Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Social sciences research in neglected tropical diseases 2: A bibliographic analysis

The official published version of the article can be found at the link below.Background There are strong arguments for social science and interdisciplinary research in the neglected tropical diseases. These diseases represent a rich and dynamic interplay between vector, host, and pathogen which occurs within social, physical and biological contexts. The overwhelming sense, however, is that neglected tropical diseases research is a biomedical endeavour largely excluding the social sciences. The purpose of this review is to provide a baseline for discussing the quantum and nature of the science that is being conducted, and the extent to which the social sciences are a part of that. Methods A bibliographic analysis was conducted of neglected tropical diseases related research papers published over the past 10 years in biomedical and social sciences. The analysis had textual and bibliometric facets, and focussed on chikungunya, dengue, visceral leishmaniasis, and onchocerciasis. Results There is substantial variation in the number of publications associated with each disease. The proportion of the research that is social science based appears remarkably consistent (<4%). A textual analysis, however, reveals a degree of misclassification by the abstracting service where a surprising proportion of the "social sciences" research was pure clinical research. Much of the social sciences research also tends to be "hand maiden" research focused on the implementation of biomedical solutions. Conclusion There is little evidence that scientists pay any attention to the complex social, cultural, biological, and environmental dynamic involved in human pathogenesis. There is little investigator driven social science and a poor presence of interdisciplinary science. The research needs more sophisticated funders and priority setters who are not beguiled by uncritical biomedical promises

Regularized gene selection in cancer microarray meta-analysis

<p>Abstract</p> <p>Background</p> <p>In cancer studies, it is common that multiple microarray experiments are conducted to measure the same clinical outcome and expressions of the same set of genes. An important goal of such experiments is to identify a subset of genes that can potentially serve as predictive markers for cancer development and progression. Analyses of individual experiments may lead to unreliable gene selection results because of the small sample sizes. Meta analysis can be used to pool multiple experiments, increase statistical power, and achieve more reliable gene selection. The meta analysis of cancer microarray data is challenging because of the high dimensionality of gene expressions and the differences in experimental settings amongst different experiments.</p> <p>Results</p> <p>We propose a Meta Threshold Gradient Descent Regularization (MTGDR) approach for gene selection in the meta analysis of cancer microarray data. The MTGDR has many advantages over existing approaches. It allows different experiments to have different experimental settings. It can account for the joint effects of multiple genes on cancer, and it can select the same set of cancer-associated genes across multiple experiments. Simulation studies and analyses of multiple pancreatic and liver cancer experiments demonstrate the superior performance of the MTGDR.</p> <p>Conclusion</p> <p>The MTGDR provides an effective way of analyzing multiple cancer microarray studies and selecting reliable cancer-associated genes.</p

Integrated use of residues from olive mill and winery for lipase production by solid state fermentation with Aspergillus sp

Two phase olive mill waste (TPOMW) is presently the major waste produced by the olive mill industry. This waste has potential to be used as substrate for solid state fermentation (SSF) despite of its high concentration of phenolic compounds and low nitrogen content. In this work, it is demonstrated that mixtures of TPOMW with winery wastes support the production of lipase by Aspergillus spp. By agar plate screening, Aspergillus niger MUM 03.58, Aspergillus ibericus MUM 03.49 and Aspergillus uvarum MUM 08.01 were chosen for lipase production by SSF. Plackett-Burman experimental design was employed to evaluate the effect of substrate composition and time on lipase production. The highest amounts of lipase were produced by A. ibericus on a mixture of TPOMW, urea and exhausted grape mark (EGM). Urea was found to be the most influent factor for the lipase production. Further optimization of lipase production by A. ibericus using a full factorial design (32) conducted to optimal conditions of substrate composition (0.073 g urea/g and 25% of EGM) achieving 18.67 U/g of lipolytic activity.Jose Manuel Salgado is grateful for Postdoctoral fellowship (EX-2010-0402) of Education Ministry of Spanish Government. Luis Abrunhosa was supported by the grant SFRH/BPD/43922/2008 from Fundacao para a Ciencia e Tecnologia-FCT, Portugal. Authors thank Fundacao para a Ciencia e a Tecnologia (FCT) for financial support through the project FCT Pest-OE/EQB/LA0023/2011

