The adaptor protein TRAF3 is an immune checkpoint that inhibits myeloid-derived suppressor cell expansion

Myeloid-derived suppressor cells (MDSCs) are aberrantly expanded in cancer patients and under other pathological conditions. These cells orchestrate the immunosuppressive and inflammatory network to facilitate cancer metastasis and mediate patient resistance to therapies, and thus are recognized as a prime therapeutic target of human cancers. Here we report the identification of the adaptor protein TRAF3 as a novel immune checkpoint that critically restrains MDSC expansion. We found that myeloid cell-specific Traf3-deficient (M-Traf3-/-) mice exhibited MDSC hyperexpansion during chronic inflammation. Interestingly, MDSC hyperexpansion in M-Traf3-/- mice led to accelerated growth and metastasis of transplanted tumors associated with an altered phenotype of T cells and NK cells. Using mixed bone marrow chimeras, we demonstrated that TRAF3 inhibited MDSC expansion via both cell-intrinsic and cell-extrinsic mechanisms. Furthermore, we elucidated a GM-CSF-STAT3-TRAF3-PTP1B signaling axis in MDSCs and a novel TLR4-TRAF3-CCL22-CCR4-G-CSF axis acting in inflammatory macrophages and monocytes that coordinately control MDSC expansion during chronic inflammation. Taken together, our findings provide novel insights into the complex regulatory mechanisms of MDSC expansion and open up unique perspectives for the design of new therapeutic strategies that aim to target MDSCs in cancer patients

Using Two-Step Cluster Analysis and Latent Class Cluster Analysis to Classify the Cognitive Heterogeneity of Cross-Diagnostic Psychiatric Inpatients

The heterogeneity of cognitive profiles among psychiatric patients has been reported to carry significant clinical information. However, how to best characterize such cognitive heterogeneity is still a matter of debate. Despite being well suited for clinical data, cluster analysis techniques, like the Two-Step and the Latent Class, received little to no attention in the literature. The present study aimed to test the validity of the cluster solutions obtained with Two-Step and Latent Class cluster analysis on the cognitive profile of a cross-diagnostic sample of 387 psychiatric inpatients. Two-Step and Latent Class cluster analysis produced similar and reliable solutions. The overall results reported that it is possible to group all psychiatric inpatients into Low and High Cognitive Profiles, with a higher degree of cognitive heterogeneity in schizophrenia and bipolar disorder patients than in depressive disorders and personality disorder patients

Label Retention Identifies a Multipotent Mesenchymal Stem Cell-Like Population in the Postnatal Thymus

Thymic microenvironments are essential for the proper development and selection of T cells critical for a functional and self-tolerant adaptive immune response. While significant turnover occurs, it is unclear whether populations of adult stem cells contribute to the maintenance of postnatal thymic epithelial microenvironments. Here, the slow cycling characteristic of stem cells and their property of label-retention were used to identify a K5-expressing thymic stromal cell population capable of generating clonal cell lines that retain the capacity to differentiate into a number of mesenchymal lineages including adipocytes, chondrocytes and osteoblasts suggesting a mesenchymal stem cell-like phenotype. Using cell surface analysis both culture expanded LRCs and clonal thymic mesenchymal cell lines were found to express Sca1, PDGFRα, PDGFRβ,CD29, CD44, CD49F, and CD90 similar to MSCs. Sorted GFP-expressing stroma, that give rise to TMSC lines, contribute to thymic architecture when reaggregated with fetal stroma and transplanted under the kidney capsule of nude mice. Together these results show that the postnatal thymus contains a population of mesenchymal stem cells that can be maintained in culture and suggests they may contribute to the maintenance of functional thymic microenvironments

Association between characteristics at birth, breastfeeding and obesity in 22 countries: the WHO European Childhood Obesity Surveillance Initiative – COSI 2015/2017

