Activation of PPARγ in Myeloid Cells Promotes Lung Cancer Progression and Metastasis

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits growth of cancer cells including non-small cell lung cancer (NSCLC). Clinically, use of thiazolidinediones, which are pharmacological activators of PPARγ is associated with a lower risk of developing lung cancer. However, the role of this pathway in lung cancer metastasis has not been examined well. The systemic effect of pioglitazone was examined in two models of lung cancer metastasis in immune-competent mice. In an orthotopic model, murine lung cancer cells implanted into the lungs of syngeneic mice metastasized to the liver and brain. As a second model, cancer cells injected subcutaneously metastasized to the lung. In both models systemic administration of pioglitazone increased the rate of metastasis. Examination of tissues from the orthotopic model demonstrated increased numbers of arginase I-positive macrophages in tumors from pioglitazone-treated animals. In co-culture experiments of cancer cells with bone marrow-derived macrophages, pioglitazone promoted arginase I expression in macrophages and this was dependent on the expression of PPARγ in the macrophages. To assess the contribution of PPARγ in macrophages to cancer progression, experiments were performed in bone marrow-transplanted animals receiving bone marrow from Lys-M-Cre+/PPARγflox/flox mice, in which PPARγ is deleted specifically in myeloid cells (PPARγ-Macneg), or control PPARγflox/flox mice. In both models, mice receiving PPARγ-Macneg bone marrow had a marked decrease in secondary tumors which was not significantly altered by treatment with pioglitazone. This was associated with decreased numbers of arginase I-positive cells in the lung. These data support a model in which activation of PPARγ may have opposing effects on tumor progression, with anti-tumorigenic effects on cancer cells, but pro-tumorigenic effects on cells of the microenvironment, specifically myeloid cells

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Measurement of the azimuthal anisotropy of Y(1S) and Y(2S) mesons in PbPb collisions at root s(NN)=5.02 TeV

The second-order Fourier coefficients (v(2)) characterizing the azimuthal distributions of Y(1S) and Y(2S) mesons produced in PbPb collisions at root s(NN) = 5.02 TeV are studied. The Y mesons are reconstructed in their dimuon decay channel, as measured by the CMS detector. The collected data set corresponds to an integrated luminosity of 1.7 nb(-1). The scalar product method is used to extract the v2 coefficients of the azimuthal distributions. Results are reported for the rapidity range vertical bar y vertical bar < 2.4, in the transverse momentum interval 0 < pT < 50 GeV/c, and in three centrality ranges of 10-30%, 30-50% and 50-90%. In contrast to the J/psi mesons, the measured v(2) values for the Y mesons are found to be consistent with zero. (C) 2021 The Author(s). Published by Elsevier B.V.Peer reviewe

Adressat*innenschaft verkörpern. Zur Institutionalisierung intersektionaler Kindheiten

Carnin J. Adressat*innenschaft verkörpern. Zur Institutionalisierung intersektionaler Kindheiten. In: Bak R, Machold C, eds. Kindheit und Kindheitsforschung intersektional denken. Theoretische, empirische und praktische Zugänge im Kontext von Bildung und Erziehung. Kinder, Kindheiten und Kindheitsforschung. Wiesbaden: Springer Fachmedien Wiesbaden; 2022: 109-120.Der Beitrag argumentiert ausgehend von einer praxis- und kindheitstheoretischen Perspektive für die Berücksichtigung des Somatischen in intersektionalen Analysen in der Generationendifferenzforschung. Dabei wird vorgeschlagen, die Verkörperung intersektionaler Kindheiten als Ausgangspunkt für eine Analyse von Sorge-, Erziehungs- und Bildungsverhältnissen zu wählen, um intersektional kodierten Entwürfen pädagogischer Adressat*innenschaft auf die Spur zu kommen

Bildungsangebote für neu zugewanderte Menschen zwischen Teilhabe und Ausschluss

IFO 2017, 31. Inklusionsforscher_innentagung 2017 in Lin

Cognitive and neural models of threat appraisal in psychosis: A theoretical integration

© 2016 The Authors. Cognitive models of psychosis propose that maladaptive appraisals of anomalous experiences contribute to distress and disability in psychosis. Attentional, attributional and reasoning biases are hypothesised to drive these threat-based appraisals. Experimental and self-report data have provided support for the presence of these biases in psychosis populations, but recently there have been calls for neurobiological data to be integrated into these findings. Currently, little investigation has been conducted into the neural correlates of maladaptive appraisals. Experimental and neuroimaging research in social cognition employing threatening stimuli provide the closest equivalent of maladaptive appraisal in psychosis. Consequently, a rapprochement of these two literatures was attempted in order to identify neural networks relevant to threat appraisal in psychosis. This revealed overlapping models of aberrant emotion processing in anxiety and schizophrenia, encompassing the amygdala, insula, hippocampus, anterior cingulate cortex, and prefrontal cortex. These models posit that aberrant activity in these systems relates to altered emotional significance detection and affect regulation, providing a conceptual overlap with threat appraisal in psychosis, specifically attentional and attributional biases towards threat. It remains to be seen if direct examination of these biases using neuroimaging paradigms supports the theoretical integration of extant models of emotion processing and maladaptive appraisals in psychosis.Medical Research Counci