Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells

Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) stress, c-Jun-N-terminal kinase (JNK), Akt, and 5′AMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 hr) ER stress characterized by an increase of Ser51P-eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P-JNK1/2/JNK1/2, Thr172P-AMPKα, Ser413P-Foxo3a, Thr308P-AKt/AKt and Thr32P-Foxo3a/Foxo3a ratios, and reduction of Ser2481P-mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim EL, Beclin-1, Bcl-xL, Bcl-2, autophagy markers, and reduction of myeloid cell leukemia-1 (Mcl-1) expression. The progressive increase of CHOP expression, and reduction of Thr308P-AKt/AKt and Ser473P-AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim EL expression and caspase-3 activity (24 hr). Small interfering-RNA (si-RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase-3 in sorafenib-treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor-derived xenograft model. In conclusion, the early sorafenib-induced ER stress and regulation of JNK and AMPK-dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK-CHOP-dependent rise of Bim EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim EL expression profile might also be related to the tight balance between AKt- and AMPK-related signaling leading to Foxo3a-dependent BIM EL upregulation.Ministerio de Economía y Competitividad BFU2016‐75352‐PInstituto de Salud Carlos III PI15/00034, PI13/ 00021, PI16/00090, PI14/01349Ministerio de Educación FPU16/05127, FPU12/01433, FPU13/01237Junta de Andalucía CTS-6264, PI-00025-2013, PI-0127-2013, PI-0198-201

Cumplimiento de intervenciones de enfermería para el mantenimiento del catéter venoso central en pacientes pediátricos

Introducción: El catéter venoso central es necesario en los cuidados pediátricos, sin embargo, es una causa importante de bacteriemia nosocomial con 25% de mortandad. El profesional de enfermería es responsable del mantenimiento del catéter venoso central con el propósito de evitar complicaciones locales y sistémicas como la endocarditis y la bacteriemia relacionadas al tratamiento endovenoso.Objetivo: Describir las intervenciones de enfermería para el mantenimiento del catéter venoso central en pacientes pediátricos de un hospital especializado.Metodología: Diseño observacional, descriptivo, transversal, muestra conformada por 85 profesionales de enfermería que otorgaron cuidados directos a niños hospitalizados y recibieron capacitación, muestreo no probabilístico, el instrumento utilizado fue una lista de verificación de mantenimiento del catéter venoso central. Se recolectaron datos con la técnica de observación. El estudio cumple con los aspectos éticos de la ley general de salud en materia de investigación.Resultados: Las intervenciones de enfermería se realizaron con un cumplimiento global de 90.1%, se enfatiza que 70.6% efectuaron lavado de manos antes de manipular el dispositivo. La limpieza y mantenimiento del sitio de inserción la realizaron 98.8%, desinfectaron puertos y conexiones, identificaron lúmenes 92.9%.Conclusión: Los profesionales de enfermería realizan las intervenciones para el mantenimiento del catéter venoso central con un cumplimiento bueno. Sin embargo, las intervenciones con menor cumplimiento que requieren mejora son la higiene de manos, los tiempos para cambios de equipo y soluciones, la desinfección de puertos y conexiones; esenciales para disminuir las infecciones del torrente sanguíneo. Además de estudios futuros acerca de los factores profesionales e institucionales asociados al cumplimiento

Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells

[Background/Aims] Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells.[Methods] The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern.[Results] The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells.[Conclusion] The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cells.We thank the Institute of Health Carlos III (ISCiii) cofinanced by the European Regional Development Fund “A way to achieve Europe” (ERDF) (PI13/00021, P16/00090 and PI19/01266), as well as the Andalusian Ministry of the Economy, Innovation, Science and Employment (CTS-6264) and Andalusian Ministry of Health (PI13/00025, PI16/0198, PIP-0215-2020 and PI-0216-2020) for their financial support to J.M. We also thank the Spanish Ministry of Economy and Competitiveness (MINECO) cofinanced by the ERDF (BFU2016-75352-P AEI/FEDER, EU) for their financial support to J.d.l.C. We thank Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCiii and cofinanced by the ERDF for their financial support. E.N-V. acknowledges IFI18/00014 fellowship from the ISCiii. P.d.l.C-O. acknowledges FPU17/00026 fellowship from the Spanish Ministry of Education (MEC). L.C. acknowledges FPU16/05127 fellowship from the MEC

Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells

Background/Aims: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells. Methods: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern. Results: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15 P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172 P-Cdk4/ Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR- 720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. Conclusion: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cellsEspaña Ministry of Economy and Competitiveness (MINECO) cofinanced by the ERDF (BFU2016-75352-P AEI/FEDER, EU

POR UNA CULTURA DE PAZ: UNA MIRADA DESDE LAS CIENCIAS DE LA CONDUCTA

En
 virtud
 de
 lo
 anterior,
 los
 estudiosos
 de
 las
 ciencias
 de
 la
 conducta
 
de
 la
 Universidad
Autónoma 
del
 Estado 
de 
México,

ante 
la
persistencia
 y 
proliferación
 de
 estos 
hechos
 en
 diversas
 partes
 del
Mundo
 y
 de
 nuestro 
país 
en 
particular, se
 convocó
 a
 los
 estudiosos
 interesados
 y
 a
 la
 sociedad
 en
 general
 a
 presentar
 trabajos
 para
 analizar,
 debatir
 y
 proponer
 estrategias
 de
 acción
 y
 dirección,
 que
 fortalezcan
 una
 convivencia y bienestar con sentido humanista para una cultura de paz. El
 presente
 texto
 es
 producto
 de 
esta convocatoria 
que
 recoge 
los
trabajos 
de 

los
 interesados 
en 
la
 temática,

 de
 diferentes 
países
(España,
Argentina,
Cuba,
Brasil,
Costa
 Rica
 y
 México)
 retomando
 con
 ello
 sus
 experiencias
 relativas
 al
 estudio,
 análisis,
 comprensión
 e
 instrumentación
 de
 la
 cultura
 de
 paz
 en
 los
 distintos
 ámbitos
 institucionales
 en
 los
 que
 participan:
 educativo,
 salud,
 penitenciario,
 social,
laboral,
familia,
alimentario,
psicológico,
por 
mencionar 
algunos.
 El
 presente
 libro,
 propicia
 un
 espacio
 de
 reflexión,
 diálogo
 y
 posicionamiento
 de
 las 
ciencias 
de 
la 
conducta
 para 
la 
apropiación,
análisis,
debate
 y 
propuestas 
que
 fortalezcan 
una
 cultura
 de 
paz
 a
través
 de 
la
 convivencia 
y
 el 
bienestar
 social 
con
 sentido 
humanista.
El
 sistema 
económico
 neoliberal
 y 
el 
proceso
 de 
globalización 
han
 contribuido
al
 logro
 de
 avances
 significativos
 en
 la
 ciencia
 y
 la
 tecnología,
 pero
 también
 han
 propiciado
 la
 polarización
 de
 las
 sociedades
 lo
 que
 ha
 impactado
 de
 manera
 negativa
 a
 la
 sociedad
 en
 su
 conjunto,
 pero
 en
 mayor
 medida
 a
 los grupos
 vulnerables. Dicha
 polarización
 ha
 traído
 consigo
 un
 desarrollo
 desigual
 del
 mundo
 que
 se
 expresa
 de
 diferentes
 maneras
 tanto
 en
 países
 desarrollados
 como
 en
 los
 llamados
 del
 tercer
 mundo,
 en
 donde
 no
 están
 satisfechas
 las
 necesidades
 humanas 
elementales
 de
 todos 
los
sectores 
de 
la 
población,
siempre 
falta 
algo. 
Si 
a
 esto 
le
 sumamos 
los
conflictos
 internacionales por
 diferentes
 motivos
 que
 enfrentan
 algunas
 naciones,
 una
 insuficiente
 cobertura
 educativa
 y
 de
 salud,

 desempleo
 y
 pobreza 
extrema,
 entre 
otras
 cosas; 
estamos
 frente
 a
retos 
de
 gran
 envergadura
 para
 los
 gobiernos,
 para
 los
 estudiosos
 y
 para
 la
 sociedad
 civil
 en
 general. Uno 
de 
los
 intentos
 para
 frenar 
y prevenir 
la
 agudización
 de 
estas 
problemáticas
 es
 la
 cultura 
de 
paz,
cuyo
 estudio
y propuestas 
han 
ido 
avanzando 
en 
diferentes
 sentidos 
y 
de 
manera 
favorable,
el 
tema 
está 
presente 
en 
diferentes 
Organismos
 Internacionales
 como
 la
 ONU,
 la
 UNESCO,
 la
 OCDE,
 El
 Banco
 Mundial,
 entre
 otros.
 Pero
 falta 
mucho 
por 
hacer.Universidad Autónoma del Estado de Méxic

una mirada desde las Ciencias de la Conducta

Este libro es el resultado de los trabajos presentados en el 1er Congreso Internacional "Convivencia y bienestar con sentido humanista para una cultura de paz"

