WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.B.R.A.I.N Child Canada; Cancer Research UK; Brain Tumour Charity; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences [TAMOP-4.2.2. A-11/1/KONV-2012-0025]; German Cancer Aid/Dr. Mildred Scheel Foundation for Cancer Research; Cure Childhood Cancer Foundation; St. Baldrick's Foundation; Southeastern Brain Tumor Foundation; Action Medical Research; [CZ.1.05/2.1.00/03.0101]; [CZ.1.07/2.3.00/20.0183

Consequences of twenty-first-century policy for multi-millennial climate and sea-level change

Most of the policy debate surrounding the actions needed to mitigate and adapt to anthropogenic climate change has been framed by observations of the past 150 years as well as climate and sea-level projections for the twenty-first century. The focus on this 250-year window, however, obscures some of the most profound problems associated with climate change. Here, we argue that the twentieth and twenty-first centuries, a period during which the overwhelming majority of human-caused carbon emissions are likely to occur, need to be placed into a long-term context that includes the past 20 millennia, when the last Ice Age ended and human civilization developed, and the next ten millennia, over which time the projected impacts of anthropogenic climate change will grow and persist. This long-term perspective illustrates that policy decisions made in the next few years to decades will have profound impacts on global climate, ecosystems and human societies — not just for this century, but for the next ten millennia and beyond.This is the publisher’s final pdf. The published article is copyrighted by Nature Publishing Group and can be found at: http://www.nature.com/nclimate/index.htm

Trifecta and Carpentier Edwards aortic bioprostheses: Comparison of six years follow-up outcomes

Contexte: Comparer les résultats cliniques à moyen terme et la performance hémodynamique de la bioprothèse péricardique stentée Trifecta (TF) pour le remplacement chirurgical de la valve aortique (RVA) avec une bioprothèse chirurgicale couramment utilisée et techniquement comparable. Méthode: Les données de patients consécutifs ayant reçu la TF ou la valve Carpentier Edwards Magna Ease (CE) ont été analysées rétrospectivement. L'analyse a été réalisée sur une cohorte appariée par score de propension. Les critères d'évaluation primaires comprenaient les décès ou réopérations et détériorations structurelles de la valve. La comparaison comprenait également des évaluations échocardiographiques une semaine après la RVS et lors du dernier suivi documenté. Résultats: Deux groupes appariés par score de propension de 170 patients chacun ont été identifiés à partir de la population globale (n=486). L'incidence de la mortalité postopératoire pour la TF et pour la CE (2,9 % vs. 7,1 %, respectivement, p=0,08) et l'inadéquation de la prothèse du patient (patient prosthesis mismatch, 1,2 % et 2,4 %, p=0,41) étaient similaires. Après un suivi moyen de 5,84 ans (TF) et de 6,1 ans (CE), l'incidence des décès/opérations toutes causes confondues (15,3 % vs. 15,9 %, p=0,88 pour la TF et la CE, respectivement) et des maladies valvulaires structurelles (1,8% vs. 2,9%, respectivement, p=0,47) a été similaire. Dans l'ensemble, les gradients de pression transvalvulaires moyens postopératoires étaient significativement plus faibles dans le groupe TF que dans le groupe CE (7,7 ±3,3 vs. 11,3±3,6 mmHg, p&lt; 0.01). Le gradient transvalvulaire moyen est demeuré significativement plus faible jusqu'au dernier suivi pour les valves TF de petite taille (19/21 mm ; 10,5±4,2 vs. 13,8 ±5,9 mmHg, p=0,039) mais pas pour les valves plus grandes (10,3 ±4,8 vs. 9,4 ±3,5 mmHg, p=0,31). Conclusion : La valve Trifecta est une alternative valable à la valve Carpentier Edwards en termes de sécurité, de performance hémodynamique et de durabilité à moyen terme. Les valves de plus petite taille offrent des avantages cliniques supplémentaires, étant donné leurs avantages hémodynamiques persistants à moyen terme

L'action de l'Armée du Salut à Hambourg

Pfister Raymond. L'action de l'Armée du Salut à Hambourg. In: Autres Temps. Cahiers d'éthique sociale et politique. N°56, 1997. pp. 46-53

Cylinder mitral and tricuspid valve replacement in neonates and small children

OBJECTIVES Atrioventricular valve replacement in small children is associated with high morbidity and mortality. There are no prostheses available with a diameter ˂15 mm. This study reports our initial experience with a cylinder valve for mitral and tricuspid valve replacement in infants and small children. METHODS Our cylinder valve was hand-made for patients requiring atrioventricuclar valve replacement with an annulus of <15 mm. A 12-mm Contegra valve was prepared and placed inside a 14-mm Gore-Tex tube graft and sutured on both extremities. RESULTS Eight patients were included, with a median age of 6.9 months (range 1 day to 38 months). Four had mitral and 4 had tricuspid valve replacement. All implants were technically successful, with no significant regurgitation, no stenosis and no left ventricular outflow tract obstruction. There were 3 early deaths from low cardiac output, in patients with significant associated lesions (severe neonatal Ebstein's, pulmonary artery-intact ventricular septum, biventricular conversion from Norwood stage 1). Two patients required early reintervention: 1 for balloon dilatation for stenosis and 1 for reoperation for paravalvular leak. During follow-up, 2 patients had mitral valve replacement with a 16-mm mechanical valve at 9 and 20 months from the cylinder valve implantation. The remaining 2 patients are alive and well 2 years and 2 months after the procedure. CONCLUSIONS Cylinder valve replacement of atrioventricular valves was feasible without any technical issues. It was successful in getting out of a difficult situation and allows for somatic growth and implantation of a reasonably-sized mechanical prosthesis on the annulus

A Provably Starvation-Free Distributed Directory Protocol ⋆

Abstract. This paper presents Combine, a distributed directory protocol for shared objects, designed for large-scale distributed systems. Directory protocols support move requests, allowing to write the object locally, as well as lookup requests, providing a read-only copy of the object. They have been used in distributed shared memory implementations and in data-flow implementations of distributed software transactional memory in large-scale systems. The protocol runs on an overlay tree, whose leaves are the nodes of the system; it ensures that the cost of serving a request is proportional to the cost of the shortest path between the requesting node and the serving node, in the overlay tree. The correctness of the protocol, including starvation freedom, is proved, despite asynchrony and concurrent requests. The protocol avoids race conditions by combining requests that overtake each other as they pass through the same node. Using an overlay tree with a good stretch factor yields an efficient protocol, even when requests are concurrent.