Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

Cigarette smoke promotes dendritic cell accumulation in COPD; a Lung Tissue Research Consortium study

<p>Abstract</p> <p>Background</p> <p>Abnormal immune responses are believed to be highly relevant in the pathogenesis of chronic obstructive pulmonary disease (COPD). Dendritic cells provide a critical checkpoint for immunity by their capacity to both induce and suppress immunity. Although evident that cigarette smoke, the primary cause of COPD, significantly influences dendritic cell functions, little is known about the roles of dendritic cells in the pathogenesis of COPD.</p> <p>Methods</p> <p>The extent of dendritic cell infiltration in COPD tissue specimens was determined using immunohistochemical localization of CD83+ cells (marker of matured myeloid dendritic cells), and CD1a+ cells (Langerhans cells). The extent of tissue infiltration with Langerhans cells was also determined by the relative expression of the CD207 gene in COPD <it>versus </it>control tissues. To determine mechanisms by which dendritic cells accumulate in COPD, complimentary studies were conducted using monocyte-derived human dendritic cells exposed to cigarette smoke extract (CSE), and dendritic cells extracted from mice chronically exposed to cigarette smoke.</p> <p>Results</p> <p>In human COPD lung tissue, we detected a significant increase in the total number of CD83+ cells, and significantly higher amounts of CD207 mRNA when compared with control tissue. Human monocyte-derived dendritic cells exposed to CSE (0.1-2%) exhibited enhanced survival <it>in vitro </it>when compared with control dendritic cells. Murine dendritic cells extracted from mice exposed to cigarette smoke for 4 weeks, also demonstrated enhanced survival compared to dendritic cells extracted from control mice. Acute exposure of human dendritic cells to CSE induced the cellular pro-survival proteins heme-oxygenase-1 (HO-1), and B cell lymphoma leukemia-x(L) (Bcl-xL), predominantly through oxidative stress. Although activated human dendritic cells conditioned with CSE expressed diminished migratory CCR7 expression, their migration towards the CCR7 ligand CCL21 was not impaired.</p> <p>Conclusions</p> <p>These data indicate that COPD is associated with increased numbers of cells bearing markers associated with Langerhans cells and mature dendritic cells, and that cigarette smoke promotes survival signals and augments survival of dendritic cells. Although CSE suppressed dendritic cell CCR7 expression, migration towards a CCR7 ligand was not diminished, suggesting that reduced CCR7-dependent migration is unlikely to be an important mechanism for dendritic cell retention in the lungs of smokers with COPD.</p

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Efficacy of insect larval meal to replace fish meal in juvenile barramundi, Lates calcarifer reared in freshwater

The present experiment was conducted to evaluate the efficacy of dietary protein from black soldier fly, Hermetia illucens, larval meal (BSFL) to replace fish meal (FM) protein in juvenile barramundi, Lates calcarifer. Larvae of black soldier fly were fed with the underutilised crop, sesbania, Sesbania grandiflora. Five isonitrogenous (44% crude protein) and isocaloric (16.0 kJ available energy/g) experimental diets were formulated to replace FM using processed BSFL meal at 0 (control), 25% (BSFL25), 50% (BSFL50), 75% (BSFL75) and 100% (BSFL100). Data for proximate and amino acid analysis suggested BSFL meal as an inferior protein ingredient than FM, but parallel to soybean meal. At the end of 8 weeks of fish feeding trial, there were no significant differences in the average weight gain (WG) and specific growth rate among the group of fish-fed control, BSFL25 and BSFL50 diets (P < 0.05). Although numerical differences were recorded in the fish whole-body proximate composition, crude protein and moisture content were not much affected by the different dietary treatments. Essential amino acids including arginine, histidine, lysine and methionine were found to be higher in the whole body of fish-fed BSFL100 diet. Broken line regression analysis of average WG showed an optimum FM replacement level of 28.4% with BSFL meal. Therefore, the present experiment clearly demonstrates that the maximal dietary inclusion level of BSFL meal as FM protein replacer for the optimum growth of juvenile barramundi reared in freshwater could be greater than 28.4% but less than 50%, without any adverse effects on the fish whole-body proximate and amino acid composition

Anticipated impact of the 2009 Four Corners raid and arrests

Archaeological looting on United States federal land has been illegal for over a century. Regardless, the activity has continued in the Four Corners region. This paper discusses how the 1979 Archaeological Resources Protection Act (ARPA) can be viewed as sumptuary law, and within a sumptuary context, subversion can be anticipated. An analysis of 1986 and June 2009 federal raids in the Four Corners will exemplify this point by identifying local discourses found in newspapers both before and after each raid, which demonstrate a sumptuary effect. Ultimately, this paper concludes that looting just adapted, rather than halted, after each federal raid and that understanding this social context of continued local justification and validation of illegal digging is a potential asset for cultural resource protection

