Targeting epidermal growth factor receptor to recruit newly generated neuroblasts in cortical brain injuries.

BACKGROUND: Neurogenesis is stimulated in the subventricular zone (SVZ) of mice with cortical brain injuries. In most of these injuries, newly generated neuroblasts attempt to migrate toward the injury, accumulating within the corpus callosum not reaching the perilesional area. METHODS: We use a murine model of mechanical cortical brain injury, in which we perform unilateral cortical injuries in the primary motor cortex of adult male mice. We study neurogenesis in the SVZ and perilesional area at 7 and 14 dpi as well as the expression and concentration of the signaling molecule transforming growth factor alpha (TGF-α) and its receptor the epidermal growth factor (EGFR). We use the EGFR inhibitor Afatinib to promote neurogenesis in brain injuries. RESULTS: We show that microglial cells that emerge within the injured area and the SVZ in response to the injury express high levels of TGF-α leading to elevated concentrations of TGF-α in the cerebrospinal fluid. Thus, the number of neuroblasts in the SVZ increases in response to the injury, a large number of these neuroblasts remain immature and proliferate expressing the epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. Restraining TGF-α release with a classical protein kinase C inhibitor reduces the number of these proliferative EGFR+ immature neuroblasts in the SVZ. In accordance, the inhibition of the TGF-α receptor, EGFR promotes migration of neuroblasts toward the injury leading to an elevated number of neuroblasts within the perilesional area. CONCLUSIONS: Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF-α, activating the EGFR present in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway stimulates neuroblast migration toward the injury and enhances the quantity of neuroblasts within the injured area. These results suggest that these proteins may be used as target molecules to regenerate brain injuries.

Specific Activation of T Cells by an ACE2-Based CAR-Like Receptor upon Recognition of SARS-CoV-2 Spike Protein.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the Coronavirus Disease 2019 (COVID-19) pandemic, which is still a health issue worldwide mostly due to a high rate of contagiousness conferred by the high-affinity binding between cell viral receptors, Angiotensin-Converting Enzyme 2 (ACE2) and SARS-CoV-2 Spike protein. Therapies have been developed that rely on the use of antibodies or the induction of their production (vaccination), but despite vaccination being still largely protective, the efficacy of antibody-based therapies wanes with the advent of new viral variants. Chimeric Antigen Receptor (CAR) therapy has shown promise for tumors and has also been proposed for COVID-19 treatment, but as recognition of CARs still relies on antibody-derived sequences, they will still be hampered by the high evasion capacity of the virus. In this manuscript, we show the results from CAR-like constructs with a recognition domain based on the ACE2 viral receptor, whose ability to bind the virus will not wane, as Spike/ACE2 interaction is pivotal for viral entry. Moreover, we have developed a CAR construct based on an affinity-optimized ACE2 and showed that both wild-type and affinity-optimized ACE2 CARs drive activation of a T cell line in response to SARS-CoV-2 Spike protein expressed on a pulmonary cell line. Our work sets the stage for the development of CAR-like constructs against infectious agents that would not be affected by viral escape mutations and could be developed as soon as the receptor is identified.

Long-Term Survival and Immune Response Dynamics in Melanoma Patients Undergoing TAPCells-Based Vaccination Therapy.

Cancer vaccines present a promising avenue for treating immune checkpoint blockers (ICBs)-refractory patients, fostering immune responses to modulate the tumor microenvironment. We revisit a phase I/II trial using Tumor Antigen-Presenting Cells (TAPCells) (NCT06152367), an autologous antigen-presenting cell vaccine loaded with heat-shocked allogeneic melanoma cell lysates. Initial findings showcased TAPCells inducing lysate-specific delayed-type hypersensitivity (DTH) reactions, correlating with prolonged survival. Here, we extend our analysis over 15 years, categorizing patients into short-term (<36 months) and long-term (≥36 months) survivors, exploring novel associations between clinical outcomes and demographic, genetic, and immunologic parameters. Notably, DTHpos patients exhibit a 53.1% three-year survival compared to 16.1% in DTHneg patients. Extended remissions are observed in long-term survivors, particularly DTHpos/M1cneg patients. Younger age, stage III disease, and moderate immune events also benefit short-term survivors. Immunomarkers like increased C-type lectin domain family 2 member D on CD4+ T cells and elevated interleukin-17A were detected in long-term survivors. In contrast, toll-like receptor-4 D229G polymorphism and reduced CD32 on B cells are associated with reduced survival. TAPCells achieved stable long remissions in 35.2% of patients, especially M1cneg/DTHpos cases. Conclusions: Our study underscores the potential of vaccine-induced immune responses in melanoma, emphasizing the identification of emerging biological markers and clinical parameters for predicting long-term remission.

