mRCC management: past, present and future

Aims and scope Over the last six years, the use of targeted agents has revolutionised the treatment of metastatic renal cell carcinoma (mRCC) and dramatically improved outcomes for patients. Multiple effective first-and second-line agents are now available or are in development, raising key questions and new challenges around the long-term management of mRCC. These topics were the focus of a Pfizer meeting held at the 7 th European International Kidney Cancer Symposium (EIKCS) in Vienna (4–5 May 2012), where leading European oncology experts discussed recent advances and ongoing issues in mRCC clinical practice. 'It is important for clinicians who see large numbers of patients with this rare disease to get together and share their experience and observations, for the benefit of those who only see few patients in their practice', said Professor Manuela Schmidinger, Chair of the meeting. This report offers an overview of the critical evidence and the issues of long-term mRCC management debated at the meeting. It also presents key conclusions from the recently launched report 'Europe 2012: is kidney cancer management at a crossroad?', written by a selected panel of European kidney cancer experts to highlight current barriers to the optimal treatment of mRCC patients and the development of solutions to address these

Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I.

NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction that manifest in a wide variety of neurodegenerative diseases. Seven subunits of human complex I are encoded by mitochondrial DNA (mtDNA) that carry an unexpectedly large number of mutations discovered in mitochondria from patients' tissues. However, whether or how these genetic aberrations affect complex I at a molecular level is unknown. Here, we used Escherichia coli as a model system to biochemically characterize two mutations that were found in mtDNA of patients. The V253AMT-ND5 mutation completely disturbed the assembly of complex I, while the mutation D199GMT-ND1 led to the assembly of a stable complex capable to catalyze redox-driven proton translocation. However, the latter mutation perturbs quinone reduction leading to a diminished activity. D199MT-ND1 is part of a cluster of charged amino acid residues that are suggested to be important for efficient coupling of quinone reduction and proton translocation. A mechanism considering the role of D199MT-ND1 for energy conservation in complex I is discussed

Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

International audienceBackground: The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors.Methods: Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT–PCR). IHC results were correlated to Fuhrman's grade and patient progression-free survival (PFS).Results: A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: P<0.001, AT2-R: P<0.001). Univariate analysis showed a correlation between PFS and AT1-R or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (P<0.001). By western blot, AT1-R and AT1-R were also found to be overexpressed in higher Fuhrman's grade (P<0.01 and P=0.001 respectively). By qRT–PCR, AT1-R but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively).Conclusion: Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy

Hypovitaminose C chez la personne âgée (étude prospective dans un service de court séjour gériatrique)

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Implication de la télomérase dans la carcinogenèse urothéliale vésicale

La télomérase, composée d'un ARN (hTR) et d'une protéine à activité transcriptase inverse (hTERT), pallie le raccourcissement des extrémités des télomères à chaque réplication. La télomérase est impliquée dans l'immortalisation cellulaire. Dans notre étude, nous avons recherché le rôle de la télomérase dans la carcinogenèse urothéliale vésicale en étudiant l'expression de hTRT par hybridation in situ et immunohistochimie dans des tumeurs et l'urothélium normal. Le niveau d'expression de hTRT est plus élevé dans les tumeurs mais aucune corrélation n'est retrouvée avec les facteurs pronostiques classiques. La carcinogenèse urothéliale fait intervenir la voie de la télomérase, et ceci probablement à une phase précoce. Dans un travail annexe sur le sarcome indifférencié (embryonnaire) hépatique, nous montrons que la télomérase n'est pas impliquée contrairement à p53.Human telomerase comprises a RNA (hTR) and a protein with reverse transcriptase activity (hTERT). Telomerase extends chromosome ends in compensation for the attrition of the telomeres during replication. Telomerase can be involved during cellular immortalisation. In our study, we explore the involvement of telomerase in bladder urothelial carcinogenesis. Expression of hTRT protein was studied respectively by in situ hybridization and immunohistochemistry in tumours and normal urothelium. The level of expression of hTR and hTERT was significantly higher in urothelial tumours than in normal urothelium. The lack of relation with the pronostic markers showed that telomerase is probably involved early in tumoral progression. In an additional work, we demonstrate that telomerase is not involved in carcinogenesis of hepatic undifferentiated (embryonal) sarcoma unlike p53.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Human mitochondrial DNA sequencing by Oxford Nanopore MinION

International audienc

Intra-axonal protein aggregation in the peripheral nervous system

International audienceIntracellular protein aggregates are common pathological hallmarks of many neurodegenerative disorders, and a defect in axonal transport is also incriminated. Here, we studied intra-axonal abnormal protein aggregation and axonopathy by using immunohistochemistry and electron microscopy on peripheral nerve biopsies from 12 patients with chronic axonal peripheral neuropathy (PN) of unknown etiology. Among these patients, three had idiopathic Parkinson's disease (PD). Intra-axonal ubiquitin aggregates were more numerous in the patients with PD. Intra-axonal aggregates of tau AT8 were found in five patients without PD. Phosphorylated α-synuclein aggregation was absent in all cases, while intra-axonal colocalization of 14-3-3 β and ubiquitin was observed in two PD cases. Electron microscopy revealed enlarged axons crowded with organelles in six cases, including the three patients with PD, thus attesting a slowing of the axoplasmic flux. The number of ubiquitin aggregates was correlated with features of reduced axonal flux, while no such correlation was found for tau and 14-3-3 β. Age did not correlate with the number of tau, ubiquitin, and 14-3-3 aggregates. Thus, both ubiquitin and/or abnormal tau intra-axonal aggregates may be found in chronic axonal PN. Ubiquitin aggregates might reduce the axonal flux or result from a disease producing slowing of axonal transport