Deregulation and Targeting of TP53 Pathway in Multiple Myeloma

Multiple Myeloma (MM) is an incurable disease characterized by a clonal evolution across the course of the diseases and multiple lines of treatment. Among genomic drivers of the disease, alterations of the tumor suppressor TP53 are associated with poor outcomes. In physiological situation, once activated by oncogenic stress or DNA damage, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. Its inactivation participates to drug resistance in MM. The frequency of TP53 alterations increases along with the progression of the disease, from 5 at diagnosis to 75% at late relapses. Multiple mechanisms of regulation lead to decreased expression of p53, such as deletion 17p, TP53 mutations, specific microRNAs overexpression, TP53 promoter methylations, and MDM2 overexpression. Several therapeutic approaches aim to target the p53 pathway, either by blocking its interaction with MDM2 or by restoring the function of the altered protein. In this review, we describe the mechanism of deregulation of TP53 in MM, its role in MM progression, and the therapeutic options to interact with the TP53 pathway

Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC).

International audienceBACKGROUND AND OBJECTIVES: High-dose chemotherapy with allogeneic stem cell transplantation (SCT) has proven to be a successful treatment for low-grade lymphoma (LGL), but is associated with considerable transplant-related mortality (TRM). In an effort to reduce toxic mortality while maintaining the graft-versus-leukemia effect, allogeneic SCT has been combined with a reduced-intensity conditioning (RIC) regimen. The aim of this study was to determine the outcome of patients with LGL treated with RIC allogeneic SCT. DESIGN AND METHODS: This retrospective multicenter study included 73 patients with relapsed or refractory LGL allografted after a RIC regimen between 1998 and 2005 whose data were recorded in a French registry. RESULTS: Patients received a median of three lines of therapy prior to RIC allogeneic SCT. The most widely used conditioning regimens were fludarabine + busulfan + antithymocyte globulin (n=43) and fludarabine + total body irradiation (n=21). Prior to allografting, patients were in complete response (CR; n=21), partial response (PR; n=33) or had chemoresistant disease (n=19). The median follow-up was 37 months (range, 16 to 77 months). In patients in CR, PR and chemoresistant disease, the 3-year overall survival rates were 66%, 64% and 32%, respectively, while the 3-year event-free survival rates were 66%, 52% and 32%, respectively. The 3-year cumulative incidences of TRM were 32%, 28% and 63%, respectively. The incidence of relapse was 9.6%. INTERPRETATION AND CONCLUSIONS: Although associated with significant TRM, RIC allogeneic SCT in advanced chemosensitive disease leads to long-term survival

Geographical limits to species-range shifts are suggested by climate velocity

The reorganization of patterns of species diversity driven by anthropogenic climate change, and the consequences for humans, are not yet fully understood or appreciated. Nevertheless, changes in climate conditions are useful for predicting shifts in species distributions at global and local scales. Here we use the velocity of climate change to derive spatial trajectories for climatic niches from 1960 to 2009 (ref. 7) and from 2006 to 2100, and use the properties of these trajectories to infer changes in species distributions. Coastlines act as barriers and locally cooler areas act as attractors for trajectories, creating source and sink areas for local climatic conditions. Climate source areas indicate where locally novel conditions are not connected to areas where similar climates previously occurred, and are thereby inaccessible to climate migrants tracking isotherms: 16% of global surface area for 1960 to 2009, and 34% of ocean for the \u27business as usual\u27 climate scenario (representative concentration pathway (RCP) 8.5)8 representing continued use of fossil fuels without mitigation. Climate sink areas are where climate conditions locally disappear, potentially blocking the movement of climate migrants. Sink areas comprise 1.0% of ocean area and 3.6% of land and are prevalent on coasts and high ground. Using this approach to infer shifts in species distributions gives global and regional maps of the expected direction and rate of shifts of climate migrants, and suggests areas of potential loss of species richness

Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

On the Origin and Spread of the Scab Disease of Apple: Out of Central Asia

Background Venturia inaequalis is an ascomycete fungus responsible for apple scab, a disease that has invaded almost all apple growing regions worldwide, with the corresponding adverse effects on apple production. Monitoring and predicting the effectiveness of intervention strategies require knowledge of the origin, introduction pathways, and population biology of pathogen populations. Analysis of the variation of genetic markers using the inferential framework of population genetics offers the potential to retrieve this information. Methodology/Principal Findings Here, we present a population genetic analysis of microsatellite variation in 1,273 strains of V. inaequalis representing 28 orchard samples from seven regions in five continents. Analysis of molecular variance revealed that most of the variation (88%) was distributed within localities, which is consistent with extensive historical migrations of the fungus among and within regions. Despite this shallow population structure, clustering analyses partitioned the data set into separate groups corresponding roughly to geography, indicating that each region hosts a distinct population of the fungus. Comparison of the levels of variability among populations, along with coalescent analyses of migration models and estimates of genetic distances, was consistent with a scenario in which the fungus emerged in Central Asia, where apple was domesticated, before its introduction into Europe and, more recently, into other continents with the expansion of apple growing. Across the novel range, levels of variability pointed to multiple introductions and all populations displayed signatures of significant post-introduction increases in population size. Most populations exhibited high genotypic diversity and random association of alleles across loci, indicating recombination both in native and introduced areas. Conclusions/Significance Venturia inaequalis is a model of invasive phytopathogenic fungus that has now reached the ultimate stage of the invasion process with a broad geographic distribution and well-established populations displaying high genetic variability, regular sexual reproduction, and demographic expansion.Contexte Venturia inaequalis est un champignon ascomycete responsable de la tavelure du pommier, une maladie qui a envahi presque toutes les régions du monde où le pommier est cultivé posant ainsi de graves problèmes en production. Prévenir et enrayer efficacement la réussite d’un tel succès invasif nécessite des connaissances approfondies sur l’origine, les voies d’introduction, la biologie et la génétique de ces populations invasives. En utilisant le potentiel d’inférence de la génétique des populations, l’analyse de la variation de marqueurs génétiques offre la possibilité d’accéder à ces informations. Méthodologie et Principaux résultats Ici nous présentons l’analyse de données microsatellites obtenues pour 1273 souches de V. inaequalis provenant de 28 vergers prélevées dans 7 régions sur les 5 continents. L’analyse de la variance moléculaire révèle que 88% de la variation se retrouve dans les vergers échantillonnés, ce qui est compatible avec d’importantes migrations historiques du champignon entre et à l’intérieur même des régions. Malgré cette très faible structuration des populations, les différentes analyses de clustering mettent en évidence un partage des populations en groupes séparés correspondant à leur origine géographique, montrant ainsi que chaque région héberge une population distincte du champignon. Ensemble, les résultats obtenus sur la comparaison du niveau de variabilité entre populations, les analyses de coalescence et les modèles de migration testés plaident en faveur d’un scénario dans lequel le champignon aurait émergé d’Asie Centrale, où le pommier a été domestiqué, avant d’être introduit en Europe puis plus récemment dans les autres continents suite à l’expansion de la culture du pommier. Les niveaux de variabilité indiquent que ces territoires ont subi des introductions multiples et que les populations portent toutes des signatures révélant de fortes expansions démographiques après leur introduction. Enfin, la forte diversité génotypique des populations et l’association aléatoire des allèles entre loci suggèrent que le champignon présente une reproduction sexuée régulière à la fois dans les régions où il a été introduit et dans sa région native. Conclusion et Portée. Venturia inaequalis est un modèle de champignons phytopathogène invasif qui a maintenant atteint le stade ultime du processus invasif, c’est à dire une très large distribution géographique par des populations bien établies montrant une grande diversité génétique, une reproduction sexuée régulière et une histoire d’expansion démographique

Intelligence et expérience : possible contribution d'une approche pathologique

Summary : Intelligence and experience : possible contribution of a pathological approach. The influence of chronological age and family environment on the performance in crystallized intelligence markers was studied in a group of persons with mental retardation aged from 6 to 20 years. Twelve fluid and crystallized intelligence markers were administered. In order to identify underlying factors, principal components and common factors analyses were carried out. Because the tests were mainly fluid and crystallized ones, it was not surprising that the application of the Kaiser-Guttman criterion clearly indicated two factors to be extracted from the correlation matrix among raw scores. The first factor had high loadings on crystallized intelligence tests, whereas the second loaded principally fluid ones. Fluid intelligence level of each participant was then determined using the mean z scores in fluid markers, and stepwise regression analyses were performed to estimate the relative contribution of CA and family environment to the crystallized intelligence tests' variance. In these analyses, fluid intelligence level was systematically entered first in the equations to partial out at the outset its influence from those of CA and family environment. Results indicate that chronological age explains an important fraction of the crystallized intelligence markers variance (from 5 to 24 %), whereas the family environment influence appears much more modest (front 0 to 3 %). However, this result seems to be attributable to the characteristics of the family environment scale used in the present study and to the restricted range of family environments in the sample. Key words : life experience, chronological age, fluid intelligence, crystallized intelligence, family environment, factorial theories of intelligence.Résumé L'influence de l'âge chronologique et du milieu familial sur les performances à divers marqueurs d'intelligence cristallisée a été étudiée sur un échantillon de personnes retardées mentales âgées de 6 à 20 ans. Douze tests d'intelligence fluide et cristallisée leur ont été administrés. La matrice de corrélations entre ces 12 tests a été soumise à plusieurs analyses factorielles (composantes principales et facteurs communs) pour en identifier les facteurs latents. Deux facteurs sont clairement apparus après rotation oblique, le premier saturant principalement les marqueurs d'intelligence fluide, le second les marqueurs d'intelligence cristallisée. Le niveau d'intelligence fluide des participants a été estimé en utilisant la moyenne de leurs scores centrés et réduits aux épreuves d'intelligence fluide. L'influence de l'âge et du milieu familial sur les différents marqueurs d'intelligence cristallisée a été ensuite évaluée par l'intermédiaire d'analyses de régression par étapes dans lesquelles le niveau d'intelligence fluide a été systématiquement entré en priorité dans les équations pour éviter de confondre son effet avec celui de l'âge et du milieu familial. Les résultats montrent que l'âge explique une part substantielle de la variance des marqueurs d'intelligence cristallisée (de 5 à 24 %), ce qui suggère une influence marquée de cette variable sur la composante cristallisée de l'intelligence chez les personnes retardées. La contribution du milieu familial apparaît bien plus modeste (de 0 à 3 % ). Mais ce résultat est sans doute lié aux caractéristiques de l'instrument élaboré pour évaluer le milieu familial des sujets ainsi qu'à la surreprésentation des familles défavorisées au sein de l'échantillon. Mots-clés : expérience éducative, âge chronologique, intelligence fluide, intelligence cristallisée, environnement familial, théories factorielles de l'intelligence.Facon Bruno, Facon-Bollengier Thérèse. Intelligence et expérience : possible contribution d'une approche pathologique. In: L'année psychologique. 1998 vol. 98, n°4. pp. 639-658

