Susceptibilidad del TLR-4 en el desarrollo de shock séptico

Introducción: TLR-4 es un receptor transmembranoso que forma parte de la inmunidad innata. Su función es reconocer patrones moleculares expresados por agentes bacterianos y, seguidamente, estimular una respuesta inflamatoria. Nuestro objetivo es analizar si el polimorfismo TLR-4 rs4986790 se asocia al desarrollo de shock séptico tras una cirugía mayor. Métodos: se realiza un estudio de casos y controles en 467 pacientes sometidos a cirugía cardíaca o abdominal. De ellos, 205 pacientes desarrollaron shock séptico (casos) y 262 pacientes desarrollaron SIRS (Controles). El polimorfismo TLR-4 rs4986790 fue genotipado por MassARRAY. El análisis de asociación se realizó bajo un modelo genético dominante (AG / GG vs. AA). Resultados: el genotipo TLR-4 rs4986790 AG / GG se asocia con una menor probabilidad de shock séptico en el análisis de los pacientes sometidos, únicamente, a cirugía abdominal [odds ratio ajustado (aOR) = 2.6 (IC del 95% = 1,75; 6,289; p = 0,034], pero no en el total de pacientes (p = 0,059) o estratificando a los sometidos a cirugía cardíaca (p=0,617). Existen parámetros preoperatorios como insuficiencia renal crónica, tabaquismo y neoplasia (aOR=2,973; p=0,031); y postoperatorios como Score APACHE-II > 19 y Ácido láctico > 2mmol/l (aOR=3,401; p=0,030), que se asocian con dicha susceptibilidad. Conclusiones: el genotipo TLR-4 rs4986790 AG / GG genera un efecto protector en el desarrollo de shock séptico en pacientes sometidos a cirugía mayor abdominal.Grado en Medicin

Importancia del perfil inflamatorio-molecular en la infección por SARS-COV-2 y su relación con el grupo sanguíneo ABO.

