Caracterización de la logística de la empresa Homecenter, basada en el modelo referencial en logística

El presente trabajo corresponde a la aplicación del modelo referencial en logística para identificar la caracterización de la logística de la empresa Homecenter, se analizarán cada una de las herramientas del plan y su desarrollo en la organización seleccionada. Se analizaran con base a las encuestas realizadas en la compañía, y su correspondiente análisis a la luz de lo indicado en modelo referencia en logística, se evaluaran los siguientes elementos del modelo; concepto logístico, organización y gestión logística, tecnología de manipulación, tecnología de almacenaje, tecnología de transporte interno, tecnología de transporte externo, tecnología de información, tecnología de software, talento humano, integración del Supply Chain, barreras del entorno, medida de desempeño logístico, y logística reversa.The present work corresponds to the application of the reference model in logistics to identify the characterization of the logistics of the company Homecenter, each one of the tools of the plan and its development in the selected organization will be analyzed. They will be analyzed based on the surveys carried out in the company, and their corresponding analysis in light of what is indicated in the reference model in logistics, the following elements of the model will be evaluated; logistic concept, logistics organization and management, handling technology, storage technology, internal transport technology, external transport technology, information technology, software technology, human talent, supply chain integration, environmental barriers, logistic performance measurement , and reverse logistics

T22-PE24-H6 Nanotoxin Selectively Kills CXCR4-High Expressing AML Patient Cells In Vitro and Potently Blocks Dissemination In Vivo

Altres ajuts: EU COST Action CA 17140; CERCA Programme/Generalitat de Catalunya; ICREA AcademiaDespite advances in the development of targeted therapies for acute myeloid leukemia (AML), most patients relapse. For that reason, it is still necessary to develop novel therapies that improve treatment effectiveness and overcome drug resistance. We developed T22-PE24-H6, a protein nanoparticle that contains the exotoxin A from the bacterium Pseudomonas aeruginosa and is able to specifically deliver this cytotoxic domain to CXCR4 + leukemic cells. Next, we evaluated the selective delivery and antitumor activity of T22-PE24-H6 in CXCR4 + AML cell lines and BM samples from AML patients. Moreover, we assessed the in vivo antitumor effect of this nanotoxin in a disseminated mouse model generated from CXCR4 + AML cells. T22-PE24-H6 showed a potent, CXCR4-dependent antineoplastic effect in vitro in the MONO-MAC-6 AML cell line. In addition, mice treated with nanotoxins in daily doses reduced the dissemination of CXCR4 + AML cells compared to buffer-treated mice, as shown by the significant decrease in BLI signaling. Furthermore, we did not observe any sign of toxicity or changes in mouse body weight, biochemical parameters, or histopathology in normal tissues. Finally, T22-PE24-H6 exhibited a significant inhibition of cell viability in CXCR4 high AML patient samples but showed no activity in CXCR4 low samples. These data strongly support the use of T22-PE24-H6 therapy to benefit high-CXCR4-expressing AML patients

A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

Altres ajuts: U COST Action CA 17140 to RM; FIS PI17/01246, RD12/0036/0071 and FIS PI14/00450 to JS; CP15/00163 to MVC; FIS PI15/00272 to EV ; CIBER-BBN [CB06/01/1031 and 4NanoMets to RM ; and VENOM4CANCER to AV. Grant from La Generalitat de Catalunya (PERIS) [SLT002/16/00433 to JSOne-third of diffuse large B-cell lymphoma patients are refractory to initial treatment or relapse after rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy. In these patients, CXCR4 overexpression (CXCR4+) associates with lower overall and disease-free survival. Nanomedicine pursues active targeting to selectively deliver antitumor agents to cancer cells; a novel approach that promises to revolutionize therapy by dramatically increasing drug concentration in target tumor cells. In this study, we intravenously administered a liganded protein nanocarrier (T22-GFP-H6) targeting CXCR4+ lymphoma cells in mouse models to assess its selectivity as a nanocarrier by measuring its tissue biodistribution in cancer and normal cells. No previous protein-based nanocarrier has been described as specifically targeting lymphoma cells. T22-GFP-H6 achieved a highly selective tumor uptake in a CXCR4+ lymphoma subcutaneous model, as detected by fluorescent emission. We demonstrated that tumor uptake was CXCR4-dependent because pretreatment with AMD3100, a CXCR4 antagonist, significantly reduced tumor uptake. Moreover, in contrast to CXCR4+ subcutaneous models, CXCR4- tumors did not accumulate the nanocarrier. Most importantly, after intravenous injection in a disseminated model, the nanocarrier accumulated and internalized in all clinically relevant organs affected by lymphoma cells with negligible distribution to unaffected tissues. Finally, we obtained antitumor effect without toxicity in a CXCR4+ lymphoma model by administration of T22-DITOX-H6, a nanoparticle incorporating a toxin with the same structure as the nanocarrier. Hence, the use of the T22-GFP-H6 nanocarrier could be a good strategy to load and deliver drugs or toxins to treat specifically CXCR4-mediated refractory or relapsed diffuse large B-cell lymphom

