TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT.

Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells

Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

<div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div

Evaluation of interventions on road traffic injuries in Peru: a qualitative approach

<p>Abstract</p> <p>Background</p> <p>Evaluation of interventions on road traffic injuries (RTI) going beyond the assessment of impact to include factors underlying success or failure is an important complement to standard impact evaluations. We report here how we used a qualitative approach to assess current interventions implemented to reduce RTIs in Peru.</p> <p>Methods</p> <p>We performed in-depth interviews with policymakers and technical officers involved in the implementation of RTI interventions to get their insight on design, implementation and evaluation aspects. We then conducted a workshop with key stakeholders to analyze the results of in-depth interviews, and to further discuss and identify key programmatic considerations when designing and implementing RTI interventions. We finally performed brainstorming sessions to assess potential system-wide effects of a selected intervention (Zero Tolerance), and to identify adaptation and redesign needs for this intervention.</p> <p>Results</p> <p>Key programmatic components were consistently identified that should be considered when designing and implementing RTI interventions. They include effective and sustained political commitment and planning; sufficient and sustained budget allocation; training, supervision, monitoring and evaluation of implemented policies; multisectoral participation; and strong governance and accountability. Brainstorming sessions revealed major negative effects of the selected intervention on various system building blocks.</p> <p>Conclusions</p> <p>Our approach revealed substantial caveats in current RTI interventions in Peru, and fundamental negative effects on several components of the sectors and systems involved. It also highlighted programmatic issues that should be applied to guarantee an effective implementation and evaluation of these policies. The findings from this study were discussed with key stakeholders for consideration in further designing and planning RTI control interventions in Peru.</p

Overweight, Obesity and Underweight Is Associated with Adverse Psychosocial and Physical Health Outcomes among 7-Year-Old Children: The 'Be Active, Eat Right' Study

Background:Limited studies have reported on associations between overweight, and physical and psychosocial health outcomes among younger children. This study evaluates associations between overweight, obesity and underweight in 5-year-old children, and parent-reported health outcomes at age 7 years.Methods:Data were used from the 'Be active, eat right' study. Height and weight were measured at 5 and 7 years. Parents reported on child physical and psychosocial health outcomes (e.g. respiratory symptoms, general health, happiness, insecurity and adverse treatment). Regression models, adjusted for potential confounders, were fitted to predict health outcomes at age 7 years.Results:The baseline study sample consisted of 2,372 children mean age 5.8 (SD 0.4) years; 6.2% overweight, 1.6% obese and 15.0% underweight. Based on parent-report, overweight, obese and underweight children had an odds ratio (OR) of 5.70 (95% CI: 4.10 to 7.92), 35.34 (95% CI: 19.16; 65.17) and 1.39 (95% CI: 1.05 to 1.84), respectively, for being treated adversely compared to normal weight children. Compared to children with a low stable body mass index (BMI), parents of children with a high stable BMI reported their child to have an OR of 3.87 (95% CI: 1.75 to 8.54) for visiting the general practitioner once or more, an OR of 15.94 (95% CI: 10.75 to 23.64) for being treated adversely, and an OR of 16.35 (95% CI: 11.08 to 24.36) for feeling insecure.Conclusion:This study shows that overweight, obesity and underweight at 5 years of age is associated with more parent-reported adverse treatment of the child. Qualitative research examining underlying mechanisms is recommended. Healthcare providers should be aware of the possible adverse effects of childhood overweight and also relative underweight, and provide parents and children with appropriate counseling

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

Stochastic upscaling of hydrodynamic dispersion and retardation factor in a physically and chemically heterogeneous tropical soil

[EN] Stochastic upscaling of flow and reactive solute transport in a tropical soil is performed using real data collected in the laboratory. Upscaling of hydraulic conductivity, longitudinal hydrodynamic dispersion, and retardation factor were done using three different approaches of varying complexity. How uncertainty propagates after upscaling was also studied. The results show that upscaling must be taken into account if a good reproduction of the flow and transport behavior of a given soil is to be attained when modeled at larger than laboratory scales. The results also show that arrival time uncertainty was well reproduced after solute transport upscaling. This work represents a first demonstration of flow and reactive transport upscaling in a soil based on laboratory data. It also shows how simple upscaling methods can be incorporated into daily modeling practice using commercial flow and transport codes.The authors thank the financial support by the Brazilian National Council for Scientific and Technological Development (CNPq) (Project 401441/2014-8). The doctoral fellowship award to the first author by the Coordination of Improvement of Higher Level Personnel (CAPES) is acknowledged. The first author also thanks the international mobility grant awarded by CNPq, through the Sciences Without Borders program (Grant Number: 200597/2015-9). The international mobility grant awarded by Santander Mobility in cooperation with the University of Sao Paulo is also acknowledged. DHI-WASI is gratefully thanked for providing a FEFLOW license.Almeida De-Godoy, V.; Zuquette, L.; Gómez-Hernández, JJ. (2019). Stochastic upscaling of hydrodynamic dispersion and retardation factor in a physically and chemically heterogeneous tropical soil. 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Formation of Toxic Oligomeric α-Synuclein Species in Living Cells

