PAX6 promoter methylation correlates with MDA-MB-231 cell migration, and expression of MMP2 and MMP9

Objective: Breast cancer is a heterogeneous disease characterized by an accumulation of genetic and epigenetic alterations that lead tumor cells to acquire characteristics like the capacity for invasion and metastasis. Metastasis remains a major challenge in cancer management and understanding of its molecular basis should result in improved prevention, diagnosis, and treatment of breast cancer patients. The aim of this study was to investigate how promoter DNA methylation regulates PAX6 gene expression and influences breast carcinoma cell migration. Methods: PAX6 promoter methylation was detected by Methyl Specific-Multiplex Ligation Probe Amplification (MS-MLPA). Gene expression was evaluated using qRT-PCR, while the effect of PAX6 on migration was ssessed by wound healing assay. In addition, MMP2 and MMP9 genes were studied using different bioinformatic tools. Results: The PAX6 promoter is methylated in breast cancer cell lines and methylation in this region impacts on its expression. Migration assays revealed that PAX6 overexpression promotes cell migration, while PAX6 inhibition decreases it. More importantly, we found that migration is affected by PAX6 methylation status. Employing bioinformatic analysis, binding sites for PAX6 on the regulatory regions of the MMP2 and MMP9 genes were established, PAX6 overexpression increasing MMP2 and MMP9 expression at the mRNA level. Conclusion: Our study provides novel insights into epigenetic events that regulate PAX6 expression and molecular mechanisms by which PAX6 modifies the migration capacity of breast cancer cells.Fil: Urrutia, Guillermo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Laurito, Sergio Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Campoy, Emanuel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Nasif, Daniela Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Branham, Maria Teresita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Roque Moreno, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Epigenetic regulation of ID4 in breast cancer: Tumor suppressor or oncogene?

Background: Inhibitor of differentiation protein 4 (ID4) is a dominant negative regulator of the basic helix-loop-helix (bHLH) family of transcription factors. During tumorigenesis, ID4 may act as a tumor suppressor or as an oncogene in different tumor types. However, the role of ID4 in breast cancer is not clear where both an oncogenic and a tumor suppressor function have been attributed. Here, we hypothesize that ID4 behaves as both, but its role in breast differs according to the estrogen receptor (ER) status of the tumor. Methods: ID4 expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and ID4 was assessed using Kaplan-Meier plotter. Correlation between methylation and expression was analyzed using the MEXPRESS tool. In vitro experiments involved ectopic expression of ID4 in MCF-7, T47D, and MDA-MB231 breast cancer cell lines. Migration and colony formation capacity were assessed after transfection treatments. Gene expression was analyzed by ddPCR and methylation by MSP, MS-MLPA, or ddMSP. Results: Data mining analysis revealed that ID4 expression is significantly lower in ER+ tumors with respect to ER- tumors or normal tissue. We also demonstrate that ID4 is significantly methylated in ER+ tumors. Kaplan-Meier analysis indicated that low ID4 expression levels were associated with poor overall survival in patients with ER+ tumors. In silico expression analysis indicated that ID4 was associated with the expression of key genes of the ER pathway only in ER+ tumors. In vitro experiments revealed that ID4 overexpression in ER+ cell lines resulted in decreased migration capacity and reduced number of colonies. ID4 overexpression induced a reduction in ER levels in ER+ cell lines, while estrogen deprivation with fulvestrant did not induce changes neither in ID4 methylation nor in ID4 expression. Conclusions: We propose that ID4 is frequently silenced by promoter methylation in ER+ breast cancers and functions as a tumor suppressor gene in these tumors, probably due to its interaction with key genes of the ER pathway. Our present study contributes to the knowledge of the role of ID4 in breast cancer.Fil: Nasif, Daniela Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo; ArgentinaFil: Campoy, Emanuel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo; ArgentinaFil: Laurito, Sergio Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo; ArgentinaFil: Branham, Richard Lacy. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Urrutia, Guillermo Alejandro. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo; ArgentinaFil: Roque Moreno, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo; ArgentinaFil: Branham, Maria Teresita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo; Argentin

Servicios de la ACOOPA en apoyo al sector agropecuario regional 2022-2023

La Asociación Cooperadora de la Estación Experimental Agropecuaria Hilario Ascasubi (ACOOPA) es una organización sin fines de lucro que apoya las actividades de investigación y extensión del Instituto Nacional de Tecnología Agropecuaria (INTA) en el extremo austral bonaerense. Los servicios ofrecidos a los productores, instituciones y otros comitentes, incluyen la clasificación y análisis de semillas, análisis de suelos y forestación con salicáceas. Entre julio de 2022 y junio de 2023, a través de la Planta de Limpieza y Clasificación de Semillas, se procesaron más de medio millón de kg de semillas. A través de los laboratorios se realizó el control de calidad de 260 muestras de semillas de varias especies de valor agronómico, y se analizaron cerca de un millar de muestras de suelos y agua. Los servicios tuvieron como destino directo a los productores o resultaron como apoyo a actividades de investigación y extensión de INTA. El servicio de forestación con salicáceas bajo el sistema de plantación profunda, con la entrega de unos 1.200 nuevos individuos, continuó fortaleciendo la adopción de la innovadora tecnología. Se estima que, en conjunto, los servicios realizados mejoraron el manejo de los suelos en cerca de 30 mil ha. La certificación de la calidad de las semillas benefició a unas 90 mil ha de cultivos, principalmente forrajeras perennes y cultivos de servicio. La mejora de la calidad física y botánica de las partidas de semillas presentes en el Valle posibilitó optimizar la siembra de unas 20 mil ha de cultivos. También en este caso existió una fuerte predominancia de semillas de pasturas y leguminosas forrajeras.EEA Hilario AscasubiFil: Cantamutto, Miguel Angel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Hilario Ascasubi; Argentina.Fil: Renzi Pugni, Juan Pablo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Hilario Ascasubi; ArgentinaFil: Iurman, Daniel Eduardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Hilario Ascasubi; Argentina.Fil: Fernández, Marianela. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Hilario Ascasubi; Argentina.Fil: Urrutia, Gustavo Alejandro. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Hilario Ascasubi; Argentina.Fil: Gonzalez, Guillermo Martin. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Hilario Ascasubi. Agencia De Extensión Rural Carmen de Patagones; Argentin