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

Altres ajuts: EU COST Action CA 17140 to R.M. A grant from La Generalitat de Catalunya (PERIS) [SLT002/16/00433 to J.S.]; a grant from the Generalitat de Catalunya CERCA Programme. The work was also supported by PERIS program from the health department of the Generalitat de Catalunya (SLT006/17/00093) [grated to U.U.] and Fundación Española de Hematología y Hemoterapia (FEHH) [granted to V.P.]. Finally, AV received an ICREA ACADEMIA Award supported by the Catalan Government.Background: current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. - Methods: monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups. - Results: T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model. - Conclusions: a novel nanoconjugate for targeted drug delivery of Auristatin reduces significantly the acute myeloid leukemic cell burden in the bone marrow and blood and blocks its dissemination to extramedullar organs in a CXCR4+ AML model. This selective drug delivery approach validates CXCR4+ AML cells as a target for clinical therapy, not only promising to improve the control of leukemic dissemination but also dramatically reducing the severe toxicity of classical AML therapy

A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model

Altres ajuts: EU COST Action CA 17140 ; CIBER-BBN [CB06/01/1031 and 4NanoMets to R.M., VENOM4CANCER to A.V., NANOREMOTE to E.V. and NANOLINK to U·U.] ; CERCA Programme/Generalitat de Catalunya ; ICREA Academia Award. Fundació la Marató de TV3 201-941-30-31-32.Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4 AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4 AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4 leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients

Selective delivery of T22-PE24-H6 to CXCR4 + diffuse large B-cell lymphoma cells leads to wide therapeutic index in a disseminated mouse model

Altres ajuts: EU COST Action CA 17140 to R.M., FIS PI17/01246 and RD16/0011/0028 to J.S., and FIS PI15/00272 to E.V. CIBER-BBN [CB06/01/1031 and 4NanoMets to R.M., and VENOM4CANCER to A.V.]. a grant from the Generalitat de Catalunya (PERIS) [SLT002/16/00433 to J.S.] and PERIS SLT006/17/00093 from the Generalitat de Catalunya to U.U. Generalitat de Catalunya CERCA Programme. A.V. received an Icrea Academia AwardBackground : Novel therapeutic strategies are urgently needed to reduce relapse rates and enhance survival in Diffuse Large B-Cell Lymphoma (DLBCL) patients. CXCR4-overexpressing cancer cells are good targets for therapy because of their association with dissemination and relapse in R-CHOP treated DLBCL patients. Immunotoxins that incorporate bacterial toxins are potentially effective in treating haematological neoplasias, but show a narrow therapeutic index due to the induction of severe side effects. Therefore, when considering the delivery of these toxins as cancer therapeutics, there is a need not only to increase their uptake in the target cancer cells, and their stability in blood, but also to reduce their systemic toxicity. We have developed a therapeutic nanostructured protein T22-PE24-H6 that incorporates exotoxin A from Pseudomonas aeruginosa, which selectively targets lymphoma cells because of its specific interaction with a highly overexpressed CXCR4 receptor (CXCR4 +) in DLBCL. Methods : T22-PE24-H6 cytotoxicity and its dependence on the CXCR4 receptor were evaluated in DLBCL cell lines using cell viability assays. Different in vitro experiments (mitochondrial membrane potential, Western Blot, Annexin V and DAPI staining) were conducted to determine T22-PE24-H6 cell death mechanisms. In vivo imaging and therapeutic effect studies were performed in a disseminated DLBCL mouse model that mimics organ infiltration in DLBCL patients. Finally, immunohistochemistry and histopathology analyses were used to evaluate the antineoplastic effect and systemic toxicity. Results : In vitro, T22-PE24-H6 induced selective cell death of CXCR4 + DLBCL cells by activating the apoptotic pathway. In addition, repeated T22-PE24-H6 intravenous administration in a CXCR4 + DLBCL-disseminated mouse model showed a significant reduction of lymphoma burden in organs clinically affected by DLBCL cells (lymph nodes and bone marrow). Finally, we did not observe systemic toxicity associated to the nanoparticle treatment in non-DLBCL-infiltrated organs. Conclusion : We have demonstrated here a potent T22-PE24-H6 antineoplastic effect, especially in blocking dissemination in a CXCR4 + DLBCL model without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4 + disseminated refractory or relapsed DLBCL patients

