Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial

Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate

Studies of ultra-intense laser plasma interactions for fast ignition

Copyright 2000 American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in Physics of Plasmas, 7(5), 2014-2022, 2000 and may be found at http://dx.doi.org/10.1063/1.87402

Establishment of a community managed marine reserve in the Bay of Ranobe, southwest Madagascar

The Bay of Ranobe, in southwest Madagascar, once noted for its high biodiversity and fish abundance, is under increasing pressure from overfishing, pollution, sedimentation and tourism. The declining health of the coral reef is reflected in fishery productivity and survey data on biological diversity. Sustainable conservation requires the engagement of all interested parties and the integration of their needs into resource management. The British NGO ReefDoctor has adopted this approach in establishing the first community-protected site in the Bay of Ranobe, the Massif des Roses. This is a large coral patch with a high percentage of live coral cover (38%) and important fish diversity compared to other sites surveyed in the lagoon. Since 25 May 2007 it has been legally recognised as a community managed marine reserve under temporary protection where fishing is banned. Tourists must now pay an entry fee to visit the site, with the proceeds contributing to the funding of community projects. In conjunction with the protection of this site, ReefDoctor has worked with local people, regional and local government, tour operators and hotels, and conservation organisations to set up ‘FIMIHARA’, an association representative of local people responsible for the management of this site and the development of sustainable conservation initiatives in the Bay of Ranobe. This paper explains the approach taken by ReefDoctor, by setting up and working with FIMIHARA, to protect the Massif des Roses site and develop other conservation initiatives and community projects in the Bay of Ranobe. RÉSUMÉ La baie de Ranobe, au sud-ouest de Madagascar, autrefois remarquable pour sa biodiversité et l’abondance de la pêche, est de plus en plus menacée par la surpêche, la sédimentation, la pollution et le tourisme. Le déclin de l’état de santé du récif corallien se reflète dans la diminution de la productivité des pêcheries et dans les suivis de la biodiversité marine. La situation est à présent critique car les ressources marines associées au récif assurent la subsistance des populations côtières vivant le long de la baie. Nous considérons ici qu’une protection pérenne nécessite un engagement concret de toutes les parties prenantes - en particulier des communautés locales - et que leurs besoins soient intégrés dans la gestion des ressources. L’ONG ReefDoctor a mis en oeuvre cette approche lors de la création de la première réserve marine dans la baie de Ranobe gérée par la communauté locale, le Massif des Roses. Cette réserve est constituée d’un grand massif de corail largement couvert de coraux et abritant une importante diversité de poissons par rapport au reste du lagon. Depuis le 25 mai 2007, ce site est légalement reconnu comme réserve marine communautaire avec un statut de protection temporaire ; la pêche et les pratiques destructrices associées au tourisme y sont interdites. De plus, les touristes doivent désormais payer un droit d’entrée pour visiter le site, qui contribue au financement de projets communautaires. En parallèle avec la protection du site, ReefDoctor a travaillé avec les communautés locales, les responsables nationaux et régionaux du gouvernement, les opérateurs touristiques et diverses organisations de protection de la nature pour créer l’association FIMIHARA, représentative de la population locale. Cette association, qui a un statut légal depuis le 11 avril 2007, a pour but d’améliorer la qualité de vie de ceux qui vivent le long de la baie de Ranobe et de mettre en oeuvre des projets de conservation des ressources marines et terrestres dans la région de la baie de Ranobe. La création de la réserve marine communautaire du Massif des Roses a rapidement connu le succès qui s’est traduit par la vente de plus d’un millier de tickets, mais l’association FIMIHARA doit encore faire face à de nombreux défis. L’objectif principal de l’association à long terme est de développer son indépendance par rapport à l’ONG ReefDoctor et sa capacité à gérer indépendamment les ressources marines de la baie de Ranobe dont les communautés locales dépendent pour leur survie

Development of a Multi-Step Leukemogenesis Model of MLL-Rearranged Leukemia Using Humanized Mice

Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rγ−/− (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American-British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia

Cryptic Diversity in Indo-Pacific Coral-Reef Fishes Revealed by DNA-Barcoding Provides New Support to the Centre-of-Overlap Hypothesis

