Expression of tumour-specific antigens underlies cancer immunoediting

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack1, 2. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced2, 3. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours4. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.National Institutes of Health (U.S.) (Grant 1 U54 CA126515-01)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship AwardJohnD. Proctor FoundationDaniel K. Ludwig Schola

Viewing Loved Faces Inhibits Defense Reactions: A Health-Promotion Mechanism?

We have known for decades that social support is associated with positive health outcomes. And yet, the neurophysiological mechanisms underlying this association remain poorly understood. The link between social support and positive health outcomes is likely to depend on the neurophysiological regulatory mechanisms underlying reward and defensive reactions. The present study examines the hypothesis that emotional social support (love) provides safety cues that activate the appetitive reward system and simultaneously inhibit defense reactions. Using the startle probe paradigm, 54 undergraduate students (24 men) viewed black and white photographs of loved (romantic partner, father, mother, and best friend), neutral (unknown), and unpleasant (mutilated) faces. Eye–blink startle, zygomatic major activity, heart rate, and skin conductance responses to the faces, together with subjective ratings of valence, arousal, and dominance, were obtained. Viewing loved faces induced a marked inhibition of the eye-blink startle response accompanied by a pattern of zygomatic, heart rate, skin conductance, and subjective changes indicative of an intense positive emotional response. Effects were similar for men and women, but the startle inhibition and the zygomatic response were larger in female participants. A comparison between the faces of the romantic partner and the parent who shares the partner’s gender further suggests that this effect is not attributable to familiarity or arousal. We conclude that this inhibitory capacity may contribute to the health benefits associated with social support.This research was funded by grant P07-SEJ-02964 from Junta de Andalucía (Spain)

Optimality conditions in convex multiobjective SIP

The purpose of this paper is to characterize the weak efficient solutions, the efficient solutions, and the isolated efficient solutions of a given vector optimization problem with finitely many convex objective functions and infinitely many convex constraints. To do this, we introduce new and already known data qualifications (conditions involving the constraints and/or the objectives) in order to get optimality conditions which are expressed in terms of either Karusk–Kuhn–Tucker multipliers or a new gap function associated with the given problem.This research was partially cosponsored by the Ministry of Economy and Competitiveness (MINECO) of Spain, and by the European Regional Development Fund (ERDF) of the European Commission, Project MTM2014-59179-C2-1-P

Paving (through) Amazonia: Neoliberal Urbanism and the Reperipheralization of Roraima

This paper examines the neoliberal reshaping of infrastructure provision in Brazil's extreme north since the mid-1990s, when roadway investments resulted in unprecedented regional connectivity. The BR-174 upgrade, the era's most important project, marked a transition from resource-based developmentalism to free-market transnationalism. Primarily concerned with urban competitiveness, the federal government funded the trunk roadway's paving to facilitate manufacturing exports from Manaus. While an effort was made to minimize deforestation, planners sidelined development implications in adjacent Roraima. The state's urban system has thus experienced reperipheralization and intensified primacy. Market-led growth now compounds the inheritance of hierarchical centralism and ongoing governmental neglect. Our study shows a vast territory dependent on primate cities for basic goods and services. Travelling with Roraimans from bypassed towns, we detected long-distance passenger transportation and surface logistics with selective routes. Heterogeneous Roraiman (im)mobilities comprise middle-class tourism and heightened consumerism as well as informal mobility tactics and transnational circulations of precarious labor. The paper exhorts neoliberal urbanism research to look beyond both Euro America's metropoles and their Global South counterparts. Urbanization dynamics in Brazil's extreme north demonstrate that market-disciplined investments to globalize cities produce far-reaching spatial effects. These are felt even by functionally-articulated-yet-marginalized peripheries in ostensibly remote locations

Gliclazide may have an antiapoptotic effect related to its antioxidant properties in human normal and cancer cells