High dose chemotherapy and autologous stem cell transplantation in patients with peripheral T-cell lymphoma not achieving complete response after induction chemotherapy. The GEL-TAMO experience

Background and objectives: patients with aggressive non-Hodgkin's lymphomas (NHL) who do not obtain a complete response (CR) after induction chemotherapy have a poor prognosis. However, provided they are sensitive to the first regimen of chemotherapy, 25-40% of them with a B-cell phenotype may achieve long-term survival when treated with high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT). The aim of this study was to analyze the efficacy of this therapy in the corresponding patients with peripheral T-cell lymphoma (PTCL). Design and methods: we retrospectively evaluated the efficacy of ASCT in 35 patients with PTCL from the GEL-TAMO registry, who did not achieve a CR to standard induction chemotherapy regimens for aggressive NHL. Thirty-one patients underwent transplantation after achieving a partial response (PR) and 4 patients were non-responders. Results: following HDC/ASCT, 23 (66%) of the patients achieved a CR, 4 (11%) a PR and in 7 (20%) cases the transplant failed. One patient was not evaluated because of early toxic death. With a median follow-up of the survivors of 37.5 months, 18 patients (51%) are alive and 15 patients (43%) are free of disease. Transplant-related mortality rate at 100 days was 11% and at 5 years the probabilities of survival, freedom from progression and disease-free survival for complete responders were 37%, 36% and 55% respectively. Pre-transplant lactate-dehydrogenase level, age-adjusted International Prognostic Index (aa-IPI) and tumor score correlated with survival. Interpretation and conclusions: one third of the patients with PTCL who fail to achieve CR to the first chemotherapeutic regimen can be rescued with HDC/ASCT. Pre-transplant values of IPI and tumor score risk systems for aggressive lymphomas were useful to predict subsequent survival

Un pensador de nuestro tiempo

1 documento en PDF de 11 páginas.Este texto es producto de las reflexiones de varios estudiosos en torno al pensamiento del filósofo Julián Marías, quien abrió caminos al pensamiento universal, y aportó claves de especial importancia para la comprensión del ser humano en nuestros días.INTRODUCCIÓN El campo Intermedio Belisario Betancur Julián Marías: etapas de una filosofía Harold Raley El sentido del quehacer filosófico en Julián Marías Luis Fernando Fernández Ochoa Julian Marías, lector e intérprete de las Meditaciones del Quijote Helio Carpintero El valor de la palabra en Julián Marías Juan Carlos Vergara Silva La “estructura empírica”, eje del pensamiento antropológico de Julián Marías Ana María Araújo La persona en Julián Marías Jorge Aurelio Díaz Hacia una interpretación personal de la mujer Nieves Gómez Álvarez Amor-enamoramiento Ana María Araújo El Dios vivencial de Julián Marías Alejandra Peñacoba Arribas Marías y la afirmación de la persona: momentos aplicables a la antropología médica Carlos A. Gómez Fajardo La defensa de la vida en el pensamiento de Julián Marías: el caso del aborto Carlos Alberto Sampedro ¿Es de orden transcendental la antropología de Julián Marías? Juan Fernando Sellés El desafío de la ilusión ante la crisis de esperanza. La sugestiva visión de Julián Marías. A propósito del centenario de su natalicio Juan Camilo Restrepo Tamayo Julián Marías, liberal Iván Garzón Vallejo Julián Marías y la II República española Jaime Prieto La transmutación anímica de Julián Marías en su crónica de viajes Imagen de la India Ricardo Visbal Sierr