Diversity in coral reef fishes is not evenly distributed and tends to accumulate in the Indo-Malay-Philippines Archipelago (IMPA). The comprehension of the mechanisms that initiated this pattern is in its infancy despite its importance for the conservation of coral reefs. Considering the IMPA either as an area of overlap or a cradle of marine biodiversity, the hypotheses proposed to account for this pattern rely on extant knowledge about taxonomy and species range distribution. The recent large-scale use of standard molecular data (DNA barcoding), however, has revealed the importance of taking into account cryptic diversity when assessing tropical biodiversity. We DNA barcoded 2276 specimens belonging to 668 coral reef fish species through a collaborative effort conducted concomitantly in both Indian and Pacific oceans to appraise the importance of cryptic diversity in species with an Indo-Pacific distribution range. Of the 141 species sampled on each side of the IMPA, 62 presented no spatial structure whereas 67 exhibited divergent lineages on each side of the IMPA with K2P distances ranging between 1% and 12%, and 12 presented several lineages with K2P distances ranging between 3% and 22%. Thus, from this initial pool of 141 nominal species with Indo-Pacific distribution, 79 dissolved into 165 biological units among which 162 were found in a single ocean. This result is consistent with the view that the IMPA accumulates diversity as a consequence of its geological history, its location on the junction between the two main tropical oceans and the presence of a land bridge during glacial times in the IMPA that fostered allopatric divergence and secondary contacts between the Indian and Pacific oceans

Changes of T-lymphocyte subpopulation and differential expression pattern of the T-bet and GATA-3 genes in diffuse large B-cell lymphoma patients after chemotherapy

BACKGROUND AND OBJECTIVE: T cell-mediated immunity plays an important role in enhancing antitumor response.This study aimed to investigate the changes in the T-lymphocyte subpopulation and to characterize the differential expression pattern of corresponding regulatory genes in peripheral blood mononuclear cells (PBMCs) from diffuse large B cell lymphoma (DLBCL) patients before and after chemotherapy. METHODS: A total of 56 DLBCL patients were recruited for analysis of T-cell subset distribution in the peripheral blood using flow cytometry; serum interferon (IFN)-γ and interleukin (IL)-4 levels using enzyme-linked immunosorbent assays; and early growth response protein 1 (EGR-1), T-bet, GATA-binding protein 3 (GATA-3), and transforming growth factor (TGF)-β mRNA levels using quantitative reverse-transcription polymerase chain reaction. Twenty-six healthy subjects served as controls. RESULTS: The percentage of CD3(+)CD4(+)T lymphocytes in peripheral blood from DLBCL patients was significantly decreased, whereas the percentages of CD3(+)CD8(+)T and CD4(+)CD25(+)T cells were significantly increased compared to those in controls (p < 0.05). Serum levels of IFN-γ and IL-4 were also significantly lower in DLBCL patients than those in controls (p < 0.05), and the levels of EGR-1, T-bet, and GATA-3 mRNA in PBMCs were lower (2.69 ± 1.48, 9.43 ± 2.14, and 20.83 ± 9.05 fold, respectively) in DLBCL patients than those in controls. Furthermore, there was a positive association between the levels of EGR-1 and T-bet mRNA (p = 0.001). However, the level of TGF-β mRNA was significantly increased in DLBCL patients, which was inversely associated with the T-bet mRNA level (p = 0.008), but positively associated with the percentage of T regulatory cells in PBMCs (p = 0.011). After three cycles of chemotherapy, the distribution of T-lymphocyte subsets in DLBCL patients were changed, and the levels of EGR-1, T-bet, and GATA-3 mRNA were significantly increased (p < 0.05) compared to those before chemotherapy. CONCLUSIONS: These results demonstrate the changes in T-lymphocyte subpopulations and the altered expression 34 pattern of the corresponding regulatory genes in PBMCs from DLBCL patients after chemotherapy, which are associated with the response of patients to treatment. The preferential expression of the T-bet gene after chemotherapy was closely correlated with the increased expression of the EGR-1 gene and decreased expression of the TGF-β gene