56 research outputs found
Cleries & Cleris: recerca de la vida i dels seus móns
No full textTreball de recerca realitzat per una alumna d'ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit cientí¬fic del Jovent l'any 2009. Aquest treball pretenia buscar inicialment una connexió entre Pau Claris (president de la Generalitat) i la família de l’autora, Cleris. Després d’unes primeres recerques, però, es va descartar aquesta opció ja que era massa difícil reconstruir el seu arbre geneològic. Finalment, l’objectiu va ser trobar i situar cada avantpassat en el seu marc històric.
Per reconstruir l’arbre geneològic es va visitar diferents arxius: la Parròquia de Sant Cugat; l’Arxiu Nacional de Catalunya, on es van consultar llibres d’allistaments, d’impostos, padrons, registres; l’Arxiu Municipal de Sant Cugat, l’Arxiu parroquial de Tàrrega i l’Arxiu comarcal de l’Urgell on es continua la recerca per elaborar l’arbre geneològic.
A través d’aquests arxius es van localitzar 6 generacions a Tàrrgea i 4 a Sant Cugat. La recerca queda tallada al 1684 en trobar l’última persona que va néixer a Tàrrega, en Josep Cleries. El seu pare, Carlos Cleries, provenia de Milà on podria continuar la recerca.
En el treball també s’estudi el context històric de cada generació. Tàrrega estava contínuament presionada pels exèrcits ja que estava situada en una cruïlla entre dos camins: Lleida i Madrid. Així la recerca mostra que al 1830 la família Cleries canvià de residència per trobar millors condicions de vida. Sant Cugat també estava situada en una cruïlla de camins: Barcelona i Terrassa. Tots van viure de l’agricultura excepte el meu avi que va començar a treballar en una indústria tèxtil.Research project carried out by a pupil of secondary education and rewarded with a Prize CIRIT to foster the scientific spirit of the Youth in year 2009. The main objective was to discover if the autor’s family was related to Pau Claris, one president of the 'Generalitat de Catalunya’. This was so difficult and, eventually, the objective of the research was to find out about the ancestors and to put them in their context of life.
Several archives were visited: Parroquia of Sant Cugat, the 'Arxiu nacional de Catalunya’, the Municipally Arxive of Sant Cugat, the Parroquia of Tarrega and to the regional Arxive of Tarrega to continue the research. The research required to be very meticulous and careful.
The result was the discovery that the family of the author may come from Italy, Milan. All were farmers and worked others land except Josep Cleries who was a trader and my grandfather who began to work in the textile industry. They were a family who didn’t have any problems with the government. 4 generations were discovered in Sant Cugat and 6 in Tarrega
Retinoids: in vitro interaction with retinol-binding protein and influence on plasma retinol
No full textFASEB J
Perifosine and sorafenib combination induces mitochondrial cell death and antitumor effects in NOD/SCID mice with Hodgkin lymphoma cell line xenografts
No full textThe effects of the Akt inhibitor perifosine and the RAF/MEK/ERK inhibitor sorafenib were investigated using two CD30(+)Hodgkin lymphoma cell lines (L-540 and HDLM-2) and the CD30(-)HD-MyZ histiocytic cell line. The combined perifosine/sorafenib treatment significantly inhibited mitogen-activated protein kinase and Akt phosphorylation in two of the three cell lines. Profiling of the responsive cell lines revealed that perifosine/sorafenib decreased the amplitude of transcriptional signatures that are associated with the cell cycle, DNA replication and cell death. Tribbles homolog 3 (TRIB3) was identified as the main mediator of the in vitro and in vivo antitumor activity of perifosine/sorafenib. Combined treatment compared with single agents significantly suppressed cell growth (40-80%, P<0.001), induced severe mitochondrial dysfunction and necroptotic cell death (up to 70%, P<0.0001) in a synergistic manner. Furthermore, in vivo xenograft studies demonstrated a significant reduction in tumor burden (P<0.0001), an increased survival time (81 vs 45 days, P<0.0001), an increased apoptosis (2- to 2.5-fold, P<0.0001) and necrosis (2- to 8-fold, P<0.0001) in perifosine/sorafenib-treated animals compared with mice receiving single agents. These data provide a rationale for clinical trials using perifosine/sorafenib combination
Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34(+) cells.