Development and Validation of a Highly Sensitive Multiplex Immunoassay for SARS-CoV-2 Humoral Response Monitorization: A Study of the Antibody Response in COVID-19 Patients with Different Clinical Profiles during the First and Second Waves in Cadiz, Spain.

There is still a long way ahead regarding the COVID-19 pandemic, since emerging waves remain a daunting challenge to the healthcare system. For this reason, the development of new preventive tools and therapeutic strategies to deal with the disease have been necessary, among which serological assays have played a key role in the control of COVID-19 outbreaks and vaccine development. Here, we have developed and evaluated an immunoassay capable of simultaneously detecting multiple IgG antibodies against different SARS-CoV-2 antigens through the use of Bio-PlexTM technology. Additionally, we have analyzed the antibody response in COVID-19 patients with different clinical profiles in Cadiz, Spain. The multiplex immunoassay presented is a high-throughput and robust immune response monitoring tool capable of concurrently detecting anti-S1, anti-NC and anti-RBD IgG antibodies in serum with a very high sensitivity (94.34-97.96%) and specificity (91.84-100%). Therefore, the immunoassay proposed herein may be a useful monitoring tool for individual humoral immunity against SARS-CoV-2, as well as for epidemiological surveillance. In addition, we show the values of antibodies against multiple SARS-CoV-2 antigens and their correlation with the different clinical profiles of unvaccinated COVID-19 patients in Cadiz, Spain, during the first and second waves of the pandemic.

[Limitations of the Water Quality Risk Index as an estimator of quality for human consumption]. / Limitaciones del IRCA como estimador de calidad del agua para consumo humano.

OBJECTIVE: To analyze the results of the Water Quality Risk Index (IRCA) in the 116 municipalities of the department of Cundinamarca, between 2007 and 2013. MATERIALS AND METHODS: Information collected from the 116 municipalities of the department of Cundinamarca, selected and classified according to the percentage data retrieved by IRCA. RESULTS: A decrease of the annual IRCA average is observed, which reflects an improvement of the water quality delivered in the department. However, 26.7% of the municipalities do not report information from their rural areas, and 56.9% of the municipalities report IRCA figures over 5, which means that even though they are at low risk, they receive water unfit for human consumption. CONCLUSIONS: A new weighting method for the parameters evaluated with the IRCA is proposed to make this index more representative of the risk to health. In addition, future studies should carry out a thorough statistical analysis on the size of the sample that allows the obtained results to be reliable for decision makers to improve the quality of drinking water.

OBJETIVO: Analizar los resultados del Índice de Riesgo de la Calidad del Agua para Consumo Humano (IRCA) para los 116 municipios del Departamento de Cundinamarca, del año 2007 a 2013. MATERIALES Y MÉTODOS: Información recolectada de los 116 municipios del Departamento de Cundinamarca, seleccionados y clasificados en función de los datos porcentuales del IRCA. RESULTADOS: Se observa una disminución del promedio anual del IRCA, lo cual refleja un mejoramiento de la calidad del agua entregada en el departamento; sin embargo, un 26,7% de municipios no reportan información de la zona rural y un 56,9% de los municipios reportan un IRCA superior a 5, que aunque se ubican en Riesgo Bajo, son un agua no apta para consumo humano. CONCLUSIONES: Se propone una nueva ponderación de los parámetros evaluados en el IRCA, con el fin de permitir que este índice sea más representativo del riesgo a la salud y, como estudios futuros un análisis estadístico concienzudo sobre el tamaño de la muestra que permita que los resultados obtenidos sean confiables para los tomadores de decisiones sobre el mejoramiento de la calidad del agua potable.

Influence of size and surface capping on photoluminescence and cytotoxicity of gold nanoparticles.

Hydrophilic and homogeneous sub-10 nm blue light-emitting gold nanoparticles (NPs) functionalized with different capping agents have been prepared by simple chemical routes. Structure, average, size, and surface characteristics of these NPs have been widely studied, and the stability of colloidal NP solutions at different pH values has been evaluated. Au NPs show blue PL emission, particularly in the GSH capped NPs, in which the thiol-metal core transference transitions considerably enhance the fluorescent emission. The influence of capping agent and NP size on cytotoxicity and on the fluorescent emission are analyzed and discussed in order to obtain Au NPs with suitable features for biomedical applications. Cytotoxicity of different types of gold NPs has been determined using NPs at high concentrations in both tumor cell lines and primary cells. All NPs used show high biocompatibility with low cytotoxicity even at high concentration, while Au-GSH NPs decrease viability and proliferation of both a tumor cell line and primary lymphocytes.

Ultrastructural Localization and Molecular Associations of HCV Capsid Protein in Jurkat T Cells.

Hepatitis C virus core protein is a highly basic viral protein that multimerizes with itself to form the viral capsid. When expressed in CD4+ T lymphocytes, it can induce modifications in several essential cellular and biological networks. To shed light on the mechanisms underlying the alterations caused by the viral protein, we have analyzed HCV-core subcellular localization and its associations with host proteins in Jurkat T cells. In order to investigate the intracellular localization of Hepatitis C virus core protein, we have used a lentiviral system to transduce Jurkat T cells and subsequently localize the protein using immunoelectron microscopy techniques. We found that in Jurkat T cells, Hepatitis C virus core protein mostly localizes in the nucleus and specifically in the nucleolus. In addition, we performed pull-down assays combined with Mass Spectrometry Analysis, to identify proteins that associate with Hepatitis C virus core in Jurkat T cells. We found proteins such as NOLC1, PP1γ, ILF3, and C1QBP implicated in localization and/or traffic to the nucleolus. HCV-core associated proteins are implicated in RNA processing and RNA virus infection as well as in functions previously shown to be altered in Hepatitis C virus core expressing CD4+ T cells, such as cell cycle delay, decreased proliferation, and induction of a regulatory phenotype. Thus, in the current work, we show the ultrastructural localization of Hepatitis C virus core and the first profile of HCV core associated proteins in T cells, and we discuss the functions and interconnections of these proteins in molecular networks where relevant biological modifications have been described upon the expression of Hepatitis C virus core protein. Thereby, the current work constitutes a necessary step toward understanding the mechanisms underlying HCV core mediated alterations that had been described in relevant biological processes in CD4+ T cells.

[Waterborne diseases and basic sanitation in Colombia]. / Enfermedades transmitidas por el agua y saneamiento básico en Colombia.

OBJECTIVE: To analyze the relationship of sewerage coverage and wastewater treatment with waterborne disease behaviour. METHODS: A descriptive retrospective study was conducted using secondary sources (document review and information available in databases) about basic sanitation coverage, treatment of domestic sewage in the country and the prevalence of waterborne diseases during the period 2008-2014. RESULTS: The country invested USD 1,100 million in the implementation of wastewater treatment systems from 2011 until the first half of 2013. However, the incidence of waterborne diseases, such as acute diarrheal disease, foodborne diseases and typhoid and paratyphoid fever did not decrease during the period 2008-2014; only hepatitis A registered a decrease. DISCUSSION: Investment in water supply and sewerage systems is relevant to improve health conditions of the population and to reduce the incidence and prevalence of various health conditions; however, it is necessary to address other aspects such as health education and social empowerment to address this problem more efficiently.

