NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2.

Enhancer of Zeste homologue 2 (EZH2) belongs to the polycomb repressive complex 2 and catalyzes the methylation of histone H3 lysine 27. These pivotal epigenetic marks are altered in many cancers, including melanoma, as a result of EZH2 overexpression. Here, we show that the non-canonical-NF-kB pathway accounts for most of the NF-kB activity in melanoma cells, in contrast to non-cancer cells. We identify the non-canonical-NF-kB pathway as a key regulator of EZH2 expression in melanoma. We show a striking correlation between NF-kB2 and EZH2 expression in human melanoma metastases. We demonstrate that inhibition of the non-canonical NF-kB pathway by targeting NF-kB2/p52 or the upstream kinase NIK restores the senescence program in melanoma cells through the decrease of EZH2. On the contrary, the overexpression of NF-kB2/p52 in normal human melanocytes prevents stress- and oncogene-induced senescence. Finally, we show in mouse models that the inhibition of the non-canonical NF-kB pathway restores senescence and induces a dramatic reduction in tumor growth compared with controls, thus providing potential drug targets for the re-induction of senescence in melanoma and other cancers where EZH2 is overexpressed.

[Evaluation of the metrological quality of the medico-administrative data for perinatal indicators: A pilot study in 3 university hospitals]. / Évaluation de la qualité métrologique des données du programme de médicalisation du système d'information (PMSI) en périnatalité : étude pilote réalisée dans 3 CHU.

BACKGROUND: In order to assess public health policies for the perinatal period, routinely produced indicators are needed for the whole population. In France, these indicators are used to compare the national public health policy with those of other European countries. French administrative and medical data (PMSI) are straightforward and reliable and may be a valuable source of information for research. This study aimed to measure the quality of PMSI data from three university health centers for core indicators in perinatal health. METHOD: PMSI data were compared with medical files in 2012 from 300 live births after 22 weeks of amenorrhea, drawn at random from University Hospitals in Dijon, Paris and Nancy. The variables were chosen based on the Europeristat Project's core and recommended indicators, as well as those of the French National Perinatal survey conducted in 2010. The information gathered blindly from the medical files was compared with the PMSI data positive predictive value (PPV) and the sensitivity was used to assess data quality. RESULTS: Data on maternal age, parity and mode of delivery as well as the rates of premature births were superimposable for the two sources. The PPV for epidural injection was 96.2% and 94.3% for perineal tears. Overall, maternal morbidity was underdocumented in the PMSI, so the PPV was 100.0% for pre-existing diabetes, 88.9% for gestational diabetes and 100.0% for high blood pressure with a rate of 9.0% in PMSI and 6.3% in the medical files. The PPV for bleeding during labor was 89.5%. CONCLUSION: To conclude, PMSI data are apparently becoming more and more reliable for two reasons: on one hand, the importance of these data for budgetary promotion in hospitals; on the other, the increasing use of this information for statistical and epidemiological purposes.

[Risks acceptability related to obstetrical epidural analgesia]. / Acceptabilité des risques associés à la mise en place d'une analgésie péridurale obstétricale.

OBJECTIVES: Evaluation of the acceptability of complications related to obstetrical epidural analgesia in two populations, parturients and anesthesiologists. STUDY DESIGN: Prospective, transversal, single center study. MATERIALS AND METHODS: Evaluation of the acceptability of complications associated with obstetric epidural analgesia performed using a questionnaire of six clinical scenarii in two populations: parturients cared at the University maternity of Nancy and anesthesiologists of Lorraine. Patients were interviewed by an anesthesiologist, physicians via Internet. Acceptability was assessed using two tools, the absolute acceptability with a visual analog scale and the relative acceptability obtained by classifying clinical scenario against each other, in ascending order of acceptability. RESULTS: One hundred and forty-six parturients and 87 anesthetists assessed the acceptability of the different scenarios. The three less serious scenarios (hypotension, failure, dural tap) were acceptable for both populations. One case (spinal hematoma) was unacceptable for parturients. Three cases of varying severity (failure, dural tap, plexus injury with sequelae) were judged significantly less acceptable by patients than physicians (5.9 vs. 7.9 [P<0.001], 5.75 vs. 8.1 [P<0.01], 4.1 vs. 5.1 [P=0.035]). Multivariate analysis did not show any predictive factor of acceptability in both populations. CONCLUSION: In this study, the overall acceptability of the inherent complications of epidural analgesia was good in the two populations. It was essentially based on the notion of severity and preventability. A large interindividual variability was observed and a better acceptance by the anesthesiologists.

