Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vi... more Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy, cell growth, and differentiation. However, PRL is nowadays known to have a strong implication in oncogenic processes, making it essential to delve into the mechanisms governing these actions. PRL and its receptor (PRLR) activate a series of effects such as survival, cellular proliferation, migration, invasion, metastasis, and resistance to treatment, being highly relevant in developing certain types of cancer. Because women produce high levels of PRL, its influence in gynecological cancers is herein reviewed. It is interesting that, other than the 23 kDa PRL, whose mechanism of action is endocrine, other variants of PRL have been observed to be produced by tumoral tissue, acting in a paracrine/autocrine manner. Because many components, including PRL, surround the microenvironment, it is interesting to understand the hor...
This article is a theoretical review essay, which aims to present the events that are considered ... more This article is a theoretical review essay, which aims to present the events that are considered most relevant in the development and consolidation of Cognitive-Behavioral Therapy (CBT) and which in turn have positioned it as a therapy of choice for Different psychological problems. A review was carried out with two of the most accessible digital search engines for undergraduate students, using search keywords according to the objective of this article. Identifying that cognitive-behavioral therapy is understood as the application of scientific psychology to clinical practice in a systematic and structured way. This model based on behavior modification because of its solid theoretical and experimental basis, which emphasizes the empirical verification of the techniques during its application. What makes CBT an effective, efficient, and timely clinical practice, improving the quality of life of users and positioning themselves in front of other psychological models in terms of efficacy.
Supplementary Figure S1. Bacteriophage titers in the CNS after IP injection. After each round of ... more Supplementary Figure S1. Bacteriophage titers in the CNS after IP injection. After each round of selection, 8 or 24 hours after IP injection heart (red), brain (yellow), and spinal cord (blue) tissue was harvested and tittered for bacteriophage load prior to amplification. Initially, a 50:50 mix of C7C and PhD-12 bacteriophage was injected. After the initial mix, bacteriophage was amplified from CNS tissue lysates prior to subsequent rounds of in vivo selection. Bacteriophage titer was normalized by protein concentration for each round.
Non-obstetric surgery is performed in 0.2-1.6% of pregnancies. Recently the FDA called for cautio... more Non-obstetric surgery is performed in 0.2-1.6% of pregnancies. Recently the FDA called for cautious use of anesthetic drugs during pregnancy. The consequences of anesthesia during pregnancy on fetal development in humans are unclear and preclinical evidence remains scarce.
El objetivo del presente trabajo de investigación fue conocer las indicaciones más frecuentes de ... more El objetivo del presente trabajo de investigación fue conocer las indicaciones más frecuentes de sedación paliativa en pacientes -hombres y mujeres- que estuvieron ingresados en una unidad de cuidados paliativos, así como los diagnósticos oncológicos, el tipo de sedación y las dosis administradas, y determinar si se logró un adecuado control de los síntomas. Esto es relevante debido a que no se cuenta con datos nacionales referentes a esta terapéutica. El tipo de investigación fue descriptiva, con diseño retrospectivo en la cual se realizó una revisión de expedientes de los pacientes ingresados en el Hospital de cuidados paliativos Divina Providencia de El Salvador, en el periodo de noviembre de 2014 a abril de 2015. Se seleccionó una muestra no probabilista por conveniencia de 49 pacientes. Según los datos obtenidos, se observó que el 30% de los pacientes necesitaron sedación paliativa sin diferencia de género; además se estableció que el 69.4% de los pacientes se encontraban entre...
Epithelial ovarian cancer is the second most lethal gynecological cancer worldwide. Ascites can b... more Epithelial ovarian cancer is the second most lethal gynecological cancer worldwide. Ascites can be found in all clinical stages, however in advanced disease stages IIIC and IV it is more frequent and could be massive, associated with worse prognosis. Due to the above, it was our interest to understanding how the ascites of ovarian cancer patients induces the mechanisms by which the cells present in it acquire a more aggressive phenotype and to know new proteins associated to this process. A proteomic analysis of SKOV-3 cells treated with five different EOC ascites was performed by two-dimensional electrophoresis coupled to MALDI-TOF. The level of expression of the proteins of interest was validated by RT-PCR because several of these proteins have only been reported at the messenger level. Among the proteins identified that increased their expression in ascites-treated SKOV-3 cells, were Ran GTPase, ZNF268, and Synaptotagmin like-3. On the other hand, proteins that were negatively re...