Limitaciones del IRCA como estimador de calidad del agua para consumo humano / Limitations of the Water Quality Risk Index as an estimator of quality for human consumption

RESUMEN Objetivo Analizar los resultados del Índice de Riesgo de la Calidad del Agua para Consumo Humano (IRCA) para los 116 municipios del Departamento de Cundinamarca, del año 2007 a 2013. Materiales y Métodos Información recolectada de los 116 municipios del Departamento de Cundinamarca, seleccionados y clasificados en función de los datos porcentuales del IRCA. Resultados Se observa una disminución del promedio anual del IRCA, lo cual refleja un mejoramiento de la calidad del agua entregada en el departamento; sin embargo, un 26,7% de municipios no reportan información de la zona rural y un 56,9% de los municipios reportan un IRCA superior a 5, que aunque se ubican en Riesgo Bajo, son un agua no apta para consumo humano. Conclusiones Se propone una nueva ponderación de los parámetros evaluados en el IRCA, con el fin de permitir que este índice sea más representativo del riesgo a la salud y, como estudios futuros un análisis estadístico concienzudo sobre el tamaño de la muestra que permita que los resultados obtenidos sean confiables para los tomadores de decisiones sobre el mejoramiento de la calidad del agua potable.(AU)

ABSTRACT Objective To analyze the results of the Water Quality Risk Index (IRCA) in the 116 municipalities of the department of Cundinamarca, between 2007 and 2013. Materials and Methods Information collected from the 116 municipalities of the department of Cundinamarca, selected and classified according to the percentage data retrieved by IRCA. Results A decrease of the annual IRCA average is observed, which reflects an improvement of the water quality delivered in the department. However, 26.7% of the municipalities do not report information from their rural areas, and 56.9% of the municipalities report IRCA figures over 5, which means that even though they are at low risk, they receive water unfit for human consumption. Conclusions A new weighting method for the parameters evaluated with the IRCA is proposed to make this index more representative of the risk to health. In addition, future studies should carry out a thorough statistical analysis on the size of the sample that allows the obtained results to be reliable for decision makers to improve the quality of drinking water.(AU)

Enfermedades transmitidas por el agua y saneamiento básico en Colombia / Waterborne diseases and basic sanitation in Colombia

RESUMEN Objetivo Analizar la relación de la cobertura de alcantarillado y tratamiento de aguas residuales con el comportamiento de las enfermedades de origen hídrico. Métodos Se realizó un estudio descriptivo de tipo retrospectivo, utilizando fuentes secundarias (revisión documental e información de bases de datos disponibles) sobre el comportamiento de la cobertura en saneamiento básico, tratamiento de aguas residuales domésticas en el país y la prevalencia de enfermedades relacionadas con la contaminación hídrica en el periodo 2008 a 2014. Resultados El país ha invertido en la puesta en marcha de sistemas de tratamiento de aguas residuales del 2011 al primer semestre de 2013, 1.100 millones de dólares, sin embargo la incidencia de enfermedades de origen hídrico como enfermedad diarreica aguda EDA, enfermedades transmitidas por alimentos ETA y fiebre tifoidea y paratifoidea, no han disminuido en el periodo 2008 a 2014, sólo la hepatitis A, ha registrado disminución. Discusión Se reconoce que la inversión en sistemas de acueducto y alcantarillado es relevante para el mejoramiento de las condiciones sanitarias de la población y para la disminución en la incidencia y la prevalencia de diversas alteraciones del estado de salud, sin embargo es necesario atender otros aspectos, tales como la educación en salud y el empoderamiento social, con el fin de avanzar en la creación de capacidades para afrontar esta problemática de manera más eficiente.(AU)

ABSTRACT Objective To analyze the relationship of sewerage coverage and wastewater treatment with waterborne disease behaviour. Methods A descriptive retrospective study was conducted using secondary sources (document review and information available in databases) about basic sanitation coverage, treatment of domestic sewage in the country and the prevalence of waterborne diseases during the period 2008-2014. Results The country invested USD 1,100 million in the implementation of wastewater treatment systems from 2011 until the first half of 2013. However, the incidence of waterborne diseases, such as acute diarrheal disease, foodborne diseases and typhoid and paratyphoid fever did not decrease during the period 2008-2014; only hepatitis A registered a decrease. Discussion Investment in water supply and sewerage systems is relevant to improve health conditions of the population and to reduce the incidence and prevalence of various health conditions; however, it is necessary to address other aspects such as health education and social empowerment to address this problem more efficiently.(AU)