Paris Descartes University

About: Paris Descartes University is a government organization based out in Paris, France. It is known for research contribution in the topics: Population & Transplantation. The organization has 20987 authors who have published 37456 publications receiving 1206222 citations. The organization is also known as: Université Paris V-Descartes & Université de Paris V.

Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new?

Abstract: Melatonin is a neurohormone that has been claimed to be involved in a wide range of physiological functions. Nevertheless, for most of its effects, the mechanism of action is not really known. In mammals, two melatonin receptors, MT1 and MT2, have been cloned. They belong to the G-protein-coupled receptor (GPCR) superfamily. They share some specific short amino-acid sequences, which suggest that they represent a specific subfamily. Another receptor from the same subfamily, the melatonin-related receptor has been cloned in different species including humans. This orphan receptor also named GPR50 does not bind melatonin and its endogenous ligand is still unknown. Nevertheless, this receptor has been shown to behave as an antagonist of the MT1 receptor, which opens new pharmacological perspectives for GPR50 despite the lack of endogenous or synthetic ligands. Moreover, MT1 and MT2 interact together through the formation of heterodimers at least in cells transfected with the cDNA of these two receptors. Lastly, signalling complexes associated with MT1 and MT2 receptors are starting to be deciphered. A third melatonin-binding site has been purified and characterized as the enzyme quinone reductase 2 (QR2). Inhibition of QR2 by melatonin may explain melatonin's protective effect that has been reported in different animal models and that is generally associated with its well-documented antioxidant properties.

First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials

Abstract: Summary Background Data suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival. Methods FOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m 2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m 2 bolus fluorouracil followed by a 2400 mg/m 2 continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m 2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m 2 bolus fluorouracil followed by a 2400 mg/m 2 continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global). Findings Between Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6–58·4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90–1·19; p=0·61). The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with 23·3 months (21·8–24·7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3–4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group. Interpretation Addition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed. Funding Bobby Moore Fund of Cancer Research UK, Sirtex Medical.

Germline deletion of the miR-17 ∼ 92 cluster causes skeletal and growth defects in humans

Abstract: MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.

Addition of brain and carotid imaging to the ABCD² score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study.

Abstract: Summary Background The ABCD 2 score improves stratification of patients with transient ischaemic attack by early stroke risk. We aimed to develop two new versions of the score: one that was based on preclinical information and one that was based on imaging and other secondary care assessments. Methods We analysed pooled data from patients with clinically defined transient ischaemic attack who were investigated while in secondary care. Items that contribute to the ABCD 2 score (age, blood pressure, clinical weakness, duration, and diabetes), other clinical variables, carotid stenosis, and abnormal acute diffusion-weighted imaging (DWI) were recorded and were included in multivariate logistic regression analysis of stroke occurrence at early time intervals after onset of transient ischaemic attack. Scores based on the findings of this analysis were validated in patients with transient ischaemic attack from two independent population-based cohorts. Findings 3886 patients were included in the study: 2654 in the derivation sample and 1232 in the validation sample. We derived the ABCD 3 score (range 0–9 points) by assigning 2 points for dual transient ischaemic attack (an earlier transient ischaemic attack within 7 days of the index event). C statistics (which indicate discrimination better than chance at >0·5) for the ABCD 3 score were 0·78 at 2 days, 0·80 at 7 days, 0·79 at 28 days, and 0·77 at 90 days, compared with C statistics for the ABCD 2 score of 0·71 at 2 days (p=0·083), 0·71 at 7 days (p=0·012), 0·71 at 28 days (p=0·021), and 0·69 at 90 days (p=0·018). We included stenosis of at least 50% on carotid imaging (2 points) and abnormal DWI (2 points) in the ABCD 3 -imaging (ABCD 3 -I) score (0–13 points). C statistics for the ABCD 3 -I score were 0·90 at 2 days (compared with ABCD 2 score p=0·035), 0·92 at 7 days (p=0·001), 0·85 at 28 days (p=0·028), and 0·79 at 90 days (p=0·073). The 90-day net reclassification improvement compared with ABCD 2 was 29·1% for ABCD 3 (p=0·0003) and 39·4% for ABCD 3 -I (p=0·034). In the validation sample, the ABCD 3 and ABCD 3 -I scores predicted early stroke at 7, 28, and 90 days. However, discrimination and net reclassification of patients with early stroke were similar with ABCD 3 compared with ABCD 2 . Interpretation The ABCD 3 -I score can improve risk stratification after transient ischaemic attack in secondary care settings. However, use of ABCD 3 cannot be recommended without further validation. Funding Health Research Board of Ireland, Irish Heart Foundation, and Irish National Lottery.