To distribute and establish the melanocyte lineage throughout the skin and other developing organs, melanoblasts undergo several rounds of proliferation, accompanied by migration through complex ...environments and differentiation. Melanoblast migration requires interaction with extracellular matrix of the epidermal basement membrane and with surrounding keratinocytes in the developing skin. Migration has been characterized by measuring speed, trajectory and directionality of movement, but there are many unanswered questions about what motivates and defines melanoblast migration. Here, we have established a general mathematical model to simulate the movement of melanoblasts in the epidermis based on biological data, assumptions and hypotheses. Comparisons between experimental data and computer simulations reinforce some biological assumptions, and suggest new ideas for how melanoblasts and keratinocytes might influence each other during development. For example, it appears that melanoblasts instruct each other to allow a homogeneous distribution in the tissue and that keratinocytes may attract melanoblasts until one is stably attached to them. Our model reveals new features of how melanoblasts move and, in particular, suggest that melanoblasts leave a repulsive trail behind them as they move through the skin.
We analyzed 661 adult patients who underwent single-unit (n = 226) or double-unit (n = 435) unrelated cord blood transplantation (UCBT) following a reduced-intensity conditioning (RIC) consisting of ...low-dose total body irradiation (TBI), cyclophosphamide, and fludarabine (Cy/Flu/TBI200). Eighty-two patients received rabbit antithymocyte globulin (ATG) as part of the conditioning regimen (ATG group), whereas 579 did not (non-ATG group). Median age at UCBT was 54 years, and diagnoses were acute leukemias (51%), myelodysplastic syndrome/myeloproliferative neoplasm (19%), and lymphoproliferative diseases (30%). Forty-four percent of patients were transplanted with advanced disease. All patients received ≥4 antigens HLA-matched UCBT. Median number of collected total nucleated cells was 4.4 × 107/kg. In the ATG group, on 64 evaluable patients, ATG was discontinued 1 (n = 27), 2 (n = 20), or > 2 days before the graft infusion (n = 17). In multivariate analyses, the use of ATG was associated with decreased incidence of acute graft-versus-host disease (hazard ratio HR, 0.31; 95% confidence interval CI, 0.17-0.55; P < .0001), higher incidence of nonrelapse mortality (HR, 1.68; 95% CI, 1.16-2.43; P = .0009), and decreased overall survival (HR, 1.69; 95% CI, 1.19-2.415; P = .003). Collectively, our results suggest that the use of ATG could be detrimental, especially if given too close to graft infusion in adults undergoing UCBT following Cy/Flu/TBI200 regimen.
•When possible, ATG should be avoided in adults undergoing UCBT following Cy/Flu/TBI200 regimen.
In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma ...(DLBCL). The 2-year overall survival was 59% (95% CI 49-67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment.
For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 day -7) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days day -7 to day -4) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m
of intravenous doxorubicin, 400 mg/m
of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m
of oral prednisone on days 1-5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714.
Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2-3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5-30·1). The 2-year overall survival was 64·7% (95% CI 55·3-72·7) and median overall survival was not reached (95% CI 30·2-not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was haematological toxicity. Among the 120 patients, grade 3-4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3-4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions.
Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years.
The Lymphoma Study Association, GlaxoSmithKline.
•Crude carob gum was fractionated into two parts soluble at 25 and 80°C.•Complete structural characterization of the two galactomannans fractions was realized.•Physical behavior analysis was carried ...out to study the formed gel networks.•Small structural differences therefore lead to very different physical behaviors.•Fractionation–purification–structure–function relationships were established.
Crude locust bean gum (CLBG) was purified and fractionated into two parts: the first was obtained by solubilization in water at 25°C (GM25) and the second consisted in a further extraction at 80°C on the residual impoverished fraction (GM80). The complete structural characterization has shown that GM80 possessed relatively longer chain lengths than GM25, a slightly lower degree of galactose substitution and a somewhat sharper galactosyl distribution in substituted and unsubstituted regions. A physical behavior analysis was carried out on solubilization kinetics, viscosity, viscoelasticity and formation of associated gels with xanthan or carrageenan. The average structure of GM80 generated larger intra-chain, inter-chain and inter-molecular interactions, resulting in the appearance of a stronger network. Small structural differences therefore generated very different physical behaviors. This study thus allowed to establish, in a precise and complete manner, fractionation–purification–structure–function relationships of galactomannans extracted from carob.
