Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.

Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.

Transcriptome Analysis of Plasmodium falciparum Isolates From Benin Reveals Specific Gene Expression Associated With Cerebral Malaria.

Cerebral malaria (CM) is the severest form of Plasmodium falciparum infection. Children under 5 years old are those most vulnerable to CM, and they consequently have the highest risk of malaria-related death. Parasite-associated factors leading to CM are not yet fully elucidated. We therefore sought to characterize the gene expression profile associated with CM, using RNA sequencing data from 15 CM and 15 uncomplicated malaria isolates from Benin. Cerebral malaria parasites displayed reduced circulation times, possibly related to higher cytoadherence capacity. Consistent with the latter, we detected increased var genes abundance in CM isolates. Differential expression analyses showed that distinct transcriptome profiles are signatures of malaria severity. Genes involved in adhesion, excluding variant surface antigens, were dysregulated, supporting the idea of increased cytoadhesion capacity of CM parasites. Finally, we found dysregulated expression of genes in the entry into host pathway that may reflect greater erythrocyte invasion capacity of CM parasites.

Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.

BACKGROUND: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS: EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS: Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS: Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.

[A phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non squamous, non-small cell lung cancer (NSCLC)]. / Protocole IFCT 0803--Étude de phase II évaluant l'association de cétuximab à une radiothérapie et chimiothérapie concomitante par cisplatine et pémétrexed dans le traitement des cancers bronchiques non à petites cellules non épidermoïdes de stade III, inopérables.

BACKGROUND: Cisplatin-based chemotherapy and concurrent radiotherapy are the standard treatments for locally advanced unresectable NSCLC. New therapeutic combinations using molecular targeted drugs are needed. METHODS: Eligible patients with previously untreated stage III non squamous, NSCLC will receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m(2)) and pemetrexed (500 mg/m(2)) on day 1 administered intravenously every 21 days for four cycles; weekly cetuximab will be added from the first week of therapy. The primary objective of this phase II study (IFCT 0803) is to assess the disease control rate at the 16th week, one month after the completion of the treatment. Based on a two-stage Simon approach, a total of 106 patients are required with an interim analysis of the first 34 planned. EXPECTED RESULTS: This trial will provide information on the feasibility, efficacy and tolerability of this new therapeutic combination. Should the primary objective be achieved, a phase III randomised study testing the position of cetuximab could be considered.

Monitoring organ donor rates: a predictive model based on routinely available data in France applied to the year 2002.

Temporal trends in organ donor harvesting rates are subject to variability. It is important to detect variations as early as possible using current data. We developed a predictive model for monitoring harvesting activity using the number of donors harvested monthly between 1996 and 2001. A Poisson model was used to predict the number of donors harvested each month along with their confidence intervals. This model also updates, on a monthly basis, the predicted number of donors for the current year. During 2002, the number of donors observed each month followed the predicted monthly variations, but a significant increase was observed in March and May. These models can be used by transplantation agencies for monitoring purposes and for the evaluation of organ donation programmes.