Experimental and clinical studies suggest that gliclazide may protect pancreatic β-cells from apoptosis induced by an oxidative stress. However, the precise mechanism(s) of this action are not fully understood and requires further clarification. Therefore, using human normal and cancer cells we examined whether the anti-apoptotic effects of this sulfonylurea is due to its free radical scavenger properties. Hydrogen peroxide (H2O2) as a model trigger of oxidative stress was used to induce cell death. Our experiments were performed on human normal cell line (human umbilical vein endothelial cell line, HUVEC-c) and human cancer cell lines (human mammary gland cell line, Hs578T; human pancreatic duct epithelioid carcinoma cell line, PANC-1). To assess the effect of gliclazide the cells were pre-treated with the drug. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was employed to measure the impact of gliclazide on cell viability. Generation of reactive oxygen species, mitochondrial membrane potential (∆Ψm), and intracellular Ca2+ concentration [Ca2+] were monitored. Furthermore, the morphological changes associated with apoptosis were determined using double staining with Hoechst 33258-propidium iodide (PI). Gliclazide protects the tested cells from H2O2-induced cell death most likely throughout the inhibition of ROS production. Moreover, the drug restored loss of ΔΨm and diminished intracellular [Ca2+] evoked by H2O2. Double staining with Hoechst 33258-PI revealed that pre-treatment with gliclazide diminished the number of apoptotic cells. Our findings indicate that gliclazide may protect both normal and cancer human cells against apoptosis induced by H2O2. It appears that the anti-apoptotic effect of the drug is most likely associated with reduction of oxidative stress

The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells

The chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR) as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNα treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner, inducing phosphorylation of the protein synthesis translation initiation factor eIF-2α and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNα combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug

Gene Expression Profiles of Beta-Cell Enriched Tissue Obtained by Laser Capture Microdissection from Subjects with Type 2 Diabetes

Background: Changes in gene expression in pancreatic beta-cells from type 2 diabetes (T2D) should provide insights into their abnormal insulin secretion and turnover. Methodology/Principal Findings: Frozen sections were obtained from cadaver pancreases of 10 control and 10 T2D human subjects. Beta-cell enriched samples were obtained by laser capture microdissection (LCM). RNA was extracted, amplified and subjected to microarray analysis. Further analysis was performed with DNA-Chip Analyzer (dChip) and Gene Set Enrichment Analysis (GSEA) software. There were changes in expression of genes linked to glucotoxicity. Evidence of oxidative stress was provided by upregulation of several metallothionein genes. There were few changes in the major genes associated with cell cycle, apoptosis or endoplasmic reticulum stress. There was differential expression of genes associated with pancreatic regeneration, most notably upregulation of members of the regenerating islet gene (REG) family and metalloproteinase 7 (MMP7). Some of the genes found in GWAS studies to be related to T2D were also found to be differentially expressed. IGF2BP2, TSPAN8, and HNF1B (TCF2) were upregulated while JAZF1 and SLC30A8 were downregulated. Conclusions/Significance: This study made possible by LCM has identified many novel changes in gene expression tha

Inside and out: the activities of senescence in cancer.

The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nrc377

Affective Pictures and the Open Library of Affective Foods (OLAF): Tools to Investigate Emotions toward Food in Adults

The authors wish to thank Jaime Vila for comments on earlier versions of the manuscript and Oscar Cervilla, Irene Forte, Alba Garrido, Laura Krutman, Lisa Mazzoni, and Teresa Mena for help with data collection and reduction.Recently, several sets of standardized food pictures have been created, supplying both food images and their subjective evaluations. However, to date only the OLAF (Open Library of Affective Foods), a set of food images and ratings we developed in adolescents, has the specific purpose of studying emotions toward food. Moreover, some researchers have argued that food evaluations are not valid across individuals and groups, unless feelings toward food cues are compared with feelings toward intense experiences unrelated to food, that serve as benchmarks. Therefore the OLAF presented here, comprising a set of original food images and a group of standardized highly emotional pictures, is intended to provide valid between-group judgments in adults. Emotional images (erotica, mutilations, and neutrals from the International Affective Picture System/IAPS) additionally ensure that the affective ratings are consistent with emotion research. The OLAF depicts high-calorie sweet and savory foods and low-calorie fruits and vegetables, portraying foods within natural scenes matching the IAPS features. An adult sample evaluated both food and affective pictures in terms of pleasure, arousal, dominance, and food craving, following standardized affective rating procedures. The affective ratings for the emotional pictures corroborated previous findings, thus confirming the reliability of evaluations for the food images. Among the OLAF images, high-calorie sweet and savory foods elicited the greatest pleasure, although they elicited, as expected, less arousal than erotica. The observed patterns were consistent with research on emotions and confirmed the reliability of OLAF evaluations. The OLAF and affective pictures constitute a sound methodology to investigate emotions toward food within a wider motivational framework. The OLAF is freely accessible at digibug.ugr.es.Yeshttp://www.plosone.org/static/editorial#pee