INTRODUCTION The emergence of SARS-CoV-2 in China in December 2019 along with its worldwide spread, has generated a need for knowledge about this new viral infection. In our country, official national data as of March 25, 2020 recorded 47,610 diagnosed cases with 3,434 deaths, assuming a mortality rate of 7.21%. Initial studies associated dysregulation of the immune response with cytokine hypersecretion, marked lymphopenia, prothrombotic status and endothelitis. The mechanism of viral replication was also beginning to be detailed, with ACE2 appearing to be, as in SARS-CoV, the host cell receptor employed by the virus. In addition, at that time the ABO blood group began to be related to susceptibility and severity of infection. Blood group A associates intrinsic prothrombotic and inflammatory characteristics, aspects superimposable to the clinical presentation of the new SARS-CoV-2 infection. On the other hand, the polyspecificity of natural antibodies to various antigens in humans is widely known. However, while a relationship between the ABO system and novel SARS-CoV-2 seemed reasonable, the lack of knowledge and the need for specific studies on this interaction were necessary. To this end, new investigations were required that included a larger sample size, the analysis of several evolutionary moments in the course of hospital admission, and the analysis of a broad set of biomarkers related to the immune response. OBJECTIVE To study the inflammatory-molecular response of SARS-CoV-2 infection in order to identify diagnostic and prognostic biomarkers and to evaluate the involvement of ABO blood group in the modulation of this inflammatory response, susceptibility and severity of this infection. METHODOLOGY Prospective and consecutive study of 108 COVID-19 patients admitted to the Hospital Clínico Universitario de Valladolid (Spain) who were recruited between March 24 and April 11, 2020. In addition, 28 healthy controls were also included. Using Luminex technology, plasma from controls and each patient was analyzed in duplicate at admission and 6 days after hospital stay to quantify 45 soluble mediators (45-plex Human XL Cytokine Luminex Performance Panel (R&D) kit). ABO blood typing was performed on a fully automated analyzer (Erytra® Automated System for Blood Typing) using DG Gel® cards. The study was approved by the Hospital's Clinical Ethics Committee (cod: PI 20-1717). Both the statistical package IBM SPSS Statistics Software (SPSS) version 25 and the statistical package R version 4.0.2 (R Core Team; Foundation for Statistical Computing, Vienna, Austria) were used for statistical analyses. RESULTS - Article 1: Patients with COVID-19 showed different levels in multiple cytokines compared to control patients. IP-10 accurately identified patients requiring hospital admission [AUC: 0.962; 95%CI (0.933-0.992); p<0.001]. Results were validated in an independent cohort by multivariate analysis [OR: 25.573; 95%CI (8.127-80.469); p<0.001] and AUROC [AUC: 0.900; 95%CI (0.846-0.954); p<0.001]. In addition, plasma IP-10 levels above 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. - Article 2: High HGF levels were associated with critically ill patients [OR: 3.51; 95%CI (1.95-6.33); p<0.001]. In addition, elevated IL-1&#945; [OR: 1.36; 95%CI (1.07-1.73; p=0.01] and low IL-27 levels [OR: 0.58; 95%CI (0.39-0.85); p<0.005] significantly increased the risk of termination in the severe group. This model was especially sensitive in predicting the critically ill patient [AUC: 0.794; specificity: 69.74%; sensitivity: 81.25%). Elevation of HGF and IL-1&#945; was also significant in survival analysis (p=0.033 and p=0.011, respectively). - Article 3: Blood group A patients had a higher Charlson comorbidity index (p=0.037), higher rate of lymphopenia (p=0.039) and thrombopenia (p=0.014), as well as higher hospital mortality (p=0.044). Blood group A was an independent factor associated with Charlson index [B: 0.582, 95%CI (0.02-1.14), p=0.041]. - Article 4: The cornerstone of the ABO system involved in susceptibility and severity to SARS-CoV-2 infection is its natural anti-A and anti-B antibodies. They are able to interfere with the binding between the S protein of the virus and ACE2 (host cell receptor), which confers protection to patients with natural antibodies (blood group O). Natural antibody titers and IgG isotype may also be determinants of susceptibility. In addition, the elderly population is associated with a worse evolution given the decrease in antibodies and the positive regulation of ACE2 expression during senescence. - Article 5: Blood group O had a 2-fold lower risk of requiring mechanical ventilation or death at 28 days (log rank: p=0.042). At admission, all statistically significant cytokine levels, except HGF, were higher in blood group O patients, while at 6 days of admission they showed a significant decrease, between 20% and 40%. In contrast, the A/B/AB group showed a maintenance of cytokine levels over time. HGF showed a significant association with the risk of intubation or mortality in non-O blood group [OR: 4.229, 95%CI (2.064-8.665), p<0.001] and was also the only biomarker of poor prognosis in O blood group patients [OR: 8.852, 95%CI (1.540-50.878), p=0.015]. At hospital admission, higher cytokine levels in blood group O were associated with a better prognosis. CONCLUSIONS In SARS-CoV-2 infection, the study of the inflammatory-molecular profile together with the involvement of ABO blood group has identified diagnostic markers (IP-10), prognostic markers (HGF, IL-1&#945; and IL-27) and delved into the role played by ABO system antibodies in the modulation of the immune response (blood group O associates higher cytokine elevation that condition a better prognosis). The main conclusions derived from the different research works carried out have been the following: 1. IP-10 was identified as a robust marker in the early detection of SARS-CoV-2 infection in hospitalized patients. 2. Elevated levels of HGF and IL-1, along with decreased IL-27 were strongly associated with disease severity and were excellent predictors of poor prognosis. In fact, IL-1 and HGF were also biomarkers of mortality. 3. In the setting of SARS-CoV-2 infection, blood group A was associated with a higher Charlson comorbidity index as well as higher hospital-level mortality. 4. Blood group O was associated with lower hospital admission rates and lower risk of intubation or mortality. 5. Natural anti-A and B antibodies of the ABO system interfere by hindering the binding between SARS-CoV-2 protein S and host cell ACE2, conferring lower susceptibility and severity to patients of blood group O. 6. The better prognosis in blood group O was associated with significantly higher levels of all cytokines analyzed at admission (except HGF) with a consequent decrease at 6 days of hospital stay, not evidenced in other blood groups. 7. The plasma concentration of antibodies, the relevance of the IgG isotype in blood group O and the positive regulation of ACE2 expression together with the decrease of immunoglobulins in senescence, are other determinants in the severity of infection.INTRODUCCIÓN La aparición del SARS-CoV-2 en China en diciembre de 2019 junto con su expansión mundial, ha generado una necesidad de conocimiento acerca de esta nueva infección viral. En nuestro país, los datos nacionales oficiales a 25 de marzo de 2020 registraban 47.610 casos diagnosticados con 3.434 fallecidos, suponiendo una tasa de mortalidad del 7,21%. Estudios iniciales asociaron una disregulación de la respuesta inmunitaria con hipersecreción de citoquinas, una linfopenia marcada, un estatus protrombótico y una endotelitis. Se empezaba a detallar también el mecanismo de replicación viral, pareciendo ser la ACE2, al igual que en el SARS-CoV, el receptor de la célula huésped empleado por el virus. Además, en ese momento el grupo sanguíneo ABO comenzó a relacionarse con la susceptibilidad y severidad a la infección. El grupo sanguíneo A asocia unas características intrínsecas protrombóticas e inflamatorias, aspectos superponibles a la presentación clínica de la nueva infección por SARS-CoV-2. Por otro lado, la poliespecificidad de los anticuerpos naturales a antígenos diversos en el ser humano es ampliamente conocida. Sin embargo, pareciendo razonable una relación entre el sistema ABO y el nuevo SARS-CoV-2, el desconocimiento y necesidad de estudios específicos sobre esta interacción eran necesarios. Para ello, se requerían nuevas investigaciones que incluyesen un mayor tamaño muestral, el análisis de varios momentos evolutivos en el transcurso del ingreso hospitalario y el análisis de un amplio conjunto de biomarcadores relacionados con la respuesta inmunitaria. OBJETIVO Estudiar la respuesta inflamatoria-molecular de la infección por SARS-CoV-2 para identificar biomarcadores diagnósticos, pronósticos y evaluar la implicación del grupo sanguíneo ABO en la modulación de esta respuesta inflamatoria, la susceptibilidad y la gravedad de esta infección. METODOLOGÍA Estudio prospectivo y consecutivo de 108 pacientes COVID-19 ingresados en el Hospital Clínico Universitario de Valladolid (España) que fueron reclutados entre el 24 de marzo y el 11 de abril de 2020. Además, también se incluyeron 28 controles sanos. Mediante tecnología Luminex se analizó, por duplicado, el plasma de los controles y cada paciente al ingreso y a los 6 días de estancia hospitalaria para cuantificar 45 mediadores solubles (kit 45-plex Human XL Cytokine Luminex Performance Panel (R&D)). La determinación del grupo sanguíneo ABO se realizó en un analizador completamente automatizado (Erytra® Automated System for Blood Typing) usando tarjetas DG Gel®. El estudio fue aprobado por el Comité de Ética Clínica del Hospital (cod: PI 20-1717). Para los análisis estadísticos se emplearon tanto el paquete estadístico Software IBM SPSS Statistics (SPSS) versión 25 como el paquete estadístico R versión 4.0.2 (R Core Team; Foundation for Statistical Computing, Viena, Austria). RESULTADOS - Artículo 1: Los pacientes con COVID-19 mostraron diferentes niveles en múltiples citoquinas en comparación con los pacientes control. La