No full textThe proapoptotic death receptor 5 (DR5) expressed by tumor associated endothelial cells (TECs) mediates vascular disrupting effects of human CD34(+) cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL (+) cells) in mice. Indeed, lack of DR5 on TECs causes resistance to CD34-TRAIL (+) cells. By xenografting in nonobese diabetic/severe combined immunodeficient mice the TRAIL-resistant lymphoma cell line SU-DHL-4V, which generates tumors lacking endothelial DR5 expression, here we demonstrate for the first time that the Akt inhibitor perifosine induces in vivo DR5 expression on TECs, thereby overcoming tumor resistance to the vascular disruption activity of CD34-TRAIL (+) cells. In fact, CD34-TRAIL (+) cells combined with perifosine, but not CD34-TRAIL (+) cells alone, exerted marked antivascular effects and caused a threefold increase of hemorrhagic necrosis in SU-DHL-4V tumors. Consistent with lack of DR5 expression, CD34-TRAIL (+) cells failed to affect the growth of SU-DHL-4V tumors, but CD34-TRAIL (+) cells plus perifosine reduced tumor volumes by 60 % compared with controls. In view of future clinical studies using membrane-bound TRAIL, our results highlight a strategy to rescue patients with primary or acquired resistance due to the lack of DR5 expression in tumor vasculature
(3)D [corrected] quantification of tumor vasculature in lymphoma xenografts in NOD/SCID mice allows to detect differences among vascular-targeted therapies
No full textQuantitative characterization of the in vivo effects of vascular-targeted therapies on tumor vessels is hampered by the absence of useful 3D vascular network descriptors aside from microvessel density. In this study, we extended the quantification of planar vessel distribution to the analysis of vascular volumes by studying the effects of antiangiogenic (sorafenib and sunitinib) or antivascular (combretastatin A4 phosphate) treatments on the quantity and spatial distributions of thin microvessels. These observations were restricted to perinecrotic areas of treated human multiple myeloma tumors xenografted in immunodeficient mice and to microvessels with an approximate cross-sectional area lower than 75 μm(2). Finally, vessel skeletonization minimized artifacts due to possible differential wall staining and allowed a comparison of the various treatment effects. Antiangiogenic drug treatment reduced the number of vessels of every caliber (at least 2-fold fewer vessels vs. controls; p<0.001, n = 8) and caused a heterogeneous distribution of the remaining vessels. In contrast, the effects of combretastatin A4 phosphate mainly appeared to be restricted to a homogeneous reduction in the number of thin microvessels (not more than 2-fold less vs. controls; p<0.001, n = 8) with marginal effects on spatial distribution. Unexpectedly, these results also highlighted a strict relationship between microvessel quantity, distribution and cross-sectional area. Treatment-specific changes in the curves describing this relationship were consistent with the effects ascribed to the different drugs. This finding suggests that our results can highlight differences among vascular-targeted therapies, providing hints on the processes underlying sample vascularization together with the detailed characterization of a pathological vascular tree
Sorafenib inhibits lymphoma xenografts by targeting MAPK/ERK and AKT pathways in tumor and vascular cells
No full textThe anti-lymphoma activity and mechanism(s) of action of the multikinase inhibitor sorafenib were investigated using a panel of lymphoma cell lines, including SU-DHL-4V, Granta-519, HD-MyZ, and KMS-11 cell lines. In vitro, sorafenib significantly decreased cell proliferation and phosphorylation levels of MAPK and PI3K/Akt pathways while increased apoptotic cell death. In vivo, sorafenib treatment resulted in a cytostatic rather than cytotoxic effect on tumor cell growth associated with a limited inhibition of tumor volumes. However, sorafenib induced an average 50% reduction of tumor vessel density and a 2-fold increase of necrotic areas. Upon sorafenib treatment, endothelial and tumor cells from SU-DHL-4V, Granta-519, and KMS-11 nodules showed a potent inhibition of either phospho-ERK or phospho-AKT, whereas a concomitant inhibition of phospho-ERK and phospho-AKT was only observed in HD-MyZ nodules. In conclusion, sorafenib affects the growth of lymphoid cell lines by triggering antiangiogenic mechanism(s) and directly targeting tumor cells
Characterization of compound 584, an Abl kinase inhibitor with lasting effects
No full textBACKGROUND: Resistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosome-positive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584).
