test results has proved useful for the identification of contact allergy. OBJECTIVES: To provide a current view on the spectrum of contact allergy to important sensitizers across Europe. PATIENTS/METHODS: Clinical and patch test data of 19 793 patients patch tested in 2005/2006 in the 31 participating departments from 10 European countries (the European Surveillance System on Contact Allergies' (ESSCA) www.essca-dc.org) were descriptively analysed, aggregated to four European regions. RESULTS: Nickel sulfate remains the most common allergen with standardized prevalences ranging from 19.7% (central Europe) to 24.4% (southern Europe). While a number of allergens shows limited variation across the four regions, such as Myroxylon pereirae (5.3-6.8%), cobalt chloride (6.2-8.8%) or thiuram mix (1.7-2.4%), the differences observed with other allergens may hint on underlying differences in exposures, for example: dichromate 2.4% in the UK (west) versus 4.5-5.9% in the remaining EU regions, methylchloroisothiazolinone/methylisothiazolinone 4.1% in the South versus 2.1-2.7% in the remaining regions. CONCLUSIONS: Notwithstanding residual methodological variation (affecting at least some 'difficult' allergens) tackled by ongoing efforts for standardization, a comparative analysis as presented provides (i) a broad overview on contact allergy frequencies and (ii) interesting starting points for further, in-depth investigation

Cross-talk between CD8(+) and CD4(+) T cells in experimental cutaneous leishmaniasis: CD8(+) T cells are required for optimal IFN-gamma production by CD4(+) T cells.

Although the importance of CD8(+) T cells for vaccination and immunity to reinfection with Leishmania parasites is well established, their role in primary infections is disputed. In the present study we further characterized the role of CD8(+) T cells in primary L. major infections. We used two groups of L. major infected BALB/c mice: both groups were immunomanipulated to heal and in one group CD8(+) T cells were depleted throughout the course of infection. Our results show that the reversal of healing caused by the absence of CD8(+) T cells did not alter the proliferation of CD4(+) T cells, however, the frequency of CD4(+) T cells expressing IFN-gamma as well as the levels of this cytokine were clearly reduced. These lower levels of IFN-gamma correlated with a higher parasite load. Our results show that transient depletion of CD4(+) T cells allows the establishment of an equilibrium between CD4(+) and CD8(+) T cells and allows CD8(+) T cell activation and effector functions to develop. In addition, our results suggest that cross-talk between CD4(+) and CD8(+) T cells is crucial for the host defence against L. major