IP-10 identificó con precisión a pacientes que requirieron ingreso hospitalario [AUC: 0,962; IC95% (0,933&#8211;0,992); p<0,001]. Los resultados fueron validados en una cohorte independiente mediante análisis multivariante [OR: 25.573; 95%CI (8.127&#8211;80.469); p<0.001] y AUROC [AUC: 0.900; 95%CI (0.846&#8211;0.954); p<0.001]. Además, niveles plasmáticos de IP-10 superiores a 173,35 pg/mL identificaron el COVID-19 con mayor sensibilidad (86,20%) que la primera PCR de SARS-CoV-2. - Artículo 2: Altos niveles de HGF se asociaron con pacientes críticos [OR: 3,51; IC95% (1,95&#8211;6,33); p<0,001]. Además, la elevación de la IL-1&#945; [OR: 1,36; IC95% (1,07&#8211;1,73; p=0,01] y niveles bajos de IL-27 [OR: 0,58; IC95% (0,39&#8211;0,85); p<0,005] aumentaron considerablemente el riesgo de terminar en el grupo severo. Este modelo fue especialmente sensible para predecir al paciente crítico [AUC: 0,794; especificidad: 69,74%; sensibilidad: 81,25%). La elevación de la HGF y la IL-1&#945; también resultó significativa en el análisis de supervivencia (p=0,033 y p=0,011, respectivamente). - Artículo 3: Los pacientes del grupo sanguíneo A tuvieron un mayor índice de comorbilidad de Charlson (p=0,037), mayor tasa de linfopenia (p=0,039) y trombopenia (p=0,014), así como mayor mortalidad hospitalaria (p=0,044). El grupo sanguíneo A fue un factor independiente asociado con el índice de Charlson [B: 0,582, IC95% (0,02&#8211;1,14), p=0,041]. - Artículo 4: La piedra angular del sistema ABO involucrada en la susceptibilidad y gravedad a la infección por SARS-CoV-2 son sus anticuerpos naturales anti-A y anti-B. Son capaces de interferir en la unión entre la proteína S del virus y la ACE2 (receptor de la célula huésped), lo que confiere protección a los pacientes con anticuerpos naturales (grupo sanguíneo O). Los títulos de anticuerpos naturales y el isotipo IgG pueden ser también determinantes en la susceptibilidad. Además, la población anciana está asociada a una peor evolución dado el descenso de anticuerpos y la regulación positiva de la expresión de ACE2 durante la senescencia. - Artículo 5: El grupo sanguíneo O presentó un riesgo dos veces inferior de requerir ventilación mecánica o fallecer a los 28 días (log rank: p=0,042). Al ingreso, todos los niveles de citoquinas estadísticamente significativos, excepto HGF, fueron más altos en los pacientes del grupo sanguíneo O, mientras que, a los 6 días de ingreso mostraron un descenso significativo, entre 20% y 40%. Por el contrario, el grupo A/B/AB presentó un mantenimiento de los niveles de citoquinas a lo largo del tiempo. HGF mostró una asociación significativa con el riesgo de intubación o mortalidad en el grupo sanguíneo no-O [OR: 4,229, IC95% (2,064&#8211;8,665), p<0,001] y también fue el único biomarcador de mal pronóstico en pacientes del grupo sanguíneo O [OR: 8,852, IC95% (1,540&#8211;50,878), p=0,015]. Al ingreso hospitalario, los mayores niveles de citoquinas en el grupo sanguíneo O asociaron un mejor pronóstico. CONCLUSIONES En la infección por SARS-CoV-2, el estudio del perfil inflamatorio-molecular junto con la implicación del grupo sanguíneo ABO ha identificado marcadores diagnósticos (IP-10), pronósticos (HGF, IL-1&#945; e IL-27) y ahondado en el papel que juegan los anticuerpos del sistema ABO en la modulación de la respuesta inmune (grupo sanguíneo O asocia mayor elevación de citoquinas que condicionan un mejor pronóstico). Las principales conclusiones derivadas de los diferentes trabajos de investigación realizados han sido las siguientes: 1. Se identificó la IP-10 como un marcador robusto en la detección precoz de la infección por SARS-CoV-2 en pacientes hospitalizados. 2. Elevados niveles de HGF e IL-1, junto con el descenso de la IL-27 estaban fuertemente asociados con la gravedad de la enfermedad y fueron excelentes predictores de mal pronóstico. De hecho, IL-1 y HGF eran también biomarcadores de mortalidad. 3. En el contexto de una infección por SARS-CoV-2, el grupo sanguíneo A se asoció con un mayor índice de comorbilidad de Charlson así como con una mayor mortalidad a nivel hospitalario. 4. El grupo sanguíneo O asoció menores tasas de ingreso hospitalario y menor riesgo de intubación o mortalidad. 5. Los anticuerpos naturales anti-A y B del sistema ABO interfieren dificultando la unión entre la proteína S del SARS-CoV-2 y la ACE2 de la célula huésped, confiriendo una menor susceptibilidad y gravedad a los pacientes de grupo sanguíneo O. 6. El mejor pronóstico en el grupo sanguíneo O se asoció con niveles significativamente mayores de todas las citoquinas analizadas al ingreso (excepto la HGF) con un consiguiente descenso a los 6 días de estancia hospitalaria, no evidenciado en otros grupos sanguíneos. 7. La concentración plasmática de los anticuerpos, la relevancia del isotipo IgG en el grupo sanguíneo O y la regulación positiva de la expresión de la ACE2 junto con el descenso de las inmunoglobulinas en la senescencia, son otros determinantes en la severidad de la infección. &#8195;Escuela de DoctoradoDoctorado en Investigación en Ciencias de la Salu