Cell type-specific targeting ligands utilized in drug delivery applications typically recognize r... more Cell type-specific targeting ligands utilized in drug delivery applications typically recognize receptors that are overexpressed on the cells of interest. Nonetheless, these receptors may also be expressed, to varying extents, on off-target cells, contributing to unintended side effects. For the selectivity profile of targeting ligands in cancer therapy to be improved, stimuli-responsive masking of these ligands with acid-, redox-, or enzyme-cleavable molecules has been reported, whereby the targeting ligands are exposed in specific environments, e.g., acidic tumor hypoxia. One possible drawback of these systems lies in their one-time, permanent trigger, which enables the "demasked" ligands to bind off-target cells if released back into the systemic circulation. A promising strategy to address the aforementioned problem is to design ligands that show selective binding based on ionization state, which may be microenvironment-dependent. In this study, we report a systematic ...
Epithelial ovarian cancer is the most lethal gynecologic malignancy. Integrins, overexpressed in ... more Epithelial ovarian cancer is the most lethal gynecologic malignancy. Integrins, overexpressed in cancer, are involved in various processes that favor the development of the disease. This study focused on determining the degree of involvement of α5, α6 and β3 integrin subunits in the establishment/development of epithelial ovarian cancer (EOC), such as proliferation, migration, invasion, and response to carboplatin. The translation of the α5, α6 and β3 integrins was blocked using morpholines, generating morphant cells for these proteins, which were corroborated by immunofluorescence assays. WST-1 proliferation assay showed that silencing of α5, α6, and β3 integrins does not affect the survival of morphants. Wound healing and transwell chamber assays showed that blocking α5 and α6 integrins decrease, in lesser and greater level respectively, the migratory and the invasive capacity of SKOV-3 cells. Finally, blocking α5 and α6 integrins partially sensitized the cells response to carboplatin, while blocking integrin β3 generated resistance to this drug. Statistical analyses were performed with the GraphPad Prism 5.0 software employing one way and two-way ANOVA tests; data are shown as average ± SD. Results suggest that α5 and α6 integrins could become good candidates for chemotherapy targets in EOC.
Tumor associated macrophages (TAMs) are a major stromal component of the tumor microenvironment i... more Tumor associated macrophages (TAMs) are a major stromal component of the tumor microenvironment in several cancers. TAMs are a potential target for adjuvant cancer therapies due to their established roles in promoting proliferation of cancer cells, angiogenesis, and metastasis. We previously discovered an M2 macrophage-targeting peptide (M2pep) which was successfully used to target and deliver a pro-apoptotic KLA peptide to M2-like TAMs in a CT-26 colon carcinoma model. However, the effectiveness of in vivo TAM-targeting using M2pep is limited by its poor serum stability and low binding affinity. In this study, we synthesized M2pep derivatives with the goals of increasing serum stability and binding affinity. Serum stability evaluation of M2pepBiotin confirmed its rapid degradation attributed to exolytic cleavage from the N-terminus and endolytic cleavages at the W10/W11 and S16/K17 sites. N-terminal acetylation of M2pepBiotin protected the peptide against the exolytic degradation while W10w and K(17,18,19)k substitutions were able to effectively protect endolytic degradation at their respective cleavage sites. However, no tested amino acid changes at the W10 position resulted in both protease resistance at that site and retention of binding activity. Therefore, cyclization of M2pep was investigated. Cyclized M2pep better resisted serum degradation without compromising binding activity to M2 macrophages. During the serum stability optimization process, we also discovered that K9R and W10Y substitutions significantly enhanced binding affinity of M2pep. In an in vitro binding study of different M2pep analogs pre-incubated in mouse serum, cyclic M2pep with K9R and W10Y modifications (cyclic M2pep(RY)) retained the highest binding activity to M2 macrophages over time due to its improved serum stability. Finally, we evaluated the in vivo accumulation of sulfo-Cy5-labeled M2pep and cyclic M2pep(RY) in both the CT-26 and 4T1 breast carcinoma models. Cyclic M2pep(RY) outperformed M2pep in both tumor localization and selective accumulation in M2-like TAMs. In conclusion, we report cyclic M2pep(RY) as our lead M2pep analog with improved serum stability and M2 macrophage-binding activity. Its enhanced utility as an in vivo M2-like-TAM-targeting agent was demonstrated in two tumor models, and is expected to be applicable for other tumor models or in models of M2 macrophage-related diseases.
... 3 EL MERCADO DE DIVISAS EN VENEZUELA ..... 28 3-1 LAS DIVISAS COMO ACTIVO FINANCIERO ..... 28... more ... 3 EL MERCADO DE DIVISAS EN VENEZUELA ..... 28 3-1 LAS DIVISAS COMO ACTIVO FINANCIERO ..... 28 3-2 CARACTERÍSTICAS DE LOS FLUJOS DE OFERTA Y DEMANDA . DE DIVISAS EN VENEZUELA ..... ...
Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vi... more Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy, cell growth, and differentiation. However, PRL is nowadays known to have a strong implication in oncogenic processes, making it essential to delve into the mechanisms governing these actions. PRL and its receptor (PRLR) activate a series of effects such as survival, cellular proliferation, migration, invasion, metastasis, and resistance to treatment, being highly relevant in developing certain types of cancer. Because women produce high levels of PRL, its influence in gynecological cancers is herein reviewed. It is interesting that, other than the 23 kDa PRL, whose mechanism of action is endocrine, other variants of PRL have been observed to be produced by tumoral tissue, acting in a paracrine/autocrine manner. Because many components, including PRL, surround the microenvironment, it is interesting to understand the hor...
This article is a theoretical review essay, which aims to present the events that are considered ... more This article is a theoretical review essay, which aims to present the events that are considered most relevant in the development and consolidation of Cognitive-Behavioral Therapy (CBT) and which in turn have positioned it as a therapy of choice for Different psychological problems. A review was carried out with two of the most accessible digital search engines for undergraduate students, using search keywords according to the objective of this article. Identifying that cognitive-behavioral therapy is understood as the application of scientific psychology to clinical practice in a systematic and structured way. This model based on behavior modification because of its solid theoretical and experimental basis, which emphasizes the empirical verification of the techniques during its application. What makes CBT an effective, efficient, and timely clinical practice, improving the quality of life of users and positioning themselves in front of other psychological models in terms of efficacy.
Supplementary Figure S1. Bacteriophage titers in the CNS after IP injection. After each round of ... more Supplementary Figure S1. Bacteriophage titers in the CNS after IP injection. After each round of selection, 8 or 24 hours after IP injection heart (red), brain (yellow), and spinal cord (blue) tissue was harvested and tittered for bacteriophage load prior to amplification. Initially, a 50:50 mix of C7C and PhD-12 bacteriophage was injected. After the initial mix, bacteriophage was amplified from CNS tissue lysates prior to subsequent rounds of in vivo selection. Bacteriophage titer was normalized by protein concentration for each round.
Non-obstetric surgery is performed in 0.2-1.6% of pregnancies. Recently the FDA called for cautio... more Non-obstetric surgery is performed in 0.2-1.6% of pregnancies. Recently the FDA called for cautious use of anesthetic drugs during pregnancy. The consequences of anesthesia during pregnancy on fetal development in humans are unclear and preclinical evidence remains scarce.
El objetivo del presente trabajo de investigación fue conocer las indicaciones más frecuentes de ... more El objetivo del presente trabajo de investigación fue conocer las indicaciones más frecuentes de sedación paliativa en pacientes -hombres y mujeres- que estuvieron ingresados en una unidad de cuidados paliativos, así como los diagnósticos oncológicos, el tipo de sedación y las dosis administradas, y determinar si se logró un adecuado control de los síntomas. Esto es relevante debido a que no se cuenta con datos nacionales referentes a esta terapéutica. El tipo de investigación fue descriptiva, con diseño retrospectivo en la cual se realizó una revisión de expedientes de los pacientes ingresados en el Hospital de cuidados paliativos Divina Providencia de El Salvador, en el periodo de noviembre de 2014 a abril de 2015. Se seleccionó una muestra no probabilista por conveniencia de 49 pacientes. Según los datos obtenidos, se observó que el 30% de los pacientes necesitaron sedación paliativa sin diferencia de género; además se estableció que el 69.4% de los pacientes se encontraban entre...
Epithelial ovarian cancer is the second most lethal gynecological cancer worldwide. Ascites can b... more Epithelial ovarian cancer is the second most lethal gynecological cancer worldwide. Ascites can be found in all clinical stages, however in advanced disease stages IIIC and IV it is more frequent and could be massive, associated with worse prognosis. Due to the above, it was our interest to understanding how the ascites of ovarian cancer patients induces the mechanisms by which the cells present in it acquire a more aggressive phenotype and to know new proteins associated to this process. A proteomic analysis of SKOV-3 cells treated with five different EOC ascites was performed by two-dimensional electrophoresis coupled to MALDI-TOF. The level of expression of the proteins of interest was validated by RT-PCR because several of these proteins have only been reported at the messenger level. Among the proteins identified that increased their expression in ascites-treated SKOV-3 cells, were Ran GTPase, ZNF268, and Synaptotagmin like-3. On the other hand, proteins that were negatively re...