Two-pion Bose-Einstein correlations in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The first measurement of two-pion Bose-Einstein correlations in central Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.Comment: 17 pages, 5 captioned figures, 1 table, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Overweight/Obesity and Respiratory and Allergic Disease in Children: International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two

BackgroundChildhood obesity and asthma are increasing worldwide. A possible link between the two conditions has been postulated.MethodsCross-sectional studies of stratified random samples of 8–12-year-old children (n = 10 652) (16 centres in affluent and 8 centres in non-affluent countries) used the standardized methodology of ISAAC Phase Two. Respiratory and allergic symptoms were ascertained by parental questionnaires. Tests for allergic disease were performed. Height and weight were measured, and overweight and obesity were defined according to international definitions. Prevalence rates and prevalence odds ratios were calculated.ResultsOverweight (odds ratio = 1.14, 95%-confidence interval: 0.98; 1.33) and obesity (odds ratio = 1.67, 95%-confidence interval: 1.25; 2.21) were related to wheeze. The relationship was stronger in affluent than in non-affluent centres. Similar results were found for cough and phlegm, rhinitis and eczema but the associations were mostly driven by children with wheeze. There was a clear association of overweight and obesity with airways obstruction (change in FEV1/FVC, −0.90, 95%-confidence interval: −1.33%; −0.47%, for overweight and −2.46%, 95%-confidence interval: −3.84%; −1.07%, for obesity) whereas the results for the other objective markers, including atopy, were null.ConclusionsOur data from a large international child population confirm that there is a strong relation of body mass index with wheeze especially in affluent countries. Moreover, body mass index is associated with an objective marker of airways obstruction (FEV1/FVC) but no other objective markers of respiratory and allergic disorders

Dendritic Cells Exposed to MVA-Based HIV-1 Vaccine Induce Highly Functional HIV-1-Specific CD8+ T Cell Responses in HIV-1-Infected Individuals

Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α). MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA) and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B

Rationale, design and methodology for Intraventricular Pressure Gradients Study: a novel approach for ventricular filling assessment in normal and falling hearts

<p>Abstract</p> <p>Background</p> <p>Intraventricular pressure gradients have been described between the base and the apex of the left ventricle during early diastolic ventricular filling, as well as, their increase after systolic and diastolic function improvement. Although, systolic gradients have also been observed, data are lacking on their magnitude and modulation during cardiac dysfunction. Furthermore, we know that segmental dysfunction interferes with the normal sequence of regional contraction and might be expected to alter the physiological intraventricular pressure gradients. The study hypothesis is that systolic and diastolic gradients, a marker of normal left ventricular function, may be related to physiological asynchrony between basal and apical myocardial segments and they can be attenuated, lost entirely, or even reversed when ventricular filling/emptying is impaired by regional acute ischemia or severe aortic stenosis.</p> <p>Methods/Design</p> <p><it>Animal Studies: </it>Six rabbits will be completely instrumented to measuring apex to outflow-tract pressure gradient and apical and basal myocardial segments lengthening changes at basal, afterloaded and ischemic conditions. Afterload increase will be performed by abruptly narrowing or occluding the ascending aorta during the diastole and myocardial ischemia will be induced by left coronary artery ligation, after the first diagonal branch.</p> <p><it>Patient Studies: </it>Patients between 65-80 years old (n = 12), both genders, with severe aortic stenosis referred for aortic valve replacement will be selected as eligible subjects. A high-fidelity pressure-volume catheter will be positioned through the ascending aorta across the aortic valve to measure apical and outflow-tract pressure before and after aortic valve replacement with a bioprosthesis. Peak and average intraventricular pressure gradients will be recorded as apical minus outflow-tract pressure and calculated during all diastolic and systolic phases of cardiac cycle.</p> <p>Discussion</p> <p>We expect to validate the application of our method to obtain intraventricular pressure gradients in animals and patients and to promote a methodology to better understand the ventricular relaxation and filling and their correlation with systolic function.</p