Characterization of excitation source LEDs and sensors without filters for measuring fluorescence in fluorescein and green leaf extract

This paper presents the characterization of excitation source LEDs and sensors without filters for measuring fluorescence in fluorescein and green leaf extract. For this purpose, eight light-emitting diodes (LEDs) were used with the following characteristics: one blue, one green, one red, one infrared, and four violets. The first four LEDs were used as sensors without filters to detect fluorescence induced by the other four violet LEDs in 11 samples of different fluorescein concentrations and in 14 samples of different dilutions of green leaf extract. The results show that infrared LEDs can detect the red emission of green leaf extract and red and infrared LEDs detect the fluorescence of fluorescein in concentrations of up to 1.8 μM. The developed system allows and facilitates teaching optical spectroscopy in basic education without incurring high costs

Agua en territorios comunales: gestión del riego en el valle del río Javita, provincia de Santa Elena

This work was proposed to analyze the management of irrigation in the Javita River Valley, Province of Santa Elena, in the context of the implementation of the San Vicente Chongón Transfer. The work was done with participatory methods, gathering information from a sample of farmers in the area. The effects of the Chongón San Vicente water transfer were insufficient in terms of efficiency, relevance, institutional environment, social, cultural, and environmental aspects, according to the opinion of the participants. As case studies, five types of production systems were analyzed. In all cases, the income from extra-farm activities is higher than that obtained from agricultural activities. The agricultural production systems that obtain the best income are those dedicated exclusively to crops under irrigation. The research determines as a guiding framework that: the organization of irrigation is done by family groups; administration, operation and maintenance are allowed by the irrigation boards; the distribution of water is carried out according to the need of the crops; the method of application is drip; the installation depends on the water saving; the crops are preferably short and transient cycle; and, the destination of the production is oriented to the regional or national market. For irrigation to become a dynamic element of the local economy, infrastructure works are not enough. It is essential that the government invest in an inclusive, equitable and efficient rural development program.Este trabajo se propuso analizar la gestión del riego en el valle del río Javita, provincia de Santa Elena, en el contexto de la puesta en marcha del trasvase Chongón San Vicente. Se trabajó con métodos participativos, recabando información de una muestra de productores. Los efectos del trasvase Chongón San Vicente se revelaron insuficientes en cuanto a eficacia, pertinencia, entorno institucional, aspectos sociales y culturales, y ambientales. Como casos de estudio, se hizo el análisis de cinco tipos de sistemas de producción. En todos los casos, los ingresos de actividades extra finca son superiores a lo obtenidos de actividades agropecuarias. Los sistemas de producción agropecuaria que mejores ingresos obtienen se dedican exclusivamente a cultivos bajo riego. La investigación determina como marco orientador que: la organización del riego se haga por grupos familiares; la administración, operación y mantenimiento corra a cargo de las juntas de riego; el reparto de agua se efectúe según la necesidad de los cultivos; el método de aplicación sea por goteo; la instalación vaya en función del ahorro de agua; los cultivos sean de preferencia de ciclo corto y transitorio; y, el destino de la producción se oriente al mercado regional o nacional. Para que el riego se convierta en un elemento dinamizador de la economía local, no basta con obras de infraestructura. Es indispensable que el Estado invierta en un programa de desarrollo rural inclusivo, equitativo y eficiente

Environmental factors are associated to hospital outcomes in COVID-19 patients during lockdown and post-lockdown in 2020: A nationwide study

Producción CientíficaThis study analyzed, at a postcode detailed level, the relation-ship between short-term exposure to environmental factors and hospital ad-missions, in-hospital mortality, ICU admission, and ICU mortality due to COVID-19 during the lockdown and post-lockdown 2020 period in Spain. Short-term exposure to air pollutants impacts COVID-19 out-comes during the lockdown, especially PM2.5, PM10, NO2, and SO2. These pollutants are associated with hospital admission, hospital mortality and ICU admission, while ICU mortality is mainly associated with PM2.5 and PM10. Our findings reveal the importance of monitoring air pollutants in respiratory infectious diseases.Ministerio de Ciencia e Innovación y Unión Europea – Next Generation EU (CB21/13/00044 y CB21/13/ 00051)Instituto Carlos III - FEDER. Río Hortega grant (CM20/00138

Epidemiology of bacterial co-infections and risk factors in COVID-19-hospitalized patients in Spain: a nationwide study

Background: We performed a nationwide population-based retrospective study to describe the epidemiology of bacterial co-infections in coronavirus disease 2019 (COVID-19)-hospitalized patients in Spain in 2020. We also analyzed the risk factors for co-infection, the etiology and the impact in the outcome. Methods: Data were obtained from records in the Minimum Basic Data Set (MBDS) of the National Surveillance System for Hospital Data in Spain, provided by the Ministry of Health and annually published with 2 years lag. COVID-19 circulated in two waves in 2020: from its introduction to 31st June and from 1st July to 31st December. The risk of developing a healthcare-associated bacterial co-infection and the risk for in-hospital and intensive care unit (ICU) mortality in co-infected patients was assessed using an adjusted logistic regression model. Results: The incidence of bacterial co-infection in COVID-19 hospitalized patients was 2.3%. The main risk factors associated with bacterial co-infection were organ failure, obesity and male sex. Co-infection was associated with worse outcomes including higher in-hospital, in-ICU mortality and higher length of stay. Gram-negative bacteria caused most infections. Causative agents were similar between waves, although higher co-infections with Pseudomonas spp. were detected in the first wave and with Haemophilus influenzae and Streptococcus pneumoniae in the second. Conclusions: Co-infections are not as common as those found in other viral respiratory infections; therefore, antibiotics should be used carefully. Screening for actual co-infection to prescribe antibiotic therapy when required should be performed.This work was supported by Instituto de Salud Carlos III (COV20/00491, PI18/01238, CIBERINFEC CB21/13/00051), Junta de Castilla y León (VA321P18, GRS 1922/A/19, GRS 2057/A/19), Consejería de Educación de Castilla y León (VA256P20) and Fundación Ramón Areces (CIVP19A5953). L. Sánchez-de Prada received a Río Hortega grant (CM20/00138) from Instituto Carlos III (Co-funded by European Regional Development Fund/European Social Fund ‘A way to make Europe’/’Investing in your future’).S

Nosocomial Vs. Community-Acquired Infective Endocarditis in Spain: Location, Trends, Clinical Presentation, Etiology, and Survival in the 21st Century

Major changes have occurred in the epidemiology and etiology of infective endocarditis (IE). Nevertheless, the differences between nosocomial infective endocarditis (NIE) and community-acquired infective endocarditis (CIE) have not been addressed in a population-based study. We conducted a retrospective, nationwide, temporal trend study from 1997 to 2014 analyzing the epidemiology, clinical, geographical, meteorological characteristics of patients diagnosed with IE in Spain, to distinguish NIE from CIE. Among 25,952 patients with IE (62.2 ± 18·6 years; 65.9% men), 45.9% had NIE. The incidence of IE increased from 2.83 to 3.73 due to the NIE incidence increment with a decline in CIE. Patients with NIE were older (63.8 years vs. 60.8 years, p < 0·001), presented a higher Charlson index (1.22 vs. 1.03, p < 0.001), a greater history of implanted cardiac devices (8.7% vs. 4.6%, p < 0.001), and higher mortality (31.5% vs. 21.7%, p < 0.001). The most frequent microorganism for both NIE and CIE was Staphylococcus (p < 0.001), and the North reported a higher incidence (p < 0.001). Risk factors of mortality for NIE were age, Charlson index, hemodialysis, shock, heart failure, and stroke. Risk factors for CIE included female sex, renal disease, and cardiac-device carriers. The etiology of IE shifted from community origins to mostly nosocomial-associated infections. Higher morbidity, mortality, and poorer outcomes are associated with NIE.This research received no external funding. The authors thank Consejería de Educación, Junta de Castilla y León, Spain (reference: VA161G18), for covering the publication charges of this article.S

Resistance to immune checkpoint inhibitors secondary to myeloid-derived suppressor cells: A new therapeutic targeting of haematological malignancies

Producción CientíficaMyeloid-derived suppressor cells (MDSCs) are a set of immature myeloid lineage cells that include macrophages, granulocytes, and dendritic cell precursors. This subpopulation has been described in relation to the tumour processes at different levels, including resistance to immunotherapy, such as immune checkpoint inhibitors (ICIs). Currently, multiple studies at the preclinical and clinical levels seek to use this cell population for the treatment of different haematological neoplasms, together with ICIs. This review addresses the different points in ongoing studies of MDSCs and ICIs in haematological malignancies and their future significance in routine clinical practice

Beneficial effects of paricalcitol on cardiac dysfunction and remodelling in a model of established heart failure

The synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of paricalcitol associated with the VDR pathway, less information is available about the structural and functional cardiac effects of paricalcitol on established heart failure (HF) and particularly its effects on associated electrophysiological or Ca2+ handling remodelling. EXPERIMENTAL APPROACH: We used a murine model of transverse aortic constriction (TAC) to study the effect of paricalcitol on established HF. Treatment was initiated 4 weeks after surgery over five consecutive weeks, and mice were sacrificed 9 weeks after surgery. Cardiac MRI (CMRI) was performed 4 and 9 weeks after surgery. Hearts were used for biochemical and histological studies and to isolate ventricular myocytes for electrophysiological and calcium imaging studies. KEY RESULTS: CMRI analysis revealed that, compared with vehicle, paricalcitol treatment prevented the progression of ventricular dilation and hypertrophy after TAC and halted the corresponding decline in ejection fraction. These beneficial effects were related to the attenuation of intracellular Ca2+ mishandling remodelling, antifibrotic and antihypertrophic effects and potentially antiarrhythmic effects by preventing the reduction of K+ current density and the long QT, JT and TpTe intervals observed in HF animals. CONCLUSION AND IMPLICATIONS: The results suggest that paricalcitol treatment in established HF hampers disease progression and improves adverse electrophysiological and Ca2+ handling remodelling, attenuating the vulnerability to HF-associated ventricular arrhythmias. Paricalcitol may emerge as a potential therapeutic option in the treatment of HFThis work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2014- 57190R, SAF2017-84777-R), ISCIII (PI17/01093 and PI17/01344), European Regional Development Fund (FEDER), Sociedad Española de Cardiología (SEC), and CIBER-CV, a network funded by ISCIII. MF-V is a Miguel Servet II researcher of ISCIII (MSII16/00047 Carlos III Health Institute). GR-H is a Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). MT is a predoctoral fellow of the Spanish Ministry of Science, Innovation and Universities (FPU-17/06135

Evaluation of biostimulation, bioaugmentation, and organic amendments application on the bioremediation of recalcitrant hydrocarbons of soil

In the present work, the operational conditions for improving the degradation rates of Total Petroleum Hydrocarbons (TPHs) in contaminated soil from a machinery park were optimized at a microcosms scale along a 90- days incubation period. In this study, bioremediation strategies and an organic amendment have been tested to verify the remediation of soil contaminated with different hydrocarbons, mineral oils, and heavy metals. Specifically, designed biostimulation and bioaugmentation strategies were compared with and without adding vermicompost. The polluted soil harboring multiple contaminants, partially attenuated for years, was used. The initial profile showed enrichment in heavy linear alkanes, suggesting a previous moderate weathering. The application of vermicompost increased five and two times the amounts of available phosphorus (P) and exchangeable potassium (K), respectively, as a direct consequence of the organic amendment addition. The microbial activity increased due to soil acidification, which influenced the solubility of P and other micronutrients. It also impacted the predominance and variability of the different microbial groups and the incubation, as reflected by phospholipid fatty acid (PLFA) results. An increase in the alkaline phosphatases and proteases linked to bacterial growth was displayed. This stimulation of microbial metabolism correlated with the degradation rates since TPHs degradation’ efficiency after vermicompost addition reached 32.5% and 34.4% of the initial hydrocarbon levels for biostimulation and bioaugmentation, respectively. Although Polycyclic Aromatic Hydrocarbons (PAHs) were less abundant in this soil, results also decreased, especially for the most abundant, the phenanthrene. Despite improving the degradation rates, results revealed that recalcitrant and hydrophobic petroleum compounds remained unchanged, indicating that mobility, linked to bioavailability, probably represents the limiting step for further soil recovery.This work is funded by the GREENER project of the European Union’s Horizon 2020 research and innovation program (Grant Agreement No. 826312). S. Curiel pre-doctoral contract was funded by Junta de Castilla y Leon ´ (ORDEN EDU/1508/2020, de 15 de diciembre)