Cell type-specific targeting ligands utilized in drug delivery applications typically recognize r... more Cell type-specific targeting ligands utilized in drug delivery applications typically recognize receptors that are overexpressed on the cells of interest. Nonetheless, these receptors may also be expressed, to varying extents, on off-target cells, contributing to unintended side effects. For the selectivity profile of targeting ligands in cancer therapy to be improved, stimuli-responsive masking of these ligands with acid-, redox-, or enzyme-cleavable molecules has been reported, whereby the targeting ligands are exposed in specific environments, e.g., acidic tumor hypoxia. One possible drawback of these systems lies in their one-time, permanent trigger, which enables the "demasked" ligands to bind off-target cells if released back into the systemic circulation. A promising strategy to address the aforementioned problem is to design ligands that show selective binding based on ionization state, which may be microenvironment-dependent. In this study, we report a systematic ...
Epithelial ovarian cancer is the most lethal gynecologic malignancy. Integrins, overexpressed in ... more Epithelial ovarian cancer is the most lethal gynecologic malignancy. Integrins, overexpressed in cancer, are involved in various processes that favor the development of the disease. This study focused on determining the degree of involvement of α5, α6 and β3 integrin subunits in the establishment/development of epithelial ovarian cancer (EOC), such as proliferation, migration, invasion, and response to carboplatin. The translation of the α5, α6 and β3 integrins was blocked using morpholines, generating morphant cells for these proteins, which were corroborated by immunofluorescence assays. WST-1 proliferation assay showed that silencing of α5, α6, and β3 integrins does not affect the survival of morphants. Wound healing and transwell chamber assays showed that blocking α5 and α6 integrins decrease, in lesser and greater level respectively, the migratory and the invasive capacity of SKOV-3 cells. Finally, blocking α5 and α6 integrins partially sensitized the cells response to carboplatin, while blocking integrin β3 generated resistance to this drug. Statistical analyses were performed with the GraphPad Prism 5.0 software employing one way and two-way ANOVA tests; data are shown as average ± SD. Results suggest that α5 and α6 integrins could become good candidates for chemotherapy targets in EOC.
Tumor associated macrophages (TAMs) are a major stromal component of the tumor microenvironment i... more Tumor associated macrophages (TAMs) are a major stromal component of the tumor microenvironment in several cancers. TAMs are a potential target for adjuvant cancer therapies due to their established roles in promoting proliferation of cancer cells, angiogenesis, and metastasis. We previously discovered an M2 macrophage-targeting peptide (M2pep) which was successfully used to target and deliver a pro-apoptotic KLA peptide to M2-like TAMs in a CT-26 colon carcinoma model. However, the effectiveness of in vivo TAM-targeting using M2pep is limited by its poor serum stability and low binding affinity. In this study, we synthesized M2pep derivatives with the goals of increasing serum stability and binding affinity. Serum stability evaluation of M2pepBiotin confirmed its rapid degradation attributed to exolytic cleavage from the N-terminus and endolytic cleavages at the W10/W11 and S16/K17 sites. N-terminal acetylation of M2pepBiotin protected the peptide against the exolytic degradation while W10w and K(17,18,19)k substitutions were able to effectively protect endolytic degradation at their respective cleavage sites. However, no tested amino acid changes at the W10 position resulted in both protease resistance at that site and retention of binding activity. Therefore, cyclization of M2pep was investigated. Cyclized M2pep better resisted serum degradation without compromising binding activity to M2 macrophages. During the serum stability optimization process, we also discovered that K9R and W10Y substitutions significantly enhanced binding affinity of M2pep. In an in vitro binding study of different M2pep analogs pre-incubated in mouse serum, cyclic M2pep with K9R and W10Y modifications (cyclic M2pep(RY)) retained the highest binding activity to M2 macrophages over time due to its improved serum stability. Finally, we evaluated the in vivo accumulation of sulfo-Cy5-labeled M2pep and cyclic M2pep(RY) in both the CT-26 and 4T1 breast carcinoma models. Cyclic M2pep(RY) outperformed M2pep in both tumor localization and selective accumulation in M2-like TAMs. In conclusion, we report cyclic M2pep(RY) as our lead M2pep analog with improved serum stability and M2 macrophage-binding activity. Its enhanced utility as an in vivo M2-like-TAM-targeting agent was demonstrated in two tumor models, and is expected to be applicable for other tumor models or in models of M2 macrophage-related diseases.
... 3 EL MERCADO DE DIVISAS EN VENEZUELA ..... 28 3-1 LAS DIVISAS COMO ACTIVO FINANCIERO ..... 28... more ... 3 EL MERCADO DE DIVISAS EN VENEZUELA ..... 28 3-1 LAS DIVISAS COMO ACTIVO FINANCIERO ..... 28 3-2 CARACTERÍSTICAS DE LOS FLUJOS DE OFERTA Y DEMANDA . DE DIVISAS EN VENEZUELA ..... ...
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