La surcharge en fer est probablement aussi toxique chez les patients âgés atteints de syndrome myélodysplasique (SMD) de faible risque que chez les jeunes patients thalassémiques. Cet impact y est ...plus difficile à démontrer en raison de comorbidités associées comme les atteintes cardiovasculaires qui augmentent la vulnérabilité aux effets toxiques de la surcharge en fer. Ces dernières années, des études de registre ont montré un avantage en termes de survie du traitement par chélateurs (ICT pour Iron Chelation Therapy) du fer chez ces patients. Ces résultats sont aujourd’hui corroborés par une amélioration de la survie sans événement dans une seule étude randomisée : l’étude Telesto. Les courbes de la survie sans événement se séparent après deux ans de suivi. Ceci témoigne d’une inertie dans la survenue de complications. Les avantages de la chélation du fer sont aussi très lentement dévoilés. Il est possible de proposer une chélation du fer aux patients avec un SMD transfusion dépendant avec une espérance de vie d’au moins deux ans. Dans Telesto, les patients présentaient un taux de ferritine sérique (F) d’au moins 1000ng/mL, les recommandations utilisant ce seuil de F comme déclencheur de la chélation semblent renforcées. La question reste ouverte de savoir si la chélation devrait être débutée plus tôt pour une suppression efficace du stress oxydatif lié à la surcharge en fer. Les chélateurs du fer pourraient être utilisés chez les patients atteints de SMD dépendants des transfusions et dont l’espérance de vie est supérieure à deux ans. Y compris peut-être chez des patients de plus haut risque répondant aux agents hypométhylants.
Iron overload (IO) is probably as toxic in elderly patients with low-risk myelodysplastic syndromes (MDS) as in young thalassemic patients. This impact is more difficult to demonstrate because of associated comorbidities. Cardiovascular disease increases vulnerability to the toxic effects of IO. In recent years, registry studies have shown a survival benefit of Iron Chelation Therapy (ICT) in these patients. These findings are now corroborated by an improvement in event-free survival in a single randomized study: the Telesto study. The EFS curves separate after two years of follow-up. This indicates inertia in the occurrence of complications. The benefits of ICT are also very slowly being revealed. It is possible to offer ICT to patients with transfusion-dependent MDS with a life expectancy of at least two years. In Telesto, patients had a serum ferritin (F) level of at least 1000ng/mL, recommendations using this F threshold as a trigger for chelation seem to be reinforced. It remains an open question whether chelation should be started earlier for effective suppression of IO-related oxidative stress. ICTs could be used in transfusion-dependent MDS patients with life expectancy greater than two years. including possibly higher risk patients responding to hypomethylating agents.
Abstract Background Iron chelation therapy (CT) improves survival in thalassemia major but its beneficial effects on survival in MDS patients remain uncertain. Methods We analyzed, by multivariate ...analysis, survival and causes of deaths in 97 low or intermediate 1 IPSS patients regularly transfused as outpatients, chelated or not, who were included during a month period and followed for 2.5 years. Results 44 (45%) of patients were not chelated and 53 (55%) received CT, mainly with deferoxamine, for at least 6 months (median duration of chelation 36 months, range 6–131+). During the follow-up period, 66 of the 97 patients died, including 51% and 73% of chelated and non-chelated patients, respectively. Median overall survival was 53 months and 124 months in non-chelated and in chelated patients ( p < 0.0003). Causes of death did not significantly differ between the two groups ( p = 0.51). In multivariate Cox analysis, adequate chelation was the strongest independent factor associated with better OS. Conclusion Iron chelation therapy appears to improve survival in heavily transfused lower risk MDS, but prospective randomized studies are required to confirm our findings, and to determine more precisely the mechanisms of this potential survival benefit.
Ces dernières décennies, les villes africaines sont confrontées à des séries d'inondations en lien avec l'urbanisation rapide, l'intensification des fortes pluies et la défaillance du réseau de ...drainage pluvial. La prévision de ces inondations constitue un enjeu majeur, et passe par la cartographie précise et lisible des écoulements de surface. Cette étude, menée dans la périphérie urbaine de l'agglomération de Dakar, vise à proposer une méthode de calcul permettant de localiser les débordements du réseau de drainage à l'échelle de l'agglomération, avec des temps de calcul compatibles avec la prévision en temps réel. Après avoir décrit brièvement la méthode, l'article s'attache à montrer comment intégrer les différents objets urbains modifiant les directions de drainage ou les caractéristiques des écoulements (bâti, collecteurs, bassins de retenue) et restituer la topologie du drainage à une échelle fine (5 m). La méthode, basée sur un MNT, est décrite en présentant les algorithmes utilisés ou développés, illustrés par des exemples. Ces algorithmes sont opérationnels dans le logiciel ATHYS et son module Vicair. Cet article sera complété ultérieurement par la description de la modélisation hydrologique et hydraulique associée à cette topologie.
We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion‐negative hypereosinophilia (HE)/hypereosinophilic syndrome ...(HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty‐five patients (54%) had at least one mutation involving the JAK‐STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK‐STAT mutations were preceded by (or associated with) myelodysplasia‐related gene mutations, especially in RNA‐splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio HR 4.95 1.87–13.13; p = .001), anemia (HR 5.50 2.24–13.49; p < .001), and the presence of a high‐risk mutation (as per the molecular international prognosis scoring system: HR 6.87 2.39–19.72; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK‐STAT‐mutated patients, ruxolitinib showed positive hematological responses including in STAT5A‐mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion‐negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK‐STAT mutations and eosinophilia as a new “gene mutated‐entity” that could be differentiated from CEL, NOS, and idiopathic HES.
Mutations of the JAK‐STAT pathway (JAK1, JAK2, STAT5B, STAT5A) are frequent (>50% of patients) in patients with tyrosine kinase fusion‐negative hypereosinophilic syndromes, and are amenable to JAK inhibition.
PDF