[Deployment of the checklist "Patient safety in the operating room" in two Lorraine hospitals. Performances and difficulties]. / Déploiement de la check-list "Sécurité du patient au bloc opératoire" dans deux hôpitaux lorrains. Performances et difficultés.

OBJECTIVE: To evaluate the implementation of the checklist HAS 2010 in two Lorraine health facilities to identify objectively brakes and levers to suggest possible improvements. STUDY DESIGN: Descriptive survey. MATERIAL AND METHODS: Operating rooms of the Neurosciences building Central University Hospital, Nancy, Belle-Isle Hospital participating public hospital service, Metz. Two stages: a retrospective audit allowed to objectify quantitatively the presence of CL in the patient record and monitor compliance with the instructions of filling. A survey by self-administered questionnaire to professionals to assess the use of CL. RESULTS: CL was present in 50 % and 100 % records. The filling did not comply with instructions of the HAS (occupancy, three different times, time out before incision, stop the procedure if "no") and it was hard for about 30 % of participants, some items have problems of understanding. CL has strengthened information sharing about one third of respondents, over half of them are of interest, it has already helped to prevent errors. The deployment strategy influences directly the involvement of professionals. The evaluation of the use of CL cannot be done only through an audit record; the association with a self-administered questionnaire appears to be relevant. CONCLUSION: Good adhesion to the concept, hope for better results after stock enhancement: optimize information and training of all professionals, avoid duplication with other documents. The audit record alone is not a good tool for evaluating the use of LBC, we must associate a self-administered questionnaire.

[Changes in circulating lymphocyte subsets in alcoholic hepatopathies. Respective role of alcohol, hepatocellular insufficiency and malnutrition]. / Etude des modifications des sous-populations lymphocytaires circulantes au cours des hépatopathies alcooliques. Rôle respectif de l'alcool, de l'insuffisance hépato-cellulaire et de la dénutrition.

Peripheral lymphocyte subpopulations have been quantified by a direct and indirect, immunofluorescence technique, using monoclonal antibodies, in 22 patients with continued heavy drinking, hepatocellular dysfunction (spider angiomata, ascites, and factor V decrease) (group I), in 16 patients with a history of heavy drinking and abstinence maintained for at least 6 months and hepatocellular dysfunction (group II) and in 28 patients admitted for continued heavy drinking, without hepatocellular dysfunction (group III). Sixteen normal subjects were studied as controls. The total number of lymphocytes and T lymphocytes (OKT3+) were significantly reduced (p less than 0.001) in groups I and II. A significant decrease of B lymphocytes was observed in group II (p less than 0.02). The OKT8+ lymphocytes were significantly reduced in group I (p less than 0.01) and in group II (p less than 0.001); the decrease of the OKT4+ lymphocytes was significant in group II (p less than 0.01) only. The OKT4/OKT8 ratio was higher in group I (p less than 0.05) and group II (p less than 0.01) than in the control group. Normal values of total lymphocytes, B lymphocytes, T lymphocytes subsets and OKT4/OKT8 ratio were observed in group III. In group III, the lymphocyte subpopulations and OKT4/OKT8 ratio were similar in patients with or without abnormalities of liver function tests. In group I and II, no correlation was found between the lymphocyte subpopulations or the OKT4/OKT8 ratio and factor V or nutritional status assessed by anthropometrical and biological tests. T-cell imbalance in alcoholic liver disease does not seem to be related to alcohol consumption, factor V decrease or malnutrition.