Université Paris-Saclay

About: Université Paris-Saclay is a education organization based out in Gif-sur-Yvette, France. It is known for research contribution in the topics: Population & Context (language use). The organization has 29307 authors who have published 43183 publications receiving 867404 citations.

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

Abstract: Tumors use several strategies to evade the host immune response, including creation of an immune-suppressive and hostile tumor environment. Tissue hypoxia due to inadequate blood supply is reported to develop very early during tumor establishment. Hypoxic stress has a strong impact on tumor cell biology. In particular, tissue hypoxia contributes to therapeutic resistance, heterogeneity and progression. It also interferes with immune plasticity, promotes the differentiation and expansion of immune-suppressive stromal cells, and remodels the metabolic landscape to support immune privilege. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this regard, manipulating host-tumor interactions in the context of the hypoxic tumor microenvironment may be important in preventing or reverting malignant conversion. We will discuss how tumor microenvironment-driven transient compositional tumor heterogeneity involves hypoxic stress. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of conventional therapies as well as cancer immunotherapy. Thus, understanding how tumor and stromal cells respond to hypoxia will allow for the design of innovative cancer therapies that can overcome these barriers. A better understanding of hypoxia-dependent mechanisms involved in the regulation of immune tolerance could lead to new strategies to enhance antitumor immunity. Therefore, discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance. In this context, critical hypoxia-associated pathways are attractive targets for immunotherapy of cancer. In this review, we summarize current knowledge regarding the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on therapeutic resistance and immune suppression. We emphasize mechanisms of manipulating hypoxic stress and its associated pathways, which may support the development of more durable and successful cancer immunotherapy approaches in the future.

Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study

Abstract: Objective To test the hypotheses that physical activity in midlife is not associated with a reduced risk of dementia and that the preclinical phase of dementia is characterised by a decline in physical activity. Design Prospective cohort study with a mean follow-up of 27 years. Setting Civil service departments in London (Whitehall II study). Participants 10 308 participants aged 35-55 years at study inception (1985-88). Exposures included time spent in mild, moderate to vigorous, and total physical activity assessed seven times between 1985 and 2013 and categorised as “recommended” if duration of moderate to vigorous physical activity was 2.5 hours/week or more. Main outcome measures A battery of cognitive tests was administered up to four times from 1997 to 2013, and incident dementia cases (n=329) were identified through linkage to hospital, mental health services, and mortality registers until 2015. Results Mixed effects models showed no association between physical activity and subsequent 15 year cognitive decline. Similarly, Cox regression showed no association between physical activity and risk of dementia over an average 27 year follow-up (hazard ratio in the “recommended” physical activity category 1.00, 95% confidence interval 0.80 to 1.24). For trajectories of hours/week of total, mild, and moderate to vigorous physical activity in people with dementia compared with those without dementia (all others), no differences were observed between 28 and 10 years before diagnosis of dementia. However, physical activity in people with dementia began to decline up to nine years before diagnosis (difference in moderate to vigorous physical activity −0.39 hours/week; P=0.05), and the difference became more pronounced (−1.03 hours/week; P=0.005) at diagnosis. Conclusion This study found no evidence of a neuroprotective effect of physical activity. Previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation—that is, due to a decline in physical activity levels in the preclinical phase of dementia.

Heavy-flavour and quarkonium production in the LHC era: from proton-proton to heavy-ion collisions

Abstract: This report reviews the study of open heavy-flavour and quarkonium production in high-energy hadronic collisions, as tools to investigate fundamental aspects of Quantum Chromodynamics, from the proton and nucleus structure at high energy to deconfinement and the properties of the Quark-Gluon Plasma. Emphasis is given to the lessons learnt from LHC Run 1 results, which are reviewed in a global picture with the results from SPS and RHIC at lower energies, as well as to the questions to be addressed in the future. The report covers heavy flavour and quarkonium production in proton-proton, proton-nucleus and nucleus-nucleus collisions. This includes discussion of the effects of hot and cold strongly interacting matter, quarkonium photo-production in nucleus-nucleus collisions and perspectives on the study of heavy flavour and quarkonium with upgrades of existing experiments and new experiments. The report results from the activity of the SaporeGravis network of the I3 Hadron Physics programme of the European Union 7th Framework Programme.

Genomewide Association Study of an AIDS-Nonprogression Cohort Emphasizes the Role Played by HLA Genes (ANRS Genomewide Association Study 02)

Abstract: To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5 rs2395029 (P = 6.79 × 10 −10 ; odds ratio, 3.47) andwaspossibly linkedto aneffect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal (P = 3.02 × 10 −19 ) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection.