personality and survival in older age the role of lifestyle behaviors and health status

Objective We intended to assess the relationship between personality and survival in an older population and to explore the role of lifestyle behaviors and health status as potential mediators. Design Population-based cohort study. Setting Swedish National Study of Aging and Care in Kungsholmen, Sweden. Participants 2,298 adults aged 60 or more years, without dementia or depression, followed for 11 years. Measurements Personality (extraversion, neuroticism, and openness) was assessed with a shortened version of the NEO-Five Factor Inventory. We tested whether personality affected mortality and examined the potential mediating effect of health status (body mass index, number of chronic diseases, impairment in instrumental activities of daily living, and C-reactive protein) and lifestyle behaviors (leisure activities, social network, smoking, and alcohol consumption). Results Over 11 years of follow-up, higher levels of extraversion were associated with a 14% reduction in mortality. Examination of different combinations of personality traits showed that independent of levels of neuroticism and openness, high extraversion were associated with up to 65% lower mortality. Decomposing the effect of extraversion on mortality, we found that the majority (44%) of the beneficial effect was mediated by healthy lifestyle behaviors. Health status accounted for 5% of the association. Conclusions Extroverted people, who are characterized by higher optimism and high self-efficacy, are prone to healthier behaviors and better health, which may result in longer survival. These results highlight the importance of a healthy lifestyle in survival

Forkhead box P3: the peacekeeper of the immune system.

Ten years ago Forkhead box P3 (FOXP3) was discovered as master gene driving CD4(+)CD25(+) T cell regulatory (Treg) function. Since then, several layers of complexity have emerged in the regulation of its expression and function, which is not only exerted in Treg cells. While the mechanisms leading to the highly selective expression of FOXP3 in thymus-derived Treg cells still remain to be elucidated, we review here the current knowledge on the role of FOXP3 in the development of Treg cells and the direct and indirect consequences of FOXP3 mutations on multiple arms of the immune response. Finally, we summarize the newly acquired knowledge on the epigenetic regulation of FOXP3, still largely undefined in human cells

Enriched environment reduces glioma growth through immune and non-immune mechanisms in mice

Mice exposed to standard (SE) or enriched environment (EE) were transplanted with murine or human glioma cells and differences in tumour development were evaluated. We report that EE exposure affects: (i) tumour size, increasing mice survival; (ii) glioma establishment, proliferation and invasion; (iii) microglia/macrophage (M/Mφ) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. Direct infusion of IL-15 or BDNF in the brain of mice transplanted with glioma significantly reduces tumour growth. We demonstrate that brain infusion of IL-15 increases the frequency of NK cell infiltrating the tumour and that NK cell depletion reduces the efficacy of EE and IL-15 on tumour size and of EE on mice survival. BDNF infusion reduces M/Mφ infiltration and CD68 immunoreactivity in tumour mass and reduces glioma migration inhibiting the small G protein RhoA through the truncated TrkB.T1 receptor. These results suggest alternative approaches for glioma treatment

Ca2+-activated K+ channels modulate microglia affecting motor neuron survivalin hSOD1G93A mice

Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the "pro-inflammatory" phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the "pro-inflammatory" phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor γ subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS

Sorafenib induces cathepsin B-mediated apoptosis of bladder cancer cells by regulating the Akt/PTEN pathway. The Akt inhibitor, perifosine, enhances the sorafenib-induced cytotoxicity against bladder cancer cells

Sorafenib, a tyrosine kinase inhibitor, has been demonstrated to exert anti-tumor effects. However, the molecular mechanisms underlying its effects on bladder cancer remain unknown. Here, we evaluated the mechanisms responsible for the sorafenib-induced anti-tumor effects on 5637 and T24 bladder cancer cells. We demonstrated that sorafenib reduces cell viability, stimulates lysosome permeabilization and induces apoptosis of bladder cancer cells. These effects are dependent by the activation of cathepsin B released from lysosomes. The sorafenib-increased cathepsin B activity induced the proteolysis of Bid into tBid that stimulates the intrinsic pathway of apoptosis characterized by mitochondrial membrane depolarization, oxygen radical generation and cytochrome c release. Moreover, we found that cathepsin B enzymatic activity, induced by sorafenib, is dependent on its dephosphorylation via PTEN activation and Akt inactivation. Pretreatment with orthovanadate rescued bladder cancer cells from apoptosis. In addition, the Akt inhibitor perifosine increased the sensitivity of bladder cancer cells to sorafenib-induced cytotoxicity. Overall, our results show that apoptotic cell death induced by sorafenib in bladder cancer cells is dependent on cathepsin B activity and involved PTEN and Akt signaling pathways. The Akt inhibitor perifosine increased the cytotoxic effects of sorafenib in bladder cancer cells

Cost-Effectiveness Analysis of Dimethyl Fumarate in the Treatment of Relapsing Remitting Multiple Sclerosis: An Italian Societal Perspective

BACKGROUND: Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate, hereafter dimethyl fumarate) is an oral disease-modifying therapy used for the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS), an autoimmune chronic inflammatory condition of the central nervous system.OBJECTIVE: The objective of this economic analysis was to compare cost-effectiveness of dimethyl fumarate with the alternatives used as first-line treatment of RRMS in Italy.METHODS: The analysis was conducted from the Italian societal perspective. Health outcomes and costs were evaluated over a 50-year time horizon (equivalent to a lifetime horizon). Both health outcomes and costs were discounted at 3.5%. The cost-effectiveness analysis was conducted by adapting a Markov model, already used in previous similar economic analyses conducted in RRMS, to the Italian context. The Markov model estimated the clinical and economic consequences of treating RRMS patients with the following therapeutic options: dimethyl fumarate; interferon (IFN) beta-1a subcutaneous (SC) at two different doses, 22 mcg and 44 mcg; IFN beta-1b SC; glatiramer acetate (GA) SC 20 mg; oral teriflunomide. Clinical efficacy data were retrieved from an elaboration of an already published mixed treatment comparison (MTC). Both direct and indirect costs (disability, treatment acquisition, administration, monitoring, relapses, adverse events) were included in the analysis. One-way and probabilistic sensitivity analyses were carried out and cost-effectiveness acceptability curves generated.RESULTS: In the base-case analysis, dimethyl fumarate was more efficacious than alternatives, in terms of both survival (19.634 vs. 19.440-19.600 life years for alternatives), and quality-of-life-adjusted survival (6.526 vs. 5.143- 6.189 QALYs for alternatives). The total lifetime cost per patient treated with dimethyl fumarate (€ 954,286) was lower than that of the other DMTs included in the analysis. Therefore, dimethyl fumarate was dominant compared with all analyzed alternatives. Dimethyl fumarate was also the therapeutic option with the highest benefit on disease burden. In fact, costs of disability management were lower than those of all the other first-line drugs included in the analysis. The results of one-way deterministic sensitivity analysis and probabilistic sensitivity analysis confirmed the reliability of base-case results.CONCLUSIONS: The results of the cost-effectiveness analysis confirm that dimethyl fumarate is an optimal first-line treatment for RRMS in Italy, compared with the other first-line alternatives included in the economic analysis, when evaluated from the societal perspective

[Budget impact analysis for peginterferon beta-1a in relapsing remitting multiple sclerosis in Italy]

 BACKGROUND: Peginterferon beta-1a, injected every two weeks, is the first approved pegylated interferon beta-1a for the treatment of relapsing remitting multiple sclerosis (RRMS). The objective of this analysis was to estimate the economic impact due to the introduction of peginterferon beta-1a in Italy.METHODS: This analysis was conducted with a three-year time horizon with the support of a simple decision-analytic model adopting the perspective of the Italian National Healthcare Service (NHS). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, monitoring, relapse management, adverse events management) were calculated over 3 years and compared in two scenarios: the base scenario where interferons-beta and glatiramer acetate (GA) are used to treat RRMS patients, and an alternative scenario where peginterferon beta-1a can also be used to treat RRMS patients. The target population was approximately 35,500, 37,500 and 39,500 patients at year 1, 2 and 3 respectively, based on the published literature and market data. The efficacy of treatments was simulated as a reduction of relapse rates and was derived from a Network Meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A one-way sensitivity analysis was developed.RESULTS: According to current price and described assumptions, it was estimated that the introduction of peginterferon beta-1a would result in a decrease of total costs when compared with the base scenario. The cost in the base scenario was estimated to be  € 321.5, € 339.7 and € 357.8 million in years 1, 2, and 3, respectively. In the alternative scenario, the same costs resulted in about € 321.1, € 338.6 and € 356.2 million, respectively. The cumulative budget impact over three years period was approximately a cost saving of € 3.1 million (about 0.3% saving).CONCLUSION: The adoption of peginterferon beta-1a for the treatment of RRMS would be viewed as economically sustainable by the Italian NHS.[Article in Italian

PI is back! Switching Acquisition Functions in Bayesian Optimization

Bayesian Optimization (BO) is a powerful, sample-efficient technique to optimize expensive-to-evaluate functions. Each of the BO components, such as the surrogate model, the acquisition function (AF), or the initial design, is subject to a wide range of design choices. Selecting the right components for a given optimization task is a challenging task, which can have significant impact on the quality of the obtained results. In this work, we initiate the analysis of which AF to favor for which optimization scenarios. To this end, we benchmark SMAC3 using Expected Improvement (EI) and Probability of Improvement (PI) as acquisition functions on the 24 BBOB functions of the COCO environment. We compare their results with those of schedules switching between AFs. One schedule aims to use EI's explorative behavior in the early optimization steps, and then switches to PI for a better exploitation in the final steps. We also compare this to a random schedule and round-robin selection of EI and PI. We observe that dynamic schedules oftentimes outperform any single static one. Our results suggest that a schedule that allocates the first 25 % of the optimization budget to EI and the last 75 % to PI is a reliable default. However, we also observe considerable performance differences for the 24 functions, suggesting that a per-instance allocation, possibly learned on the fly, could offer significant improvement over the state-of-the-art BO designs.Comment: 2022 NeurIPS Workshop on Gaussian Processes, Spatiotemporal Modeling, and Decision-making System

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: role of HSP70/TLR2/NF-kB axis

Exosomes are a class of nanovesicles formed and released through the late endosomal compartment and represent an important mode of intercellular communication. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Here, we investigated whether genotoxic stress could promote the release of exosomes from multiple myeloma (MM) cells and studied the immunomodulatory properties they exert on NK cells, a major component of the antitumor immune response playing a key role in the immunosurveillance of MM. Our findings show that melphalan, a genotoxic agent used in MM therapy, significantly induces an increased exosome release from MM cells. MM cell-derived exosomes are capable of stimulating IFNg production, but not the cytotoxic activity of NK cells through a mechanism based on the activation of NF-kB pathway in a TLR2/ HSP70-dependent manner. Interestingly, HSP70 positive exosomes are primarily found in the bone marrow (BM) of MM patients suggesting that they might have a crucial immunomodulatory action in the tumor microenvironment. We also provide evidence that the CD56high NK cell subset is more responsive to exosome-induced IFNg production mediated by TLR2 engagement. All together, these findings suggest a novel mechanism of synergism between chemotherapy and antitumor innate immune responses based on the drug-promotion of nanovesicles exposing DAMPs for innate receptors