Objectives: It was the aim of this paper to investigate the association of early-life factors, namely breastfeeding, exclusive breastfeeding and birth weight, with obesity among children. ----- Method: Data from 22 participating countries in the WHO European COSI study (round 4: 2015/2017) were collected using cross-sectional, nationally representative samples of 6- to 9-year-olds (n = 100,583). The children's standardized weight and height measurements followed a common WHO protocol. Information on the children's birth weight and breastfeeding practice and duration was collected through a family record form. A multivariate multilevel logistic regression analysis regarding breastfeeding practice (both general and exclusive) and characteristics at birth was performed. ----- Results: The highest prevalence rates of obesity were observed in Spain (17.7%), Malta (17.2%) and Italy (16.8%). A wide between-country disparity in breastfeeding prevalence was found. Tajikistan had the highest percentage of children that were breastfed for ≥6 months (94.4%) and exclusively breastfed for ≥6 months (73.3%). In France, Ireland and Malta, only around 1 in 4 children was breastfed for ≥6 months. Italy and Malta showed the highest prevalence of obesity among children who have never been breastfed (21.2%), followed by Spain (21.0%). The pooled analysis showed that, compared to children who were breastfed for at least 6 months, the odds of being obese were higher among children never breastfed or breastfed for a shorter period, both in case of general (adjusted odds ratio [adjOR] [95% CI] 1.22 [1.16-1.28] and 1.12 [1.07-1.16], respectively) and exclusive breastfeeding (adjOR [95% CI] 1.25 [1.17-1.36] and 1.05 [0.99-1.12], respectively). Higher birth weight was associated with a higher risk of being overweight, which was reported in 11 out of the 22 countries. Bulgaria, Croatia, France, Italy, Poland and Romania showed that children who were preterm at birth had higher odds of being obese, compared to children who were full-term babies. ----- Conclusion: The present work confirms the beneficial effect of breastfeeding against obesity, which was highly increased if children had never been breastfed or had been breastfed for a shorter period. Nevertheless, adoption of exclusive breastfeeding is below global recommendations and far from the target endorsed by the WHO Member States at the World Health Assembly Global Targets for Nutrition of increasing the prevalence of exclusive breastfeeding in the first 6 months up to at least 50% by 2025

Observation of the TeV gamma-ray source MGRO J1908+06 with ARGO-YBJ

The extended gamma ray source MGRO J1908+06, discovered by the Milagro air shower detector in 2007, has been observed for about 4 years by the ARGO-YBJ experiment at TeV energies, with a statistical significance of 6.2 standard deviations. The peak of the signal is found at a position consistent with the pulsar PSR J1907+0602. Parametrizing the source shape with a two-dimensional Gauss function we estimate an extension \sigma = 0.49 \pm 0.22 degrees, consistent with a previous measurement by the Cherenkov Array H.E.S.S.. The observed energy spectrum is dN/dE = 6.1 \pm 1.4 \times 10^-13 (E/4 TeV)^{-2.54 \pm 0.36} photons cm^-2 s^-1 TeV^-1, in the energy range 1-20 TeV. The measured gamma ray flux is consistent with the results of the Milagro detector, but is 2-3 times larger than the flux previously derived by H.E.S.S. at energies of a few TeV. The continuity of the Milagro and ARGO-YBJ observations and the stable excess rate observed by ARGO-YBJ along 4 years of data taking support the identification of MGRO J1908+06 as the steady powerful TeV pulsar wind nebula of PSR J1907+0602, with an integrated luminosity above 1 TeV about 1.8 times the Crab Nebula luminosity.Comment: 6 pages, accepted for pubblication by ApJ. Replaced to correct the author lis

Clustering of Multiple Energy Balance-Related Behaviors in School Children and Its Association with Overweight and Obesity—WHO European Childhood Obesity Surveillance Initiative (COSI 2015–2017)

It is unclear how dietary, physical activity and sedentary behaviors co-occur in school-aged children. We investigated the clustering of energy balance-related behaviors and whether the identified clusters were associated with weight status. Participants were 6- to 9-year-old children (n = 63,215, 49.9% girls) from 19 countries participating in the fourth round (2015/2017) of the World Health Organization (WHO) European Childhood Obesity Surveillance Initiative. Energy balance-related behaviors were parentally reported. Weight and height were objectively measured. We performed cluster analysis separately per group of countries (North Europe, East Europe, South Europe/Mediterranean countries and West-Central Asia). Seven clusters were identified in each group. Healthier clusters were common across groups. The pattern of distribution of healthy and unhealthy behaviors within each cluster was group specific. Associations between the clustering of energy balance-related behaviors and weight status varied per group. In South Europe/Mediterranean countries and East Europe, all or most of the cluster solutions were associated with higher risk of overweight/obesity when compared with the cluster 'Physically active and healthy diet'. Few or no associations were observed in North Europe and West-Central Asia, respectively. These findings support the hypothesis that unfavorable weight status is associated with a particular combination of energy balance-related behavior patterns, but only in some groups of countries