MAREJADAS RURALES Y LUCHAS POR LA VIDA, VOL. II: CONFLICTOS SOCIOTERRITORIALES Y POR RECURSOS NATURALES

Volumen 2. Conflictos socioterritoriales y por recursos naturales, coordinado por: Rosalía López Paniagua, Dante Ariel Ayala Ortiz y Armando Contreras Hernández, constituido por 19 trabajos, divididos en tres secciones. La primera titulada Tierra: tenencia y cultivos transgénicos, contiene 6 trabajos, que abordan el persistente conflicto por la tenencia de la tierra y la producción de soya y maíz transgénico y la asociada acumulación del capital por despojo que caracteriza la agricultura transgénica en México, pero también formas de resistencia como la denuncia de contaminación transgénica en la Sierra Juárez de Oaxaca y las instituciones, actores y gestión en la Reserva de la Biósfera El Triunfo en la Sierra Madre de Chiapas. La segunda sección: Territorio: Explotación y envenenamiento, está compuesta por 5 trabajos que hacen referencia a los conflictos socioambientales derivados de la minería en manos de empresas nacionales y extranjeras omisas y gobiernos cómplices de las consecuencias depredadoras que generan en territorios campesinos e indígenas, debido a su asociación con el narcotráfico y por la contaminación del agua y la tierra que provocan, además de las consecuencias perversas en la salud humana y el entorno natural en diversas regiones del país. En la tercera y última sección, Agua: contaminación y escases, los 8 trabajos que la integran, analizan los conflictos socioterritoriales y luchas por la vida, en diversos estados del país. Se trata de investigaciones que estudian movimientos y conflictos sociales actuales en el campo mexicano, como son las luchas por la defensa del territorio y la defensa de la naturaleza, trabajos que abordan especialmente las disputas por el agua, y los problemas asociados del acceso, la escasez y la contaminación, no solo internos sino con empresas y con el Estado mismo que con la aprobación y aplicación de leyes y reglamentos, el despojo a los campesinos de su territorio en el que han trabajado y vivido por generaciones.INSTITUTO DE CIENCIAS AGROPECUARIAS Y RURALES (ICAR), UNIVERSIDAD DE GUADALAJARA, EL COLEGIO DE MICHOACÁN A.C., FACULTAD DE ESTUDIOS SUPERIORES ACATLÁN-UNAM, ECOSUR, CUCOSTA SUR GRANA, ASOCIACIÓN MEXICANA DE ESTUDIOS RURALES A.C

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Trends in the epidemiology of catheter-related bloodstream infections; towards a paradigm shift, Spain, 2007 to 2019

Altres ajuts: Departament de Salut. Generalitat de Catalunya ("Pla estratègic de recerca i innovació en salut (PERIS) 2019-2021"); Ministerio de Asuntos Económicos y Transformación Digital; Red Española de Investigación en Patología Infecciosa (REIPI).Background: Catheter-related bloodstream infections (CRBSI) are frequent healthcare-associated infections and an important cause of death. Aim: To analyse changes in CRBSI epidemiology observed by the Infection Control Catalan Programme (VINCat). Methods: A cohort study including all hospital-acquired CRBSI episodes diagnosed at 55 hospitals (2007-2019) in Catalonia, Spain, was prospectively conducted. CRBSI incidence rates were adjusted per 1,000patientdays. To assess the CRBSI rate trend per year, negative binomial models were used, with the number of events as the dependent variable, and the year as the main independent variable. From each model, the annual rate of CRBSI diagnosed per 1,000patientdays and the incidence rate ratio (IRR) with its 95% confidence intervals (CI) were reported. Results: During the study, 9,290 CRBSI episodes were diagnosed (mean annual incidence rate:0.20episodes/1,000patientdays). Patients' median age was 64.1years; 36.6% (3,403/9,290) were female. In total, 73.7% (n=6,845) of CRBSI occurred in non-intensive care unit (ICU) wards, 62.7% (n=5,822) were related to central venous catheter (CVC), 24.1% (n=2,236) to peripheral venous catheters (PVC) and 13.3% (n=1,232) to peripherally-inserted central venous catheters (PICVC). Incidence rate fell over the study period (IRR:0.94;95%CI:0.93-0.96), especially in the ICU (IRR:0.88;95%CI:0.87-0.89). As a whole, while episodes of CVC CRBSI fell significantly (IRR:0.88;95%CI:0.87-0.91), peripherally-inserted catheter CRBSI (PVC and PICVC) rose, especially in medical wards (IRR PICVC:1.08;95%CI:1.05-1.11; IRR PVC: 1.03; 95% 1.00-1.05). Conclusions: Over the study, CRBSIs associated with CVC and diagnosed in ICUs decreased while episodes in conventional wards involving peripherally-inserted catheters increased. Hospitals should implement preventive measures in conventional wards

Gestión del conocimiento: perspectiva multidisciplinaria. Volumen 12

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 12, de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro cuenta con el apoyo de los grupos de investigación: Universidad Sur del Lago “Jesús María Semprúm” (UNESUR), Zulia – Venezuela; Universidad Politécnica Territorial de Falcón Alonso Gamero (UPTAG), Falcón – Venezuela; Universidad Politécnica Territorial de Mérida Kleber Ramírez (UPTM), Mérida – Venezuela; Universidad Guanajuato (UG) - Campus Celaya - Salvatierra - Cuerpo Académico de Biodesarrollo y Bioeconomía en las Organizaciones y Políticas Públicas (C.A.B.B.O.P.P), Guanajuato – México; Centro de Altos Estudios de Venezuela (CEALEVE), Zulia – Venezuela, Centro Integral de Formación Educativa Especializada del Sur (CIFE - SUR) - Zulia - Venezuela, Centro de Investigaciones Internacionales SAS (CIN), Antioquia - Colombia.y diferentes grupos de investigación del ámbito nacional e internacional que hoy se unen para estrechar vínculos investigativos, para que sus aportes científicos formen parte de los libros que se publiquen en formatos digital e impreso