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STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Th2-polarised PrP-specific transgenic T-cells confer partial protection against murine scrapie.

Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only during early, asymptomatic disease, well before diagnosis is made. If efficient immunotherapy of prion diseases is to be achieved, it is crucial to understand precisely how immune tolerance against the prion protein can be overcome and which effector pathways may delay disease progression. To this end, we generated a transgenic mouse that expresses the ß-chain of a T cell receptor recognizing a PrP epitope presented by the class II major histocompatibility complex. The fact that the constraint is applied to only one TCR chain allows adaptation of the other chain according to the presence or absence of tolerogenic PrP. We first show that transgene-bearing T cells, pairing with rearranged α-chains conferring anti-PrP specificity, are systematically eliminated during ontogeny in PrP+ mice, suggesting that precursors with good functional avidity are rare in a normal individual. Second, we show that transgene-bearing T cells with anti-PrP specificity are not suppressed when transferred into PrP+ recipients and proliferate more extensively in a prion-infected host. Finally, such T cells provide protection through a cell-mediated pathway involving IL-4 production. These findings support the idea that cell-mediated immunity in neurodegenerative conditions may not be necessarily detrimental and may even contribute, when properly controlled, to the resolution of pathological processes

[Pemetrexed development in oncology]

International audienceThe pemetrexed disodium (Alimta), LY231514) is the first antifolate able to inhibit at the same time the synthesis of purins and pyrimidins. Many therapeutic tests were carried out in clinical situations where the methotrexate and the fluorouracil had been the proof of their effectiveness. It then showed an interesting activity in a great number of tumours but with very different profiles of tolerance according to the studies and pathologies. The explanation will come in 2001 by the description from the relation between the vitamin deficiencies among treated patients and occurred from toxicities. The two randomized studies carried out in the malignant pleural mesothelioma and the non small cell lung cancer made it possible to establish its utility and to record the pemetrexed in these clinical situations. Others axes of development remain possible, but the results are stanby or to confirm as in squamous-cell cancer in the head and neck and breast, digestive or urinary tracts cancer. In all the cases, the optimization of the pemetrexed in terms of amount/methods of administration and associations possible because of its profile of tolerance makes of it a molecule of chemotherapy with a future

Anticancer therapy in patients with porphyrias: evidence today.

International audienceBACKGROUND: Porphyrias are rare diseases, and for these patients every administration of drugs may induce an acute attack of porphyria. The list of safe compounds allowed in these patients is available for clinicians from specific websites cited in the text. OBJECTIVES: However, data concerning anticancer therapy in patients with such diseases remain poor. Therefore any publications can help clinicians to deal with this very specific group of patients. METHODS: In our institution, three patients received docetaxel and hematologic growth factors (erythropoietin and GCSF) without unexpected toxicities. Aromatase inhibitors (anstrozole and letrozole) were also given in one patient without any related problem. CONCLUSION: The present observation adds some useful data for the possible treatment of cancer in patients with porphyria

Glacial terminations and rates of sea-level rise

International audienceGlacial terminations in the late Pleistocene are notable for their high rates of sea-level rise. Occurring ~340 thousand years before the present (kyr BP), Termination IV (T-IV) stands out as a significant one, during which sea-level rise rates exceeded 4 meters per century. The underlying causes of such rapid deglaciation during T-IV, however, remain poorly understood due to limited absolute age constraints on marine records. We present new, radiometrically dated speleothem records obtained from Bàsura cave in northern Italy from 320 to 380 kyr BP. By transferring the speleothem-based chronology to the co-registered marine and terrestrial changes within the same sample set, we gain valuable insights into the dynamics of T-IV in the North Atlantic and Mediterranean regions. Our findings reveal that the maximum sea-level rise rates during T-IV were not synchronous with the major millennial-scale climate shifts, but rather linked to the initial phase of the subsequent interglacial period, characterized by abrupt warming in the North Atlantic. We will discuss our findings from T-IV in the context of other glacial terminations to shed light on the processes that control the high rates of sea level rise at glacial-interglacial transitions

Naftazone in advanced Parkinson's disease: An acute L-DOPA challenge randomized controlled trial

International audienceIntroduction: There is an unmet need to better control motor complications in Parkinson's disease (PD). Naftazone, which exhibits glutamate release inhibition properties, has shown antiparkinsonian and antidyskinetic activity in preclinical models of PD and in a clinical proof of concept study.Methods: We conducted a double-blind randomized placebo-controlled cross-over trial in PD patients with motor fluctuations and dyskinesia testing naftazone 160 mg/day versus placebo for 14 days. The two co-primary endpoints were the area under curve (AUC) of motor (MDS-UPDRS part III) and dyskinesia (AIMS) scores during an acute levodopa challenge performed at the end of each period. Secondary endpoints were UDysRS and axial symptoms scores during the challenge; AIMS, UDysRS, and time spent with or without dyskinesia the day before the challenge. The primary analysis was performed in the per protocol population.Results: Sixteen patients were included in the analysis. There was no difference between naftazone and placebo for the AUC of MDS-UPDRS III (-89, 95%CI[-1071; 893], p = 0.85), and AIMS (70, 95%CI[-192; 332], p = 0.57). At the end of treatment periods, AIMS score tended to be lower with naftazone than placebo (4.4 ± 3.4 versus 6.7 ± 4.4, p = 0.07), but UDysRS scores and other secondary outcomes were not different. Naftazone was safe and well tolerated.Conclusions: This study did not confirm previous results on the efficacy of naftazone on dyskinesia nor motor fluctuations highlighting the problem of translating results obtained in preclinical models into clinical trials. Further investigation of naftazone may be conducted in PD with longer treatment duration

Descriptive analysis of the French NS-Park registry: Towards a nation-wide Parkinson's disease cohort?

International audienceIntroduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's. The French clinical research network for PD (NS-Park) has created a national patient registry to i)report medical activity of Parkinson Expert Centers (PECs) to the Ministry of Health, ii)facilitate PD patients pre-screening for clinical trials, iii) provide a source for pharmaco-epidemiology studies.Objective: Assess the French Parkinsonian population at a nation-wide level and discover new clinical characteristics.Methods: In this feasibility study, PECs prospectively collected clinical data in a standardized manner. The population main clinical characteristics are described, focusing on motor and non-motor symptoms and treatments, assessing its representativeness. By using an unbiased clustering with multiple correspondence analysis (MCA), we also investigate potential relationships between multiple variables like symptoms and treatments, as clues for future studies.Results: Between 2012 and 2016, among 11,157 included parkinsonian syndromes, 9454 (85%) had PD. MCA identified various profiles depending on disease duration. Occurrences of motor complications, axial signs, cognitive disorders and Levodopa use increase over time. Neurovegetative symptoms, psychiatric disorders, sleep disturbances and impulse control disorders (ICDs) seem stable over time. As expected, ICDs were associated to dopaminergic agonist use but other associations, such as ICDs and sleep disturbances for instance, or anxiety and depression, were found.Conclusions: Our results report one of the biggest PD registries ever reported and demonstrate the feasibility of implementing a nation-wide registry of PD patients in France, a potent tool for future longitudinal studies and clinical trials' population selection, and for pharmaco-epidemiology and cost-effectiveness studies

New advances in DPYD genotype and risk of severe toxicity under capecitabine.

Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine.Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement.Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3-4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR.Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3-4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V