Regulatory iNKT cells lack PLZF expression and control Treg cell and macrophage homeostasis in adipose tissue

iNKT cells are CD1d-restricted lipid-sensing innate T cells that express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, and their targets in adipose tissue are unknown. Here we report that adipose tissue iNKT cells have a unique transcriptional program and produce interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lack PLZF, but express the transcription factor E4BP4, which controls their IL-10 production. Adipose iNKT cells are a tissue resident population that induces an anti-inflammatory phenotype in macrophages and, through production of IL-2, controls the number, proliferation and suppressor function of adipose regulatory T (Treg) cells. Thus, adipose tissue iNKT cells are unique regulators of immune homeostasis in this tissue

Parental Perceptions of Children’s Weight Status in 22 Countries: The WHO European Childhood Obesity Surveillance Initiative: COSI 2015/2017

Introduction: Parents can act as important agents of change and support for healthy childhood growth and development. Studies have found that parents may not be able to accurately perceive their child’s weight status. The purpose of this study was to measure parental perceptions of their child’s weight status and to identify predictors of potential parental misperceptions. Methods: We used data from the World Health Organization (WHO) European Childhood Obesity Surveillance Initiative and 22 countries. Parents were asked to identify their perceptions of their children’s weight status as “underweight,” “normal weight,” “a little overweight,” or “extremely overweight.” We categorized children’s (6–9 years; n = 124,296) body mass index (BMI) as BMI-for-age Z-scores based on the 2007 WHO-recommended growth references. For each country included in the analysis and pooled estimates (country level), we calculated the distribution of children according to the WHO weight status classification, distribution by parental perception of child’s weight status, percentages of accurate, overestimating, or underestimating perceptions, misclassification levels, and predictors of parental misperceptions using a multilevel logistic regression analysis that included only children with overweight (including obesity). Statistical analyses were performed using Stata version 15 1. Results: Overall, 64.1% of parents categorized their child’s weight status accurately relative to the WHO growth charts. However, parents were more likely to underestimate their child’s weight if the child had overweight (82.3%) or obesity (93.8%). Parents were more likely to underestimate their child’s weight if the child was male (adjusted OR [adjOR]: 1.41; 95% confidence intervals [CI]: 1.28–1.55); the parent had a lower educational level (adjOR: 1.41; 95% CI: 1.26–1.57); the father was asked rather than the mother (adjOR: 1.14; 95% CI: 0.98–1.33); and the family lived in a rural area (adjOR: 1.10; 95% CI: 0.99–1.24). Overall, parents’ BMI was not strongly associated with the underestimation of children’s weight status, but there was a stronger association in some countries. Discussion/Conclusion: Our study supplements the current literature on factors that influence parental perceptions of their child’s weight status. Public health interventions aimed at promoting healthy childhood growth and development should consider parents’ knowledge and perceptions, as well as the sociocultural contexts in which children and families live.The authors gratefully acknowledge support from a grant from the Russian Government in the context of the WHO European Office for the Prevention and Control of NCDs. Data collection in the countries was made possible through funding by: Albania: World Health Organization through the Joint Programme on Children, Food Security and Nutrition “Reducing Malnutrition in Children,” funded by the Millennium Development Goals Achievement Fund, and the Institute of Public Health; Bulgaria: Ministry of Health, National Center of Public Health and Analyses, World Health Organization Regional Office for Europe; Croatia: Ministry of Health, Croatian Institute of Public Health and World Health Organization Regional Office for Europe; Czechia: Grants AZV MZČR 17-31670 A and MZČR – RVO EÚ 00023761; Denmark: Danish Ministry of Health; France: French Public Health Agency; Georgia: World Health Organization; Ireland: Health Service Executive; Italy: Ministry of Health; Istituto Superiore di sanità (National Institute of Health); Kazakhstan: Ministry of Health of the Republic of Kazakhstan and World Health Organization Country Office; Latvia: n/a; Lithuania: Science Foundation of Lithuanian University of Health Sciences and Lithuanian Science Council and World Health Organization; Malta: Ministry of Health; Montenegro: World Health Organization and Institute of Public Health of Montenegro; Poland: National Health Programme, Ministry of Health; Portugal: Ministry of Health Institutions, the National Institute of Health, Directorate General of Health, Regional Health Directorates and the kind technical support of Center for Studies and Research on Social Dynamics and Health (CEIDSS); Romania: Ministry of Health; Russia (Moscow): n/a; San Marino: Health Ministry; Educational Ministry; Social Security Institute; the Health Authority; Spain: Spanish Agency for Food Safety and Nutrition (AESAN); Tajikistan: World Health Organization Country Office in Tajikistan and Ministry of Health and Social Protection; and Turkmenistan: World Health Organization Country Office in Turkmenistan and Ministry of Health. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.info:eu-repo/semantics/publishedVersio