Alemtuzumab in the up-front setting

Alemtuzumab is a humanized chimeric monoclonal antibody targeting CD52. Although this agent already has an important role in the treatment of chronic lymphocytic leukemia (CLL), many of its uses are still being defined. Early trials showed alemtuzumab’s value in refractory disease and helped to define its excellent activity in the bone marrow, spleen and 17p deleted patients. The CAM307 trial has demonstrated alemtuzumab’s efficacy as monotherapy in the front-line setting, and ultimately led to its FDA approval as frontline therapy. Especially promising is the trend toward improved response in patients with high risk cytogenic abnormalities (17p del, 11q del, trisomy 12). The various consolidation trials have also provided promising results of achieving eradication of minimal residual disease (MRD). Although the ultimate benefit of achieving MRD negativity remains under investigation, alemtuzumab’s potent activity on the bone marrow will likely make it an important part of combination therapy

Augmenting NF-kappaB in poor-risk CLL: A general paradigm for other cancers?

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder of B lymphocytes. It has an extremely variable clinical course. Some patients have a rather indolent course, whereas others are known to have a rapidly progressive disease. Most patients die from causes related to CLL that can be due to bone marrow failure, infection, or transformation to a high-grade lymphoma. Clinical stratification of CLL has revealed that a subset of patients with poor prognosis harbor cytogenetic alterations and lack mutations at the immunoglobulin locus. Therefore, the development of additional molecular biomarkers for patients at high risk for early lethality from CLL could help direct their care toward enrollment in clinical trials of promising experimental approaches such as inhibitors of BCL2 or BCR signaling or CD19 chimeric antigen receptor T cells (which have been shown to eradicate CLL in patients who have failed other approaches). In this issue, Mansouri et al. report that somatic mutations in the NFKBIE gene occur in 7% of poor prognosis patients, and this may be a common mechanism contributing to disease progression by sustaining the survival of malignant CLL cells

Izvod kozmoloških modela V Bianchijeve vrste s volumnim trenjem i vremenski-ovisnim članom λ

Bianchi type V bulk viscous fluid cosmological models are investigated with dynamic cosmological term λ(t). Using a generation technique (Camci et al., 2001), it is shown that the Einstein\u27s field equations are solvable for any arbitrary cosmic scale function. Solutions for particular forms of cosmic scale functions are also obtained. The cosmological constant is found to be a decreasing function of time, which is supported by results from recent type Ia supernovae observations. Some physical and geometrical aspects of the models are also discussed.Istražujemo kozmološke modele V-e Bianchijeve vrste s volumnim trenjem i dinamičnim kozmološkim članom Λ(t). Primjenom metode izvođenja (Camci et al., 2001) pokazujemo da se Einsteinove jednadžbe polja mogu riješiti za proizvoljnu funkciju kozmičke mjere. Postigli smo rješenja za posebne funkcije kozmičkih mjera. Nalazimo da je kozmološka konstanta opadajuća funkcija vremena, što je u skladu s nedavnim opažanjima supernova Ia. Raspravljamo također neka fizička svojstva modela

Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Key Points Combining phosphatidylinositol-3-kinase δ inhibition with rituximab, bendamustine, or both is feasible and active in relapsed iNHL. The safety of novel combinations should be proven in phase 3 trials before adoption in clinical practice.</jats:p

Chronic Lymphocytic Leukemia B Cells Can Undergo Somatic Hypermutation and Intraclonal Immunoglobulin VHDJH Gene Diversification

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5+ B lymphocyte that is thought not to undergo intraclonal diversification. Using VHDJH cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1–35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their VHDJH genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone

Metabolomics-Driven Mining of Metabolite Resources:Applications and Prospects for Improving Vegetable Crops

Vegetable crops possess a prominent nutri-metabolite pool that not only contributes to the crop performance in the fields, but also offers nutritional security for humans. In the pursuit of identifying, quantifying and functionally characterizing the cellular metabolome pool, biomolecule separation technologies, data acquisition platforms, chemical libraries, bioinformatics tools, databases and visualization techniques have come to play significant role. High-throughput metabolomics unravels structurally diverse nutrition-rich metabolites and their entangled interactions in vegetable plants. It has helped to link identified phytometabolites with unique phenotypic traits, nutri-functional characters, defense mechanisms and crop productivity. In this study, we explore mining diverse metabolites, localizing cellular metabolic pathways, classifying functional biomolecules and establishing linkages between metabolic fluxes and genomic regulations, using comprehensive metabolomics deciphers of the plant’s performance in the environment. We discuss exemplary reports covering the implications of metabolomics, addressing metabolic changes in vegetable plants during crop domestication, stage-dependent growth, fruit development, nutri-metabolic capabilities, climatic impacts, plant-microbe-pest interactions and anthropogenic activities. Efforts leading to identify biomarker metabolites, candidate proteins and the genes responsible for plant health, defense mechanisms and nutri-rich crop produce are documented. With the insights on metabolite-QTL (mQTL) driven genetic architecture, molecular breeding in vegetable crops can be revolutionized for developing better nutritional capabilities, improved tolerance against diseases/pests and enhanced climate resilience in plants

Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy