IGF-1 regulates Cyr61 induced breast cancer cell proliferation and invasion.

BackgroundStudies from our laboratory and others have shown that cysteine-rich 61 (Cyr61) may be involved in tumor proliferation and invasion. In earlier studies, we demonstrated increased insulin-like growth factor-I (IGF-1) is associated with breast tumor formation and poor clinical outcomes. In our current study we have investigated IGF-1 regulation of Cyr61 and whether targeting IGF-1 could inhibit Cyr61 induced tumor growth and proliferation.MethodsSeveral ATCC derived normal and breast cancer cell lines were used in this study: MDA-MB231, BT474, MCF-7, and SKBR3. We also tested cells stably transfected in our laboratory with active Akt1 (pAkt; SKBR3/AA and MCF-7/AA) and dominant negative Akt1 (SKBR3/DN and MCF-7/DN). In addition, we used MCF-7 cells transfected with full length Cyr61 (CYA). Monolayer cultures treated with IGF-1 were analyzed for Cyr61 expression by RT-PCR and immunohistochemical staining. Migration assays and MTT based proliferation assays were used to determine invasive characteristics in response to IGF-1/Cyr61 activation.ResultsCells with activated Akt have increased levels of Cyr61. Conversely, cells with inactive Akt have decreased levels of Cyr61. IGF-1 treatment increased Cyr61 expression significantly and cells with high level of Cyr61 demonstrate increased invasiveness and proliferation. Cyr61 overexpression and activation led to decrease in E-cadherin and decrease in FOXO1. Inhibition of the PI3K and MAPK pathways resulted in significant decrease in invasiveness and proliferation, most notably in the PI3K pathway inhibited cells.ConclusionThe findings of this study show that IGF-1 upregulates Cyr61 primarily through activation of the Akt-PI3K pathway. IGF-1 induced MAPK plays a partial role. Increase in Cyr61 leads to increase in breast cancer cell growth and invasion. Hence, targeting Cyr61 and associated pathways may offer an opportunity to inhibit IGF-1 mediated Cyr61 induced breast cancer growth and invasion

The Role of p16INK4a Expression in the Age-related Risk of Venous Thromboembolism

Venous thromboembolism (VTE) is a pathophysiologically complex disease involving dysregulation of pro and anticoagulant processes in the vasculature. Aging is the strongest risk factor for VTE, although the mechanism is not well understood. Senescence is a physiologic process limiting cellular proliferation, caused by age-dependent expression of the cell cycle inhibitor p16INK4a. p16INK4a expression and senescence could promote vascular dysfunction and predispose elderly individuals to VTE. This dissertation is focused on researching the contribution of p16INK4a expression and aging to venous thrombosis. Murine in vivo vascular injury models are commonly used to study venous and arterial thrombosis. We found that p16INK4a overexpression in mice was associated with augmented venous thrombosis and increased thrombin generation. Bone marrow transplantation analysis demonstrated that this phenotype was dependent on p16INK4a expression in hematopoietic cells. Furthermore, p16INK4a transgenic mice display significant elevation monocyte and macrophage marker, F4/80 staining following IVC ligation. Depletion of monocytes and macrophages, abolished the difference in thrombus mass between p16INK4a overexpressing and wild-type mice. This suggests that p16INK4a expression in hematopoeitic cells, and specifically monocytes and macrophages, contribute to venous thrombosis. Senescence in vascular endothelial cells is associated with phenotypic changes that could promote vascular dysfunction. We observed that senescence induced by serial passaging in vitro caused more rapid rates of clot formation, increased thrombin generation, and formation of denser fibrin networks on the endothelial cell surface. Furthermore, senescent endothelial cells generate less activated protein C due to downregulation of thrombomodulin expression. These results suggest that endothelial cell senescence promotes a procoagulant phenotype. Age-related changes in venous thrombus formation and resolution have not been well defined. Aged mice display a prothrombotic phenotype in a FeCl?3? injury to the saphenous vein, however there was no difference compared to young mice in thrombus mass after IVC-ligation. This suggests the susceptibility of aged mice to venous thrombosis is coagulation stimulus dependent. Additionally, aging in mice is associated with changes in blood composition and plasma coagulability that differ from changes observed in human aging, suggesting mice are a challenging model to study hemostasis during aging. Collectively these studies suggest that p16INK4a expression and cellular senescence contribute to venous thrombosis.Doctor of Philosoph

Criterios para el estudio y diseño universal del espacio público: el caso de las calles en Lima.

Aspectos como las condiciones urbanas y la calidad de vida de las personas se han visto afectados debido al excesivo y desordenado uso de modos de transporte motorizados, caso del automóvil, restándole cada vez más espacio a las actividades públicas, entre ellas la circulación y estancia peatonal. Esta situación comenzó a ponerse en cuestión en los años setenta a partir de la toma de conciencia del estado de las ciudades y su futuro; es así que desde entonces los estudios entorno al espacio público se encuentran experimentado una constante evolución, lo que ha producido la regeneración de un considerable número de espacios alrededor del mundo. En Perú, específicamente en Lima, este concepto aún se encuentra poco desarrollado y con recursos limitados; sin embargo, es un tema que se hace cada vez más urgente a considerar debido a los problemas de movilidad que enfrente la ciudad actualmente. La presente investigación plantea aplicar una metodología basada en experiencias de otros países para el estudio integral del espacio público adaptado a un área de Lima como es la Av. Javier Prado en el distrito de San Isidro. Se estudia la interacción de las actividades y usos del suelo para percibir las dinámicas del área. Asimismo, se analiza la calidad de la escena urbana tanto para la dimensión física como en la dimensión humana, es decir, si este espacio es accesible y confortable para todos sus usuarios, incluyendo a los más vulnerables como niños y personas con movilidad reducida; de esta forma se busca definir si el espacio estudiado ofrece calidad en su diseño o no, en cuyo caso podría renovarse. Finalmente, esta tesis se presenta como una propuesta de referencia para futuros estudios del espacio público urbano en Lima y otros puntos del país.Tesi

“Clima organizacional y su incidencia en la atención de los socios de las Cooperativas de Ahorro y Crédito del cantón La Maná, provincia de Cotopaxi, período 2020”

The objective of the research is to identify how the organizational climate affects the service to members of the Savings and Credit Cooperative in La Maná Canton, Cotopaxi province, period 2020 despite the assessment made by the management, administrative and service staff, the members' perspective regarding the quality of service in these financial organizations. A descriptive-analytical method applied through a survey integrating a random sample, which resulted in people in correspondence to the population size, to diagnose the current state of the organizational climate in the different institutions concerning the dimensions of the Organizational Climate: formal structure, responsibility, reward, affective environment, identity-growth, leadership, clarity, professional commitment, attention to the members. The results showed a lack of organizational climate within the company, 87% of survey respondents that there isn't attention to the partners since it has not improved in the last six months. A significant way is made with a proposal for the design of a strategic guide to improve and guide the efforts of the workers, leading to optimizing the quality of customer service and therefore the efficiency and effectiveness of the organization.En la presente investigación tiene como objetivo identificar de qué manera incide el clima organizacional en la atención de los socios de las Cooperativas de Ahorro y Crédito del Cantón La Maná, provincia de Cotopaxi, período 2020, contrastando la valoración que hace la gerencia, el personal administrativo y de servicio; así como también, la perspectiva de los socios en cuanto a la calidad de atención en estas organizaciones financieras. se aplicó un método descriptivo analítico aplicando una encuesta integrando una muestra aleatoria, dando como resultado 398 sujetos en correspondencia al tamaño poblacional, para diagnosticar el estado actual del clima organizacional en las diferentes instituciones con respecto a las dimensiones del Clima Organizacional: estructura formal, responsabilidad, recompensa, ambiente afectuoso, identidad-crecimiento, liderazgo, claridad, compromiso profesional, atención a los socios. Los resultados arrojaron que existe falta de clima organizacional dentro de la empresa y un 87% de los encuestados manifestaron que existe deficiente atención a los socios ya que no ha mejorado en los últimos 6 meses, se contribuye de forma significativa con una propuesta de un diseño de una guía estratégica que mejore y oriente los esfuerzos en los trabajadores, conducente a optimizar la calidad de atención al cliente y por consiguiente la eficiencia y eficacia organizacional

Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Angiotensin II (Ang II) plays an important role in cardiovascular disease. It also leads to the activation of coagulation. The coagulation protease thrombin induces cellular responses by activating protease activated receptor 1 (PAR-1). We investigated if PAR-1 contributes to Ang II-induced cardiovascular remodeling and inflammation

Evaluación del desarrollo del lenguaje expresivo en niños de una I.E.I.P del distrito de Chaclacayo según sexo y edad

Esta investigación titulada “Evaluación del lenguaje expresivo en niños de una I.E.P.I del distrito de Chaclacayo según sexo y edad”, se justifica en la medida que sus resultados sirven para incrementar el bagaje teórico del lenguaje expresivo en niños en edad preescolar, además brinda información sobre los aspectos involucrados en el desarrollo del lenguaje expresivo, así como también describe las diferencias en los distintos grupos evaluados según sexo y edad. Por lo tanto, en este estudio se plantea como hipótesis: ¿Existen diferencias en el desarrollo del lenguaje expresivo en niños de una I.E.P.I del distrito de Chaclacayo, según sexo y edad? Para la realización de este estudio se utiliza pruebas que abarcan todos los componentes del lenguaje dentro del proceso expresivo: el Test Figura Palabra de Vocabulario Expresivo GARDNER Adaptado, Test para Evaluar Procesos de Simplificación Fonológica TEPROSIF-R, Protocolo pragmático y la muestra de lenguaje que permitió obtener la longitud media del enunciado. Los resultados demuestran que no existen diferencias significativas en el desarrollo del lenguaje expresivo según sexo, sólo se hallaron diferencias en cuanto a habilidades conversacionales en la categoría toma de turnos, obteniendo las mujeres el mayor puntaje. Por otro lado, se encontraron diferencias significativas en el desarrollo del lenguaje expresivo según edad, ya que los niños de 5 años tuvieron los puntajes más altos. En conclusión se puede comprobar parcialmente la hipótesis general ya que existen diferencias en el desarrollo del lenguaje expresivo en niños de una I.E.I.P. del distrito de Chaclacayo, según sexo y edadThis research entitled "Evaluation of expressive language in children of an IEPI of the Chaclacayo district by sex and age", is justified to the extent that the results for the theoretical baggage of expressive language in preschool children, in addition to information involved in the development of the express language, as well as describing the differences in the groups evaluated according to sex and age. Therefore, this research is presented as a hypothesis: Are there differences in the development of expressive language in children of a secondary school in the Chaclacayo district, by sex and age? To carry out this study, tests are used that cover all the components of the language within the expressive process: the Test Figure Word Word of Vocabulary Expressive GARDNER Adapted, Test to Evaluate Processes of Phonological Simplification TEPROSIF-R, Pragmatic Protocol and the sample of language Please get the average length of the sentence. The results show that there are no significant differences in language development expressed by sex, only differences were found in terms of conversational skills in the turn-taking category, with women obtaining the highest score. On the other hand, in the development of the expressive language by age, that the children of 5 years had the highest scores. In conclusion, you can verify the general hypothesis that already exists in the development of expressive language in children of an I.E.I.P. of the Chaclacayo district, by sex and age.Tesi

In Vitro Cecal Gas and Methane Production of Soybean Hulls–Containing Diets in the Presence of Salix babylonica Extract as a Fermentation Modulator in Horses

The aim of the present study was to evaluate the cecal gas production (GP) and methane (CH4) production as well as cecal fermentation kinetics when corn grain (CG) was replaced with soybean hulls (SHs) in horse diets in the presence of different levels of Salix babylonica (SB) extract. Corn grains were replaced with SH at different levels (/kg): 0 g (control), 75 g (SH75), or 150 g (SH150), with the inclusion of SB extract at: 0, 0.6, 1.2, and 1.8 mL/g dry matter (DM) of substrates. Ration type extract dose interactions were observed for GP and CH4 production at some incubation hours. Diets containing SH, without the inclusion of SB extract, increased the asymptotic GP (P ¼ .031) and decreased (P <.01) the rate of GP and lag time of GP. The inclusion of SB increased (P ¼.009) the rate of GP, without affecting the asymptotic GP or lag time of GP. Besides, the SH-containing rations decreased (P < .05) CH4 production, with no effect for SB extract dose. The SH75 ration increased (P < .05) cecal fermentation pH, metabolizable energy, short chain fatty acids, and gas yield at 24 hours of incubation, but quadratically decreased partitioning factor at 24 hours of incubation (P ¼ .023), whereas SB extract dose had no effect. It is concluded that SH-containing rations had higher potential fermentation efficiency and fermentation kinetics superior to that of CG. The level of 75 g SH/kg DM was the best level of inclusion to replace 30% CG in the diets of horses. The inclusion of SB extract did not affect the cecal fermentation kinetics of horse diets containing SH at different levels

Hypofibrinogenemia Following Injury in 186 Children and Adolescents: Identification of the Phenotype, Current Outcomes, and Potential for Intervention

OBJECTIVES: Recent studies evaluating fibrinogen replacement in trauma, along with newly available fibrinogen-based products, has led to an increase in debate on where products such as cryoprecipitate belong in our resuscitation strategies. We set out to define the phenotype and outcomes of those with hypofibrinogenemia and evaluate whether fibrinogen replacement should have a role in the initial administration of massive transfusion. METHODS: All patients/17-4/21 were reviewed. We then evaluated all patients who received emergency-release and massive transfusion protocol (MTP) products. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen(r-TEG) angleHYPOFIB, the impact on outcomes, and whether early replacement improved mortality. RESULTS: 4169 patients were entered into the trauma registry, with 926 level 1 trauma activations, of which 186 patients received emergency-release blood products during this time; 1%, 3%, and 10% were HYPOFIB, respectively. Of the 186 patients of interest, 18 were HYPOFIB and 168 were non-HYPOFIB. The HYPOFIB patients were significantly younger, had lower field and arrival Glasgow Coma Scale, had higher head Abbreviated Injury Scale, arrived with worse global coagulopathy, and died from brain injury. Non-HYPOFIB patients were more likely to have (+)focused assessment for the sonography of trauma on arrival, sustained severe abdominal injuries, and die from hemorrhage. 12% of patients who received early cryoprecipitate (0-2 hours) had higher mortality by univariate analysis (55% vs 31%, p=0.045), but no difference on multivariate analysis (OR 0.36, 95% CI 0.07 to 1.81, p=0.221). Those receiving early cryoprecipitate who survived after pediatric intensive care unit (PICU) admission had lower PICU fibrinogen and r-TEG alpha-angle values. CONCLUSION: In pediatric trauma, patients with hypofibrinogenemia on admission are most likely younger and to have sustained severe brain injury, with an associated mortality of over 80%. Given the absence of bleeding-related deaths in HYPOFIB patients, this study does not provide evidence for the empiric use of cryoprecipitate in the initial administration of a massive transfusion protocol. LEVEL OF EVIDENCE: Level III - Therapeutic/Care Management

Hypofibrinogenemia Following Injury in 186 Children and Adolescents: Identification of the Phenotype, Current Outcomes, and Potential for Intervention

OBJECTIVES: Recent studies evaluating fibrinogen replacement in trauma, along with newly available fibrinogen-based products, has led to an increase in debate on where products such as cryoprecipitate belong in our resuscitation strategies. We set out to define the phenotype and outcomes of those with hypofibrinogenemia and evaluate whether fibrinogen replacement should have a role in the initial administration of massive transfusion. METHODS: All patients/17-4/21 were reviewed. We then evaluated all patients who received emergency-release and massive transfusion protocol (MTP) products. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen(r-TEG) angleHYPOFIB, the impact on outcomes, and whether early replacement improved mortality. RESULTS: 4169 patients were entered into the trauma registry, with 926 level 1 trauma activations, of which 186 patients received emergency-release blood products during this time; 1%, 3%, and 10% were HYPOFIB, respectively. Of the 186 patients of interest, 18 were HYPOFIB and 168 were non-HYPOFIB. The HYPOFIB patients were significantly younger, had lower field and arrival Glasgow Coma Scale, had higher head Abbreviated Injury Scale, arrived with worse global coagulopathy, and died from brain injury. Non-HYPOFIB patients were more likely to have (+)focused assessment for the sonography of trauma on arrival, sustained severe abdominal injuries, and die from hemorrhage. 12% of patients who received early cryoprecipitate (0-2 hours) had higher mortality by univariate analysis (55% vs 31%, p=0.045), but no difference on multivariate analysis (OR 0.36, 95% CI 0.07 to 1.81, p=0.221). Those receiving early cryoprecipitate who survived after pediatric intensive care unit (PICU) admission had lower PICU fibrinogen and r-TEG alpha-angle values. CONCLUSION: In pediatric trauma, patients with hypofibrinogenemia on admission are most likely younger and to have sustained severe brain injury, with an associated mortality of over 80%. Given the absence of bleeding-related deaths in HYPOFIB patients, this study does not provide evidence for the empiric use of cryoprecipitate in the initial administration of a massive transfusion protocol. LEVEL OF EVIDENCE: Level III - Therapeutic/Care Management

Interferon-γ signaling is associated with BRCA1 loss-of-function mutations in high grade serous ovarian cancer

Loss-of-function mutations of the breast cancer type 1 susceptibility protein (BRCA1) are associated with breast (BC) and ovarian cancer (OC). To identify gene signatures regulated by epigenetic mechanisms in OC cells carrying BRCA1 mutations, we assessed cellular responses to epigenome modifiers and performed genome-wide RNA- and chromatin immunoprecipitation-sequencing in isogenic OC cells UWB1.289 (carrying a BRCA1 mutation, BRCA1-null) and UWB1.289 transduced with wild-type BRCA1 (BRCA1+). Increased sensitivity to histone deacetylase inhibitors (HDACi) was observed in BRCA1-null vs. BRCA1+ cells. Gene expression profiles of BRCA1-null vs. BRCA1+ cells and treated with HDACi were integrated with chromatin mapping of histone H3 lysine 9 or 27 acetylation. Gene networks activated in BRCA1-null vs. BRCA1 + OC cells related to cellular movement, cellular development, cellular growth and proliferation, and activated upstream regulators included TGFβ1, TNF, and IFN-γ. The IFN-γ pathway was altered by HDACi in BRCA1+ vs. BRCA1-null cells, and in BRCA1-mutated/or low vs. BRCA1-normal OC tumors profiled in the TCGA. Key IFN-γ-induced genes upregulated at baseline in BRCA1-null vs. BRCA1+OC and BC cells included CXCL10, CXCL11, and IFI16. Increased localization of STAT1 in the promoters of these genes occurred in BRCA1-null OC cells, resulting in diminished responses to IFN-γ or to STAT1 knockdown. The IFN-γ signature was associated with improved survival among OC patients profiled in the TCGA. In all, our results support that changes affecting IFN-γ responses are associated with inactivating BRCA1 mutations in OC. This signature may contribute to altered responses to anti-tumor immunity in BRCA1-mutated cells or tumors