The role of charge and proton transfer in fragmentation of hydrogen-bonded nanosystems: the breakup of ammonia clusters upon single photon multi-ionization

The charge and proton dynamics in hydrogen-bonded networks are investigated using ammonia as a model system. The fragmentation dynamics of medium-sized clusters (1-2 nm) upon single photon multi-ionization is studied, by analyzing the momenta of small ionic fragments. The observed fragmentation pattern of the doubly- and triply- charged clusters reveals a spatial anisotropy of emission between fragments (back-to-back). Protonated fragments exhibit a distinct kinematic correlation, indicating a delay between ionization and fragmentation (fission). The different kinematics observed for channels containing protonated and unprotonated species provides possible insights into the prime mechanisms of charge and proton transfer, as well as proton hopping, in such a nanoscale system.Comment: 9 pages, 6 figure

Using a structural and logics systems approach to infer bHLH–DNA binding specificity determinants

Numerous efforts are underway to determine gene regulatory networks that describe physical relationships between transcription factors (TFs) and their target DNA sequences. Members of paralogous TF families typically recognize similar DNA sequences. Knowledge of the molecular determinants of protein–DNA recognition by paralogous TFs is of central importance for understanding how small differences in DNA specificities can dictate target gene selection. Previously, we determined the in vitro DNA binding specificities of 19 Caenorhabditis elegans basic helix-loop-helix (bHLH) dimers using protein binding microarrays. These TFs bind E-box (CANNTG) and E-box-like sequences. Here, we combine these data with logics, bHLH–DNA co-crystal structures and computational modeling to infer which bHLH monomer can interact with which CAN E-box half-site and we identify a critical residue in the protein that dictates this specificity. Validation experiments using mutant bHLH proteins provide support for our inferences. Our study provides insights into the mechanisms of DNA recognition by bHLH dimers as well as a blueprint for system-level studies of the DNA binding determinants of other TF families in different model organisms and humans.National Institute of General Medical Sciences (U.S.) (DK068429)National Institute of General Medical Sciences (U.S.) (HG003985)European Union (PROSPECTS HEALTH-F4-2008-201648

Current approaches to the treatment of non-Hodgkin's lymphoma

Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has long been a standard treatment for lymphoma. Improvements to the efficacy of this regimen can be made by increasing the doses of doxorubicin and cyclophosphamide, as in the chemotherapeutic regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP), and by reducing the standard dosing interval, as seen with the CHOP-14 regimen. Adding the immunotherapeutic agent rituximab (R) to either CHOP or ACVBP has been shown to improve outcomes significantly, such that six cycles of R-CHOP plus two cycles of rituximab are as effective as eight cycles of R-CHOP, and R-CHOP-21 appears to be at least as effective as the more dose-intense R-CHOP-14. In patients who have several adverse prognostic factors, RACVBP plus autologous stem-cell transplantation has been shown to produce good treatment outcomes. The use of positron emission tomography scanning before and early in treatment should allow prediction of long-term outcomes, and therefore the adaptation of treatment to individual prognosis and treatment needs. In patients with follicular lymphoma, rituximab has been shown to improve the efficacy of conventional chemotherapies. In addition, rituximab alone or yttrium-90-ibritumomab tiuxetan are effective maintenance therapies in this condition

Current and Future Developments in the Treatment of CD30+ Lymphomas

CD30 is a cell membrane protein expressed on the surface of a range of lymphomas, which has important diagnostic, pathogenic, and prognostic roles. The most common CD30+ lymphomas are Hodgkin’s lymphoma (HL) and anaplastic large cell lymphoma (ALCL), but other types of lymphoma also express CD30, although less frequently. Attempts to develop a monoclonal antibody therapy that targets CD30 were initially unsuccessful, but recent Phase I and II trials have shown promising results from the use of the immune conjugate brentuximab vedotin in HL and ALCL. Phase III trials are ongoing to evaluate clearly the benefit–risk ratio when compared with standard treatment. The first of these to report preliminary findings, the AETHERA trial, showed improved progression-free survival times in relapsing/refractory HL patients treated with brentuximab vedotin as a consolidation therapy after autologous stem cell transplantation compared with those receiving placebo. Patients with rarer CD30+ lymphomas may also benefit from brentuximab vedotin therapy in the future. Moreover, combination treatment with immunomodulatory and cell cycle checkpoint modulators that are currently under development, as well as conventional chemotherapeutic agents, may yield further benefits. To this end, improved methods of CD30 detection and quantitation will improve the delineation of non-HL subtypes in which CD30-targeted therapy may be clinically indicated

Diversity in antibody-based approaches to non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) remains one of the most common cancers in the US, with survival dependent on the type and stage of disease. B-cell lymphomas account for similar to 85% of all cases of NHL, and are commonly treated with chemotherapy, or monoclonal antibodies (mAbs) that t arget CD20 antigens on the surface of malignant tumors. The use of mAbs, either as single agents or in combination with chemotherapy, has made a huge impact on NHL survival rates. Rituximab remains the most commonly used and established mAb, and is used in a wide range of NHLs, but does not produce an effective therapeutic response in all patients. Novel therapeutics with enhanced binding affinity or alternative antigen targets are currently in development and in some cases have demonstrated improved efficacy over currently available treatments. Radioimmunotherapy has been included in transplant conditioning regimens to improve long-term disease control while limiting toxicity. These regimens have been safe, effective, and feasible, and are therefore promising for patients who cannot tolerate high-dose chemotherapy and/or total body irradiatio

Pr Bertrand Coiffier

Le professeur Bertrand Coiffier est décédé à l’âge de 71 ans le 02 janvier dernier. Il avait dédié dès le début de sa carrière hospitalo-universitaire tous ses efforts pour développer, en précurseur, la recherche clinique autour des lymphomes, fédérant au fil des ans les efforts cliniques, anatomo-pathologiques et biologiques à Lyon mais aussi à l’échelon national et international. Ceci l’a engagé dès 1984 dans la création du Groupe d’études des lymphomes de l’adulte, le GELA, où se réuniront rapidement un grand nombre de centres cliniques de France et de Belgiqu