Background: Misfolding, oligomerization, and fibrillization of α-synuclein are thought to be central events in the onset and progression of Parkinson's disease (PD) and related disorders. Although fibrillar α-synuclein is a major component of Lewy bodies (LBs), recent data implicate prefibrillar, oligomeric intermediates as the toxic species. However, to date, oligomeric species have not been identified in living cells. Methodology/Principal Findings: Here we used bimolecular fluorescence complementation (BiFC) to directly visualize α-synuclein oligomerization in living cells, allowing us to study the initial events leading to α-synuclein oligomerization, the precursor to aggregate formation. This novel assay provides us with a tool with which to investigate how manipulations affecting α-synuclein aggregation affect the process over time. Stabilization of α-synuclein oligomers via BiFC results in increased cytotoxicity, which can be rescued by Hsp70 in a process that reduces the formation of α-synuclein oligomers. Introduction of PD-associated mutations in α-synuclein did not affect oligomer formation but the biochemical properties of the mutant α-synuclein oligomers differ from those of wild type α-synuclein. Conclusions/Significance: This novel application of the BiFC assay to the study of the molecular basis of neurodegenerative disorders enabled the direct visualization of α-synuclein oligomeric species in living cells and its modulation by Hsp70, constituting a novel important tool in the search for therapeutics for synucleinopathies

Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.: Apoptosis and regulatory T cells

International audienceApoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover

The Terneuzen Birth Cohort. Longer exclusive breastfeeding duration is associated with leaner body mass and a healthier diet in young adulthood

<p>Abstract</p> <p>Background</p> <p>Breastfeeding (BF) is protective against overweight and is associated with dietary behaviour. The aims of our study were to assess the relationship between exclusive BF duration and BMI, waist circumference (WC) and waist-hip ratio (WHR) at adulthood, and to study whether dietary behaviour could explain the relationship between BF duration and the proxies of fat mass.</p> <p>Methods</p> <p>In 2004-2005, 822 subjects from the Terneuzen Birth Cohort (n = 2,604), aged 18-28 years, filled in postal questionnaires including sociodemographic factors and aspects of dietary behaviour (dietary pattern, and consumption of fruit and vegetables, snacks, sweetened beverages and alcohol); 737 subjects also underwent anthropometric measurements of weight, height, and waist and hip circumference. The relationship between exclusive BF duration and dietary outcomes was investigated by logistic regression analysis. The relationships of BF duration with the anthropometric measures were investigated by linear regression analyses. All results were corrected for age, gender and possible confounders. Finally, regression analyses were performed to investigate if diet factors had a mediating effect on the relationship between BF duration and fat mass.</p> <p>Results</p> <p>A significant inverse dose-response relationship of BF duration was found for BMI (β-0.13, SE 0.06), WC (β-0.39, SE 0.18) and WHR (β-0.003, SE 0.001), after correction for age, gender and confounders. The odds ratio (OR) of exclusive BF duration in months for a breakfast frequency of at least 5 times a week was 1.16 (95%CI 1.06-1.27), and for snack consumption of less than twice a week was 1.15 (95%CI 1.06-1.25). Both ORs were corrected for age, gender and confounders. For other dietary outcomes, the results point in the same direction, i.e. a positive relationship with BF duration, but these were not statistically significant. A mediating effect of the diet factors on the association between BF and anthropometric outcomes was not shown.</p> <p>Conclusions</p> <p>Exclusive BF duration had a significant inverse dose-response relationship with BMI, WC and WHR at young adulthood. BF duration was positively related to a healthier diet at adulthood, but this did not explain the protective effect of BF against body fat. Our results underline the recommendation of the WHO to exclusively breastfeed for 6 months or longer.</p