DESIGN AND METHODS: To increase the potency, we rationally designed cmp-584, a compound with enhanced shape complementarity with the kinase domain of Abl. cmp-584 was synthesized and characterized in vitro against a panel of 67 serine/threonine and tyrosine kinases using radioactive and enzyme-linked immunosorbent kinase assays. We studied inhibitory cellular activity using Bcr/Abl-positive human cell lines, murine transfectants in proliferation experiments, and a murine xenotrans-planted model. Kinase assays on isolated Bcr/Abl protein were also performed. Finally, we used a wash-out approach on whole cells to study the binding kinetics of the inhibitor.
RESULTS: cmp-584 showed potent anti-Abl activity both on recombinant protein (IC(50): 8 nM) and in cell-based assays (IC(50): 0.1-10 nM). The drug maintained inhibitory activity against platelet-derived growth factor receptors and c-KIT and was also active against Lyn (IC(50): 301 nM). No other kinase of the panel was inhibited at nanomolar doses. cmp-584 was 20- to 300-fold more active than imatinib in cells. This superior activity was evident in intact cells, in which full-length Bcr-Abl is present. In vivo experiments confirmed the activity of cmp-584. Wash-out experiments showed that short exposure to the drug impaired cell proliferation and Bcr-Abl phosphorylation for a substantially longer period of time than imatinib.
CONCLUSIONS: The present results suggest a slower off-rate (dissociation rate) of cmp-584 compared to imatinib as an explanation for the increased cellular activity of the former
In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells
No full textResistance to imatinib represents an important scientific and clinical issue in chronic myelogenous leukemia. In the present study, the effects of the novel inhibitor SKI-606 on various models of resistance to imatinib were studied. SKI-606 proved to be an active inhibitor of Bcr-Abl in several chronic myelogenous leukemia cell lines and transfectants, with IC(50) values in the low nanomolar range, 1 to 2 logs lower than those obtained with imatinib. Cells expressing activated forms of KIT or platelet-derived growth factor receptor (PDGFR), two additional targets of imatinib, were unaffected by SKI-606, whereas activity was found against PIM2. SKI-606 retained activity in cells where resistance to imatinib was caused by BCR-ABL gene amplification and in three of four Bcr-Abl point mutants tested. In vivo experiments confirmed SKI-606 activity in models where resistance was not caused by mutations as well as in cells carrying the Y253F, E255K, and D276G mutations. Modeling considerations attribute the superior activity of SKI-606 to its ability to bind a conformation of Bcr-Abl different from imatinib
Therapeutic effects of the combination of fenretinide and all-trans-retinoic acid and of the two retinoids with cisplatin in a human ovarian carcinoma xenograft and in a cisplatin-resistant sub-line
No full textAbcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro.
No full textThe success of Imatinib (IM) therapy in chronic myeloid leukemia (CML) is compromised by the development of IM resistance and by a limited IM effect on hematopoietic stem cells. Danusertib (formerly PHA-739358) is a potent pan-aurora and ABL kinase inhibitor with activity against known BCR-ABL mutations, including T315I. Here, the individual contribution of both signaling pathways to the therapeutic effect of Danusertib as well as mechanisms underlying the development of resistance and, as a consequence, strategies to overcome resistance to Danusertib were investigated. Starting at low concentrations, a dose-dependent inhibition of BCR-ABL activity was observed, whereas inhibition of aurora kinase activity required higher concentrations, pointing to a therapeutic window between the two effects. Interestingly, the emergence of resistant clones during Danusertib exposure in vitro occurred considerably less frequently than with comparable concentrations of IM. In addition, Danusertib-resistant clones had no mutations in BCR-ABL or aurora kinase domains and remained IM-sensitive. Overexpression of Abcg2 efflux transporter was identified and functionally validated as the predominant mechanism of acquired Danusertib resistance <i>in vitro</i>. Finally, the combined treatment with IM and Danusertib significantly reduced the emergence of drug resistance <i>in vitro</i>, raising hope that this drug combination may also achieve more durable disease control <i>in vivo</i>
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