Gastric cancer is associated with NOS2 -954G/C polymorphism and environmental factors in a Brazilian population

<p>Abstract</p> <p>Background</p> <p>Gastric cancer can progress from a chronic inflammation of the gastric mucosa resulting from <it>Helicobacter pylori </it>infection that activates the inflammatory response of the host. Therefore, polymorphisms in genes involved in the inflammatory response, such as inducible nitric oxide synthase (<it>NOS2</it>), have been implicated in gastric carcinogenesis. The aim of this study was to evaluate the association of <it>NOS2 </it>polymorphisms Ser⁶⁰⁸Leu (rs2297518) in exon 16, -954G/C and -1173C/T, both in the promoter region, with gastric cancer and chronic gastritis and the association of cancer with risk factors such as smoking, alcohol intake and <it>H. pylori </it>infection.</p> <p>Methods</p> <p>We conducted a population-based case-control study in 474 Southeast Brazilian individuals (150 with gastric cancer, 160 with chronic gastritis, and 164 healthy individuals), in which we performed <it>NOS2 </it>genotyping by PCR-RFLP.</p> <p>Results</p> <p>SNP Ser⁶⁰⁸Leu was not associated with risk of chronic gastritis or gastric cancer. The polymorphic allele -1173T was not found in the studied population. However, the frequency of -954GC+CC genotypes was significantly higher (p < 0.01) in the cancer group (48.7%) than in both the gastritis (28.1%) and the control (29.9%) groups. Multivariate logistic regression showed that the <it>NOS2 </it>SNP -954G/C was associated with higher risk of gastric cancer (OR = 1.87; 95% CI = 1.12-3.13). We also observed an association with risk factors such as smoking and alcohol intake in both the gastric cancer (OR = 2.68; 95% CI = 1.58-4.53; OR = 3.60; 95% CI = 2.05-6.32, respectively) and the chronic gastritis (OR = 1.93; 95% CI = 1.19-3.13; OR = 2.79; 95% CI = 1.55-5.02, respectively) groups. This is the first report of increased risk of gastric cancer in association with the -954G/C polymorphism. These findings show that several polymorphisms in the promoter region of the <it>NOS2 </it>gene may contribute to the susceptibility to gastric cancer.</p> <p>Conclusions</p> <p>Polymorphism <it>NOS2 </it>-954 G/C, along with alcohol intake and tobacco smoking, is associated with gastric cancer. However, the <it>NOS2 </it>Ser⁶⁰⁸Leu polymorphism was not associated with gastric carcinogenesis. The <it>NOS2 </it>-1173C/T polymorphism was absent in the studied population.</p

Patients with persistent medically unexplained symptoms in general practice: characteristics and quality of care

<p>Abstract</p> <p>Background</p> <p>Medically unexplained physical symptoms (MUPS) are common in general practice (GP), and are even more problematic as they become persistent. The present study examines the relationship between persistent MUPS in general practice on the one hand and quality of life, social conditions, and coping on the other hand. Additionally, it is examined how patients with persistent MUPS evaluate the quality of GP-care.</p> <p>Methods</p> <p>Data were used from a representative survey of morbidity in Dutch general practice, in which data from the electronic medical records were extracted. A random sample of patients participated in an extensive health interview and completed self-reported measures on social isolation, coping and the quality of GP-care. Patients with persistent MUPS (N = 192) were compared with general practice patients not meeting the criteria for persistent MUPS (N = 7.314), and with a group of patients that visited the GP in comparable rates for medical diagnoses (N = 2.265). Multiple logistic regression analyses were used to control for relevant socio-demographic variables and chronic diseases.</p> <p>Results</p> <p>After adjustment for demographics and chronic diseases, patients with persistent MUPS reported more psychological distress, more functional impairment, more social isolation, and they evaluated the quality of GP-care less positive than the other two patient groups. Although the majority of MUPS patients were positive about the quality of GP-care, they more often felt that they were not taken seriously or not involved in treatment decisions, and more often reported that the GP did not take sufficient time. The three groups did not differ with respect to the statement that the GP unnecessarily explains physical problems as psychological ones.</p> <p>Conclusion</p> <p>Strengthening MUPS patients' social network and encouraging social activities may be a meaningful intervention in which the GP may play a stimulating role. To further improve MUPS patients' satisfaction with GP-care, GPs may pay extra attention to taking sufficient time when treating MUPS patients, taking the problems seriously, and involving them in treatment decisions.</p