1,721,041 research outputs found
Coinvolgimento della proteina HS1 nella sopravvivenza dei linfociti B neoplastici di pazienti con leucemia linfatica cronica
Full text linkB-cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in adults and is characterized by the accumulation of clonal CD5+ B lymphocytes due to uncontrolled growth and resistance to apoptosis. Several protein kinase pathways have been claimed to be involved in the regulation of cell survival. We previously demonstrated that the Src kinase Lyn is overexpressed, constitutively active and anomalously distributed in malignant B cells as compared to normal B
lymphocytes. Our attention was subsequently focused on the 75 kDa HS1 protein, which is one of the major substrate of Lyn kinase upon BCR cross-linking and plays a crucial role in BCR-induced apoptosis in the mouse B lymphoma cell line WEHI-231. In the present study HS1 protein level was measured by western blotting analysis in 43 untreated B-CLL patients and in 26 normal controls. We found a significant difference in HS1 protein level between CLL and normal B cells, being mainly expressed in the leukemic patients with respect to normal controls (p<0.01). When we correlated HS1 protein level with prognostic factors, we observed that patients with more negative prognostic factors had a higher expression of HS1 protein regarding those with a better prognosis. We also analyzed HS1 in 10 CLL patients before and after in vivo therapy with fludarabine and cyclophosphamide; we found a significant reduction of both HS1 protein and mRNA levels in those patients which responded to therapy (n°=7) while non-responder patients (n°=3) did not show any change in HS1 levels.
Using confocal microscopy and subcellular cell fractionation, we observed an abnormal distribution of HS1 in leukemic cells with respect to normal B cells. In particular, the pattern of expression of HS1 appeared with a spotting distribution and a 4-7% aliquot of HS1 was present in the nucleus of leukemic B cells but not in
normal B lymphocytes. This nuclear localization could not be observed following BCR triggering. In other words, after BCR engagement, we observed a redistribution of HS1 that was no longer detectable in the nucleus of stimulated leukemic cells. The pre-incubation of cells with PP2, a Src kinase inhibitor, prevents the IgM-mediated redistribution of HS1; so the disappearance of nuclear HS1 is attributable to Src kinases that act at some level of the signal cascade. Since HS1 can interact with actin through the Arp 2/3 complex we performed additional experiments to investigate whether HS1 could interact with cytoskeletal components. We observed that cytosolic HS1 co-localizes with ß-actin both in normal and leukemic B cells. Moreover, for the first time, we demonstrated that in B-CLL,
but not in normal B cells, HS1 co-localizes with ?-tubulin and, in particular, with the centrosome, suggesting that this protein could play a role in the cytoskeletal reorganization of leukemic B cells.
All these findings seem to suggest a pivotal role for HS1 in the regulation of cell survival of leukemic B cells and hint that this protein might represent a target for the development of new therapeutic approaches
Le HDL desensibilizzano i sinoviociti al rilascio di MCP-1 dai granuli secretori citoplasmatici indotto da cristalli di urato.
No full textHow receptor tyrosine kinase-like orphan receptor 1 meets its partners in chronic lymphocytic leukemia
Full text linkChronic lymphocytic leukemia (CLL) is the most common leukemia in western societies, recognized by clinical and molecular heterogeneity. Despite the success of targeted therapies, acquired resistance remains a challenge for relapsed and refractory CLL, as a consequence of mutations in the target or the upregulation of other survival pathways leading to the progression of the disease. Research on proteins that can trigger such pathways may define novel therapies for a successful outcome in CLL such as the receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 is a signaling receptor for Wnt5a, with an important role during embryogenesis. The aberrant expression on CLL cells and several types of tumors, is involved in cell proliferation, survival, migration as well as drug resistance. Antibody-based immunotherapies and small-molecule compounds emerged to target ROR1 in preclinical and clinical studies. Efforts have been made to identify new prognostic markers having predictive value to refine and increase the detection and management of CLL. ROR1 can be considered as an attractive target for CLL diagnosis, prognosis, and treatment. It can be clinically effective alone and/or in combination with current approved agents. In this review, we summarize the scientific achievements in targeting ROR1 for CLL diagnosis, prognosis, and treatment
Lyn tyrosine kinase accumulates as a protein-complex in the cytosol of leukemic B-CLL cells
No full textTargeting Brutons Tyrosine Kinase in Chronic Lymphocytic Leukemia at the Crossroad between Intrinsic and Extrinsic Pro-survival Signals
Full text linkChemo immunotherapies for chronic lymphocytic leukemia (CLL) showed a positive impact on clinical outcome, but many patients relapsed or become refractory to the available treatments. The main goal of the researchers in CLL is the identification of specific targets in order to develop new therapeutic strategies to cure the disease. The B cell receptor-signalling pathway is necessary for survival of malignant B cells and its related molecules recently become new targets for therapy. Moreover, leukemic microenvironment delivers survival signals to neoplastic cells also overcoming the apoptotic effect induced by traditional drugs. In this context, the investigation of Bruton’s tyrosine kinase (Btk) is useful in: i) dissecting CLL pathogenesis; ii) finding new therapeutic approaches striking simultaneously intrinsic as well as extrinsic pro-survival signals in CLL. This paper will review these main topics
Focal adhesion kinase as a new player in the biology of onco-hematological diseases: the starting evidence
Full text linkBiophysical Characterization of the Potassium Channel Kv1.3 in B Cells from Patients Affected by Chronic Lymphocytic Leukemia
No full textEndogenous reactive oxygen species content and modulation of tyrosine phosphorylation during sperm capacitation.
Full text linkGeneration of controlled amounts of reactive oxygen species (ROS) and phosphorylation of protein tyrosine (Tyr) residues are two main cellular changes involved in sperm capacitation. This study examined the relationship between tyrosine-phosphorylation (Tyr-P) and endogenous ROS production during sperm capacitation, and correlated them with both sperm motility and functionality expressed as acrosome-reacted cells. Immediate ROS generation was observed to peak after a 45-min incubation, followed by a rapid decrease in ROS content and successive regeneration of the ROS peak in 3 h and later. These two peaks were directly correlated with both the Tyr-P process involving sperm heads and tails, and the acrosome reaction (69 ± 8% and 65 ± 4%, respectively). The period of low-ROS content resulted in low Tyr-P patterns, located exclusively in the cell midpiece, and drastic reduction in acrosome-reacted cells. Ascorbic acid addition inhibited both Tyr-P patterns and acrosome reactions, whereas NADPH induced high ROS generation, with Tyr-P patterns located only on sperm tails, and prevented the acrosome reaction. Sperm hyperactivation was insensitive to ROS content. This is an important parameter for evaluation of sperm capacitation, which is achieved only when both ROS generation reaches a peak and Tyr-P involves the sperm head
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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