1,721,337 research outputs found
Revised European-American Lymphoma Classification
No full textThe recently proposed Revised European-American Lymphoma Classification represents a serious attempt to overcome the controversies that have divided both pathologists and clinicians over the past three decades. It was formulated by 19 experienced hematopathologists, who agreed on a list of clinicopathologic entities, all well known from the literature and daily practice. Compared with previous schemes, the Revised European-American Lymphoma Classification offers the following advantages: 1) it incorporates all nodal and extranodal lymphoid tumors, including Hodgkin's disease; 2) it is histogenetically updated by recognizing new categories (such as the mantle cell category) and grouping tumors that need further validation to be considered as separate entities (eg, diffuse large B-cell lymphomas); 3) it avoids any morphologic grading, the clinical course of lymphomas being influenced by factors other than histology (tumor burden, cell kinetics, apoptotic rate, and so forth) and 4) it includes all molecular data (phenotype, genotype, cytogenetics, and so forth), which can assist in the diagnosis
BRAF V600E mutation in hairy cell leukemia: From bench to bedside
No full textHairy cell leukemia (HCL) is a distinct clinicopathological entity whose underlying genetic lesion has remained a mystery for over half a century. The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. Sensitive molecular assays for detecting BRAF V600E allow HCL (highly responsive to purine analogs) to be better distinguished from HCL-like disorders, which are treated differently. In vitro pre-clinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from "hairy" to "smooth," and eventually apoptosis. The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). The median relapse free-survival was about 19 months in patients who had achieved CR and 6 months in those who had obtained a partial response. Future therapeutic perspectives include: (1) combining BRAF inhibitors with MEK inhibitors or immunotherapy (anti-CD20 monoclonal antibody) to increase the percentage of CRs and (2) better understanding of the molecular mechanisms underlying resistance of HCL cells to BRAF inhibitors
Folding mechanism of the C-terminal domain of nucleophosmin: residual structure in the denatured state and its pathophysiological significance
No full textNucleophosmin (NPM1) is a ubiquitously expressed protein and is one of the most abundant proteins found in the nucleolus. Naturally occurring mutations in the C-terminal domain of nucleophosmin (Cter-NPM1) are found in similar to 30% of patients with acute myeloid leukemia (AML). These mutations cause changes at the C terminus of NPM1 that lead to denaturation of the protein, a critical factor in determining aberrant translocation of NPM1 to the cytosol. Hence, this protein system represents an ideal candidate to investigate the relations between folding and unfolding and disease. Here we report the characterization of the folding and unfolding kinetics of Cter-NPM1. Data reveal that this small helical domain folds via a compact denatured state, displaying a malleable residual structure. Moreover, analysis of folding rate constants measured under different experimental conditions suggests that the existence of a preorganized structure in the denatured state accelerates folding, implying a native-like residual structure. Because a major feature of Cter-NPM1 mutants responsible for AML is a reduction in stability of the protein and thus prevalence of a denatured state even under physiological conditions, our findings may pave the way to further studies with the aim of designing chemicals capable of interacting with the "pathological" mutants to stabilize the native conformation.-Scaloni, F., Gianni, S., Federici, L., Falini, B., Brunori, M. Folding mechanism of the C-terminal domain of nucleophosmin: residual structure in the denatured state and its pathophysiological significance. FASEB J. 23, 2360-2365 (2009
Folding mechanism of the C-terminal domain of nucleophosmin: residual structure in the denatured state and its pathophysiological significance
No full textNucleophosmin (NPM1) is a ubiquitously expressed protein and is one of the most abundant proteins found in the nucleolus. Naturally occurring mutations in the C-terminal domain of nucleophosmin (Cter-NPM1) are found in approximately 30% of patients with acute myeloid leukemia (AML). These mutations cause changes at the C terminus of NPM1 that lead to denaturation of the protein, a critical factor in determining aberrant translocation of NPM1 to the cytosol. Hence, this protein system represents an ideal candidate to investigate the relations between folding and unfolding and disease. Here we report the characterization of the folding and unfolding kinetics of Cter-NPM1. Data reveal that this small helical domain folds via a compact denatured state, displaying a malleable residual structure. Moreover, analysis of folding rate constants measured under different experimental conditions suggests that the existence of a preorganized structure in the denatured state accelerates folding, implying a native-like residual structure. Because a major feature of Cter-NPM1 mutants responsible for AML is a reduction in stability of the protein and thus prevalence of a denatured state even under physiological conditions, our findings may pave the way to further studies with the aim of designing chemicals capable of interacting with the "pathological" mutants to stabilize the native conformation
Modulatory effect of mycobacterial heat schock protein 70 in DNA vaccination against lymphoma. Haematologica
No full textNew classification of acute myeloid leukemia and precursor-related neoplasms: changes and unsolved issues.
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