Sur la loi des rendements décroissants. Efficience intellectuelle et facteur général

Summary : On the law of diminishing returns : Intellectual efficiency and g factor. WISC-R results of 1 069 subjects with moderate and mild mental retardation aged from 8 to 16;6 years were collected and analyzed to determine whether the degree of correlation between subtests is a function of the level of mental retardation. All subtests of the WISC-R were successively used to split the sample into two groups (low vs high score). Analyses revealed that the correlations between subtests and the variance explained by the first factor extracted from the correlation matrices were higher in the low score group, regardless of the subtest used to divide the sample. These results seem to confirm the law of diminishing returns and indicate that it is valid below the limits of normal variations. Several implications and limits of this study are discussed. Key words : mental retardation, WISC-R, g factor, law of diminishing returns.Résumé Les résultats au WISC-R de 1 069 sujets retardés modérés et légers âgés de 8 à 16;6 ans ont été collectés puis analysés de manière à déterminer si l'importance des corrélations entre les sous-tests varie en fonction de l'efficience intellectuelle. Les sous-tests qui composent le WISC-R ont été successivement utilisés pour subdiviser l'échantillon en deux groupes (note faible vs note élevée). Les analyses montrent que le degré de liaison entre les sous-tests et la part de variance expliquée par le premier facteur extrait des matrices de corrélations sont plus élevés pour les participants crédités des notes les plus faibles, quel que soit le sous-test utilisé pour constituer les groupes. Ces résultats confirment la loi des rendements décroissants et indiquent qu'elle est valide en deçà de la limite des variations normales. Les implications et les limites de l'étude font l'objet de la discussion. Mots-clés : retard mental, WISC-R, facteur général, loi des rendements décroissants.Facon Bruno. Sur la loi des rendements décroissants. Efficience intellectuelle et facteur général. In: L'année psychologique. 2003 vol. 103, n°1. pp. 81-102

Vieillissement cognitif et retard mental. Une analyse transversale des performances intellectuelles d'adultes retardés mentaux

Summary : Aging and mental retardation : A cross-sectional analysis of intellectual performance of adults with mental retardation. WAIS-R results of 559 adults with moderate and mild mental retardation aged from 20 to 54 years were collected and analysed by the means of hierarchical regression analyses. Analyses revealed the classical aging pattern observed in adults without mental retardation, that is, a stability of scores on the verbal scale and a decrease of scores on the performance scale. Likewise, even if scores of participants with mild mental retardation are logically superior to those of participants with moderate mental retardation, the aging pattern is nearly the same whatever the level of mental retardation. Indeed, even ifthey are significant, the interactions between age and IQ explain only a very small part of the variance of scores on the two WAIS-R scales. These results suggest that persons with mild or moderate mental retardation do not present a specific age decline of their cognitive skills. Several implications and limits ofthis study are discussed. Key words : mental retardation, WAIS-R, cognitive aging, cross-sectional analysis.Résumé Les résultats au WAIS-R de 559 adultes retardés mentaux modérés et légers âgés de 20 à 54 ans ont été collectés puis analysés par l'intermédiaire d'analyses de régression hiérarchiques. Les analyses montrent que leurs scores aux sous-tests verbaux tiennent avec l'âge alors qu'ils se dégradent pour les sous-tests de performance. En cela, les adultes retardés ne se distinguent pas de leurs pairs non retardés. D'autre part, si les performances des participants retardés légers sont logiquement supérieures à celles des participants retardés modérés, l'effet de l'âge ne semble pas être fonction du niveau de retard mental. Les interactions entre l'âge et le QI sont certes significatives, pour l'échelle verbale comme pour l'échelle performance, mais n'expliquent qu'une part très réduite de la variance. Leur portée est donc toute relative. Ces résultats suggèrent que les personnes retardées ne présentent pas un déclin cognitif spécifique, que ce soit en cas de retard mental modéré ou léger. Les implications et les limites de cette étude font l'objet de la discussion. Mots-clés : retard mental, WAIS-R, vieillissement cognitif, analyse transversale.Facon Bruno. Vieillissement cognitif et retard mental. Une analyse transversale des performances intellectuelles d'adultes retardés mentaux. In: L'année psychologique. 2002 vol. 102, n°2. pp. 235-253