Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

A novel mechanism for BAFF-induced survival of peripheral B cells

After successful rearrangement of the B cell receptor (BCR) in the bone marrow (BM), B cells migrate to the spleen where they become mature. From this moment of their life, they depend mostly on non-redundant survival signais provided by the BCR and by BAFFR, the receptor of B cell activating factor of the TNF family (BAFF). BAFF binds to three receptors, BAFFR, TACI and BCMA, while its close homologue APRIL (A Proliferation-Inducing Ligand) binds to TACI and BCMA, but not to BAFFR. Although BAFF is produced as a membrane-bound protein, its soluble form is responsible for survival of mature B cells. Because BAFFR, TACI and BCMA respond differently to soluble BAFF trimers and to higher order multimers thereof, this study aimed at characterizing the physiological rôle of the "flap" loop of BAFF that mediates interactions between BAFF trimers. Another aim was to refine requirement of plasma cells for BAFF, APRIL and their receptors using genetic and pharmacological approaches. Two distinct mutations in the flap, a peripheral and a central one, both prevented mutimerization of BAFF trimers, but only the central mutation additionally destroyed signaling of BAFF via BAFFR in vitro and in vivo, including in knock-in mice. Remarkably, receptor binding was unaffected for both flap mutants. The signaling defect was overcome by cross-linking anti-BAFF antibodies, supporting the foliowing scénario: after BAFFR binding, interactions of individual BAFF trimer via flap-flap interactions are required to reach the multimerization threshold required for BAFFR signaling. Regarding plasma cells, a central rôle for BAFF and APRIL in their génération and maintenance was confirmed pharmacologically and genetically, but further investigations will be required to establish the respective contributions of receptors in that process. The discovery that receptor binding can be uncoupled from biological effects reveal how the TNF family ligand BAFF initiâtes signaling. This also establishes an essential and non-redundant function for the flap of BAFF and suggests that binding and activation of BAFFR by BAFF can be targeted independently to inhibit or activate the function of BAFF. -- Les cellules B de la moelle osseuse ayant réarrangé avec succès leur récepteur (BCR, récepteur des cellules B) migrent dans la rate où elles terminent leur maturation. Elles dépendront dès cet instant de deux signaux principaux et indépendants pour leur survie: ceux qui proviennent du récepteur des cellules B et ceux générés par BAFFR, le récepteur du facteur d'activation des cellules B de la famille TNF (BAFF). Le BAFF lie trois récepteurs, BAFFR, TACI et BCMA, tandis que son plus proche homologue, APRIL (A Proliferation-Inducing Ligand) lie TACI et BCMA mais pas BAFFR. Bien que BAFF soit produit sous forme membranaire, c'est sa forme soluble qui détermine la survie des cellules B matures. Comme BAFFR, TACI et BCMA répondent de manière différenciée aux trimers de BAFF et à ses multimères de plus grande taille, cette étude visait la caractérisation du rôle physiologique du "flap" de BAFF, une boucle structurelle qui permet une interaction entre les trimers de BAFF. Un second objectif était l'étude, par des approches génétiques et pharmacologiques, de la dépendance des cellules plasmatiques pour BAFF, APRIL et leurs récepteurs. Deux mutations distinctes du flap, l'une périphérique et l'autre centrale, ont toutes deux prévenu la mutimérisation des trimer de BAFF, mais seule la mutation centrale a interféré en plus avec la signalisation de BAFF via BAFFR in vitro et in vivo, y compris chez des souris knock-in. Par contre, les mutations n'ont aucunement empêché la liaison des mutants de BAFF aux récepteurs, y compris à BAFFR. Le défaut d'activation du signal a pu être corrigé par l'addition d'anticorps anti-BAFF qui pontent les trimers de BAFF, ce qui suggère la séquence d'événements suivants: après la liaison des trimers de BAFF à BAFFR, ceux-ci s'apparient par des interactions flap-flap jusqu'à atteindre le niveau limite d'agrégation de BAFFR requis pour la signalisation. En ce qui concerne les cellules plasmatiques, la contribution importante de BAFF et d'APRIL à la génération et au maintien de ces cellules a été confirmée tant par les approches pharmacologiques que génétiques, alors que d'autres recherches seront nécessaires pour établir les implications respectives des récepteurs dans ce processus. La découverte selon laquelle l'engagement de BAFFR peut être découplé de son activation révèle la manière dont BAFF initie un signal dans les cellules B. L'identification d'une fonction essentielle et irremplaçable du flap suggère que la liaison et l'activation de BAFFR par BAFF peuvent être exploitées de manière indépendante pour inhiber ou activer la fonction de BAFF

Changes in Accident & Emergency Visits and Return Visits in Relation to the Enforcement of Daylight Saving Time and Photoperiod

Daylight saving time (DST) is a source of circadian disruption impinging on millions of people every year. Our aim was to assess modifications, if any, in the number, type, and outcome of Accident & Emergency (A&E) visits/return visits over the DST months. The study included 366,527 visits and 84,380 return visits to the A&E of Padova hospital (Northern Italy) over 3 periods between the years 2007 and 2016: period 1 (2 weeks prior to DST to 19 weeks after), period 2 (2 weeks prior to the return to "winter time" to 4 weeks after), and period 3 (5 consecutive non-DST weeks). For each A&E visit/return visit, information was obtained on triage severity code, main medical complaint, and outcome. Data were aggregated by day, cumulated over the years, and analyzed by generalized Poisson models. Generalized additive models for Poisson data were then used to include photoperiod as an additional covariate. An increase in A&E visits and return visits (mostly white codes, resulting in discharges) was observed a few weeks after the enforcement of DST and was significant over most weeks of period 1 (increase of 4830 [2.8%] visits and 4825 [10%] return visits per week per year). After the return to winter time, a decrease in absolute number of return visits was observed (mostly white codes, resulting in discharges), which was significant at weeks 3 and 4 of period 2 (decrease of 4525 [10%] return visits per week per year). When photoperiod was taken into account, changes in A&E visits (and related white codes/discharges) were no longer significant, while changes in return visits (and related white codes/discharges) were still significant. In conclusion, changes in A&E visits/return visits were observed in relation to both DST and photoperiod, which are worthy of further study and could lead to modifications in A&E organization/staffing

CB‐103: A novel CSL‐NICD inhibitor for the treatment of NOTCH‐driven T‐cell acute lymphoblastic leukemia: A case report of complete clinical response in a patient with relapsed and refractory T‐ALL

Abstract Relapsed T cell acute lymphoblastic leukaemia (T‐ALL) has a very poor prognosis. A 24‐year‐old patient with relapsed high‐risk T‐ALL (PTEN gene deletion; NOTCH1 mutation), was treated with the NOTCH inhibitor CB‐103. Within 1 week of starting CB‐103, the bone marrow was free of T‐ALL blast infiltration (MRD+) and successfully underwent allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Sequential samples of ctDNA to monitor the disease after allo‐HSCT showed a decrease of circulating Notch1 and PTEN alterations. This is the first T‐ALL patient treated with CB‐103. The observed clinical response encourages further exploration of CB‐103 in ALL

Pharmacological disruption of the Notch transcription factor complex

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers