Efecto reproductivo y productivo de grasas bypass como alternativa para la nutrición y alimentación de ganado lechero Holstein

The present study evaluated the effects of the addition of bypass fats or the so-called passing fats on the reproductive and productive behavior in 12 Holstein crossbred cows in Chimborazo, Ecuador. The cows were randomly selected and divided into a control group and three treatment versus TO groups – T1: (90 gr of fat + balanced); T2: (180 gr of fat + balanced); and T3: (270 gr of fat + balanced). The variables analyzed were milk production (kg), body condition at delivery (CCP), body condition at service (CCS), days to first heat, and days to second heat. The experiment continued for 60 days. An ADEVA was performed to check the significance between the treatments using the IBM SPSS Statistics 25, with a comparison of means using the Tukey test. The measures of central tendency were obtained: Mean:Standard Deviation. Statistically significant differences were observed for milk production in kg (p < 0.05), where the best treatment was reported with T3. However, for the other variables analyzed, no differences were reported (p > 0.05). The bypass fat supplementation had effects that favored milk production, which is why the benefit of these fats was demonstrated as a strategy to improve reproductive and productive indicators, since at the time of pregnancy the cow loses weight. Undernourishment especially in energy intake prolongs open days, delays follicular development, widens the interval between parturition and first fertile heat or the heat interval and the first service. Keywords: Holstein, Production, Reproduction, Bypass fats, Body condition. Resumen En Chimborazo-Ecuador se evaluó los efectos de la adición de grasas by pass o llamadas grasas pasantes sobre el comportamiento reproductivo y productivo en 12 vacas mestizas Holstein, seleccionadas al azar y agrupadas en tres tratamientos versus un TO: testigo; T1: (90 g de grasa+balanceado); T2: (180 g de grasa+balanceado); T3: (270 g de grasa+balanceado). Las variables analizadas fueron producción de leche (kg), condición corporal al parto (CCP), condición corporal al servicio (CCS), días al primer celo, días al segundo celo. El trabajo experimental tuvo una duración de 60 días. Se realizó un ADEVA para comprobar la significancia entre los tratamientos, mediante el paquete estadístico IBM SPSS Statistics 25, con una comparación de medias mediante el estadístico Tukey; así como también se obtuvo medidas de tendencia central: Media; desviación estándar. Para la producción de leche en Kg se observaron diferencias estadísticas significativas (p<0,05), en donde el mejor tratamiento se reportó con el T3; mientras que para las otras variables analizadas no se reportó diferencias (p>0,05). La suplementación con grasas by pass tuvo efectos que favoreció la producción la leche, por lo que se demostró el beneficio de dichas grasas, como estrategia para mejorar los indicadores reproductivos y productivos, ya que en el momento de la preñez la hembra se encuentra bajando de peso, y con la máxima producción. La subnutrición especialmente en el aporte energético: prolonga los días abiertos, demora el desarrollo folicular, amplia el intervalo entre parto-primer celo fértil o el intervalo celo- primer servicio. Palabras Clave: Holstein, Producción, Reproducción, Grasas bypass, Condición corporal

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatmentsPeer ReviewedPostprint (author's final draft

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Depto. de Teorías y Análisis de la ComunicaciónFac. de Ciencias de la InformaciónFALSEsubmitte

Sterol Regulatory Element-binding Protein-2 Negatively Regulates Low Density Lipoprotein Receptor-related Protein Transcription

Low density lipoprotein receptor-related protein (LRP1) binds aggregated LDL (agLDL) leading to a high intracellular cholesteryl ester (CE) accumulation. AgLDL up-regulates LRP1 expression concomitantly with an LDL receptor (LDLR) and sterol regulatory element binding protein (SREBP-2) down-regulation. The objectives were to investigate whether SREBP-2 regulates LRP1 transcription and determine the molecular mechanisms involved in the process. Down-regulation of active SREBP-2 by nLDL and agLDL led to LDLR down-regulation and LRP1 up-regulation. Enforced expression of an active form of SREBP-2 (SREBP-2-NT, amino acid residues 1-468) decreased LRP1 expression and LRP1 promoter (WT-LRP1) luciferase activity in a dose-dependent manner. LDL did not exert any significant effect on LRP1 promoter activity when a putative sterol regulatory element (SRE) (5-GTGGGGTGA-3′; +225 to +233) was mutated (SRE-MT-LRP1). SREBP-2 overexpression exerted stronger down-regulatory effects on WT-LRP1 than on SRE-MT-LRP1 promoter activity both in control, nLDL- and agLDL-exposed HeLa cells. Gel mobility shift assays showed that recombinant SREBP-2-NT protein (1-468) binds to a double-stranded LRP1 DNA fragment (215 to 245) containing a wild-type (wt) SRE sequence but not to a mutated SRE (mt) sequence (5-GAATTCGA-3′). Our results demonstrate that LDL stimulates LRP1 transcription and decreases SREBP-2 active form which negatively regulates LRP1 transcription. SRE sequence (+225 to +233) plays a pivotal role for the down-regulatory effect of SREBP-2 on LRP1 promoter activity. © 2006 Elsevier Ltd. All rights reserved.This work was possible thanks to funding from FIS C03-01 (RECAVA), FIS PI051717, SAF2003-03187, MSD-Unrestricted Grant and the Fundación Investigación Cardiovascular (FIC) Catalana-Occidente. S.C.L. and P.C. are pre-doctoral fellows from FIC and SAF2003-03187, respectivelyPeer Reviewe

The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia

Patients with AML harboring constitutively active mutations in the FLT3 receptor generally have a poor prognosis (FLT3-ITDMUT). Despite the fact that several FLT3 inhibitors have been developed, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin (a well-known FLT3 inhibitor). Our in vitro and in vivo experiments showed that EC-70124 exerts a robust and specific antileukemia activity against FLT3-ITDMUT AML cells while sparing healthy hematopoietic cells. Collectively, EC-70124 is a promising and safe agent for the treatment of this aggressive type of AML

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatmentsPeer Reviewe

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q-AML

Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.This work was supported by the European Research Council (CoG-2014-646903 to P.M), the Spanish Ministry of Economy and Competitiveness (SAF-SAF2013-43065, RTC-2016-4603-1 to P.M), the Asociación Española Contra el Cáncer (AECC-CI-2015), FERO Foundation, and the ISCIII/FEDER (PI14-01191) to C.B and the ‘‘Fundación Hay Esperanza’’ to E.A. P.M also acknowledges financial support from The Obra Social La Caixa-Fundaciò Josep Carreras, The Inocente Inocente Foundation and The Generalitat de Catalunya (SGR330). P.M an investigator of the Spanish Cell Therapy cooperative network (TERCEL). We thank Celgene Corporation (San Diego, CA) for providing IMiDs. We thank Judit Sopena and Mariano Graupera (IDIBELL, Barcelona) for their technical assistance with immunohistochamical analysi