Lipid droplet formation drives pathogenic ILC2 responses in airway inflammation

The Western world is affected by a dramatic increase of chronic inflammatory diseases like asthma, Crohn’s disease and psoriasis. Innate lymphoid cells (ILC) play an important role in the control and maintenance of barrier immunity but also in the development of several inflammatory diseases. Chronic activation of ILC results in immune-mediated pathology probably promoted by higher nutrient availability through life style changes coinciding with industrialization. In this thesis is shown that, in the context of allergen-driven airway inflammation, tissue resident ILC2 increase the uptake of both external lipids and glucose in the lung. Since gene expression analysis of ILC2 activated upon papain challenge did not reveal any substantial upregulation of genes involved in de novo lipid synthesis, it was suggested that externally acquired FA may be directly funneled into membrane lipids to support proliferation. Externally acquired fatty acids are transiently stored in lipid droplets to prevent lipotoxicity and promote the proliferation of ILC2 by using external lipids for membrane synthesis. This metabolic program is imprinted upon exposure to IL-33 and it is positively regulated by Pparγ and Dgat1, both partially controlled by glucose availability. Inhibition of PPARγ or DGAT1 leads to a strong decrease in ILC2 and eosinophil accumulation, as well as to lower inflammatory cytokine release by impacting lipid droplet formation. In vitro studies show that absence of glucose resulted in lower external FA uptake, lower lipid droplet formation and a strong downregulation of Pparγ and Dgat1. Strikingly, restriction of dietary glucose by feeding mice a ketogenic diet largely ablated ILC2-mediated airway inflammation by impairing fatty acid metabolism and the formation of lipid droplets. Taken together, these results reveal that pathogenic ILC2 responses require both lipid and glucose metabolism and identify ketogenic programs as a potent dietary intervention strategy to treat airway inflammation

Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia

Here we present the 3-year results of ZUMA-4, a phase I/II multicenter study evaluating the safety and efficacy of KTEX19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Phase I explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities. Thirty-one patients were enrolled; KTE-X19 was administered to 24 patients (median age 13.5 years, range 3-20; median follow-up 36.1 months). No dose-limiting toxicities were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33% in all treated patients, 75% in patients given the dose of 2×106 CAR T cells/kg, 27% in patients given the dose of 1×106 cells/kg in the 68 mL formulation, and 22% in patients given the dose of 1×106 cells/kg in the 40 mL formulation; the percentages of patients experiencing grade ≥3 neurologic events were 21%, 25%, 27%, and 11% respectively. Overall complete remission rates (including complete remission with incomplete hematologic recovery) were 67% in all treated patients, 75% in patients given 2×106 CAR T cells/kg, 64% in patients given 1×106 cells/kg in the 68 mL formulation, and 67% in patients given 1×106 cells/kg in the 40 mL formulation. Overall minimal residual diseasenegativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplantation. In the 1×106 (40 mL) group (recommended phase II dose), the median duration of remission censored at allogeneic stem-cell transplantation and median overall survival were not reached. Pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia achieved high minimal residual disease-negative remission rates with a manageable safety profile after a single dose of KTE-X19. Phase II of the study is ongoing at the dose of 1×106 CAR T cells/kg in the 40 mL formulation. ClinicalTrials.gov: NCT02625480

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

The Effect of a Morpho-Phonemic Intervention on Decoding and Comprehension of Complex Academic Words for Bilingual Students with Reading Difficulties.