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Plan de mejora integral Centro Rehabilitación Coaniquem Santiago

Tesis (Ingeniero Industrial)La Corporación de Ayuda al Niño Quemado COANIQUEM, es una Institución de Salud sin fines de lucro, reconocida mundialmente, que atiende gratuitamente a niños y adolecentes tanto de Chile como de Latinoamérica. Actualmente el Centro de Rehabilitación COANIQUEM Santiago, lugar donde se desarrolló el estudio, se encuentra en un proceso de expansión que se ve potenciado por el interés que existe, por parte de la Dirección, en obtener la certificación entregada por el Ministerio de Salud, con el fin de otorgar las prestaciones establecidas en las patologías GES. Para la elaboración del Plan de Mejora, se utilizaron herramientas de Ingeniería Industrial que permitieron caracterizar los procesos y sus interacciones e identificar problemas de gestión. A partir de esta información, se elaboran dos proyectos denominados “Sistema de Información Clínico” compuesto por los módulos: Ficha Clínica Electrónica, Agenda Electrónica, Sistema de Gestión de Proveedores, Sistema de Costeo ABC y Sistema de Gestión de Insumos; y “Proyecto de Gestión” conformado por: Documentación de Procedimientos, Plan Estratégico de Operaciones, Rediseño de la Estructura Organizacional y Regularización Técnica Normativa. El costo que implica llevar a cabo el proyecto Sistema de Información Clínico es de $97.442.647. Para realizar el Proyecto de Gestión es necesario realizar una inversión de al menos$ 57.158.000

Characterization of Al-Ni intermetallics around 30-60 at% Al for TLPB application

Interest on the Al–Ni equilibrium diagram along the latest years is associated with the attractive properties of its intermetallic phases, such as high thermal stability, high corrosion resistance and high strength to density ratio. The Transient Liquid Phase Bonding (TLPB) is a technological process which can be applied to manufacture new pieces and to perform reparations. Morphology, composition profiles, growth kinetic and hardness as a function of temperature and composition of the Intermetallic Layers (ILs) were analyzed, especially focused on solid–solid interactions during isothermal annealing in reactive diffusion couples Ni/Al (800–1170 °C). The study yields to the following association of the Al–Ni Intermetallic Phases (IPs) to the ILs: L1 (Al3Ni), L2 (Al3Ni2), L3 (Ni-poor AlNi), L4 (Ni-rich AlNi) and L5 (AlNi3). The composition ranges of L3 and L4 are 36–46 and 53–58 at% Al, respectively. Martensitic transformation was found in the half thickness of L4 (L4M and L4S) at 1170 °C. Kinetics show diffusion controlled growth for L2 and L5 and interface reaction control for L4 at 800–1170 °C, while L3 revealed a mixed kinetic behavior: parabolic at 800–1000 °C and linear at 1170 °C. The growth rate constants presented temperature dependence according to the Arrhenius model. Vickers microhardness values decrease with annealing temperature and Ni concentration for ILs, and put in evidence different mechanical properties of L3, L4M and L4S.Fil: Urrutia, Guillermo Alejandro. Universidad Nacional del Comahue; ArgentinaFil: Tumminello, Silvana Deisy Paulina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. IDEPA - Subsede San Antonio Oeste; Argentina. Universidad Nacional del Comahue; ArgentinaFil: Aricó, Sergio Fabián. Comision Nacional de Energia Atomica. Centro Atomico Constituyentes. Departamento de Materiales; ArgentinaFil: Sommadossi, Silvana Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. IDEPA - Subsede San Antonio Oeste; Argentina. Universidad Nacional del Comahue; Argentin

Modulation of the Akt pathway reveals a novel link with PERK/eIF2α, which is relevant during hypoxia.

The unfolded protein response (UPR) and the Akt signaling pathway share several regulatory functions and have the capacity to determine cell outcome under specific conditions. However, both pathways have largely been studied independently. Here, we asked whether the Akt pathway regulates the UPR. To this end, we used a series of chemical compounds that modulate PI3K/Akt pathway and monitored the activity of the three UPR branches: PERK, IRE1 and ATF6. The antiproliferative and antiviral drug Akt-IV strongly and persistently activated all three branches of the UPR. We present evidence that activation of PERK/eIF2α requires Akt and that PERK is a direct Akt target. Chemical activation of this novel Akt/PERK pathway by Akt-IV leads to cell death, which was largely dependent on the presence of PERK and IRE1. Finally, we show that hypoxia-induced activation of eIF2α requires Akt, providing a physiologically relevant condition for the interaction between Akt and the PERK branch of the UPR. These data suggest the UPR and the Akt pathway signal to one another as a means of controlling cell fate