Background: The high rate of increase in the amount and complexity of English academic vocabulary in upper elementary years poses a challenge for bilingual students who exhibit reading difficulties. It is well documented that phonemic awareness and morphological awareness are associated with word decoding skills; and morphological analysis, the ability to infer meanings of complex words based on morphemes, is correlated with vocabulary knowledge and reading comprehension. A growing body of literature has examined the impact of morphological or phonological skills on students’ reading outcomes. However, a combined effect of an integrated morpho-phonemic approach such as using morphological segmentation and phonological awareness (e.g., multi-syllabic flexibility) instructional techniques for young bilingual students with reading difficulties remains unknown. Purpose: This study examined the impact of a morpho-phonemic intervention on decoding and comprehension of morphologically complex academic words for upper elementary bilingual students with reading difficulties. The research questions for this study were 1) To what extent does morpho-phonemic instruction improve the decoding and comprehension of complex academic words taught during the intervention for bilingual students ages 9-11 years with reading difficulties? 2) To what extent does the gain from morpho-phonemic intervention retained for exposed words and transferred for the decoding and comprehension of unexposed words? Method: This study used a single case multiple-baseline-across-participants design with three staggered Tiers receiving varying baseline and intervention lengths. Four students from a metropolitan area of the Southwestern United States participated in three consecutive phases: baseline, intervention, and post-intervention. One participant was assigned to Tier III, one to Tier II, and two to Tier I. All participants received individual sessions via a digital interactive platform and were assessed on their word decoding and comprehension skills after each session. Each session lasted between 30 to 40 minutes. For the intervention phase, a group of 15 suffixes was instructed to all participants either once (Tier III, 5 sessions), twice (Tier II, 10 sessions), or three times (Tier I, 5 sessions). Each session comprised six target derivatives (two per suffix) and six example words. The percentage of correct responses for each session was used to conduct a visual analysis and calculate the effect sizes. Results: The visual analysis of data indicated an increase in average performance levels from baseline to intervention for all participants on word decoding and comprehension. The Non-Overlap of All Pairs (NAP) effect size for word decoding was moderate to large for three participants (NAP= 0.72-0.96) with one student showing a small NAP= 0.33. The NAP for word comprehension was small for all except for one participant, showing a moderate NAP= 0.84. For the post-intervention phase, two students demonstrated retention and transfer of gained skills in word decoding and comprehension measures. One student retained and transferred skills, while one only retained skills for word comprehension. Conclusion: These findings suggest that bilingual students with reading difficulties can benefit from explicit targeted instruction with an emphasis on the linkage between phonological and morphological analysis to increase their word reading and comprehension abilities

Metabolic Regulation of Innate Lymphoid Cell-Mediated Tissue Protection—Linking the Nutritional State to Barrier Immunity

Innate lymphoid cells (ILC) are a recently described group of tissue-resident immune cells that play essential roles in maintaining and protecting the tissue barrier against invading pathogens. Extensive research has revealed that ILC-mediated immune responses are controlled by dietary components and metabolites. An additional role of ILC as important direct regulators of host metabolism and glucose tolerance is emerging. This suggests that ILC may act as key dietary sensors integrating nutritional and metabolic stress to facilitate both maintenance of barrier sites and a coordinated immune response protecting these tissues. In this respect, investigations have begun to determine how different ILC responses are metabolically fueled and the impact of nutrient availability on the regulation of ILC function. Here, we discuss the current literature concerning dietary and metabolic control of ILC. In particular, we address whether the dietary and metabolic control of ILC and their simultaneous influence on host metabolism may function as a coordinated program of barrier defense

Factors determining the implementation of the cultural policy of Iran Tobacco Company: A model with an environmental responsibility approach

Background: This study aims to investigate the cultural policies of the tobacco company in the framework of social responsibility theory. Method: This study was a cross-sectional study. The statistical population included the managers of the tobacco company (335 people). The research sample size was determined to be 275 people based on Cochran's formula and by using cluster sampling. Data were collected through a researcher-made questionnaire consisting of 32 questions. The content validity of the questionnaire was confirmed by 22 experts. The Cronbach's alpha coefficient of the variables was obtained higher than 0.7. Data were analyzed by confirmatory factor analysis and path analysis in AMOS software. Results: The results of the path coefficient between the factors related to the implementation of cultural policies and environmental responsibility were close to 0.80, and the path coefficient between environmental responsibility and cultural policies was equal to 0.18 and less than 0.3, indicating the model weakness.  Most of the factor loads belonged to the indicators of environmental advertising, contextualization, warning against tobacco consumption, information, monitoring system, legal policies, policy implementation, management style, high-quality product and cultural implications. Conclusion: It seems necessary to have a social and environmental responsibility of the tobacco company with the dimensions of "providing a quality product", "following the policies", "providing cultural messages" and "warning against tobacco consumption" as components of the policy the cultural activities of the tobacco company are considered by policymakers for implementation in three indicators: "information-information", "environmental advertising" and "cultural background"