A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere

Soy Niña

Este libro pretende contribuir al reencuentro de la educación con esas finalidades que verdaderamente importan a una niña o un niño: ser feliz, jugar, vivir juntos y (no) aprender. Para ello hemos puesto el arte, nuestras experiencias y el saber acumulado al servicio del disfrute, el cuestionamiento, el análisis crítico y la construcción común de un presente deseable. Un texto colaborativo coordinado por Ignacio Calderón Almendros y realizado por alumnado de Educación y Cambio Social en el Grado en Educación Infantil de la Universidad de Málaga

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

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

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases

Low-dose ozone acts as a bioregulator in chronic inflammatory diseases, biochemically characterized by high oxidative stress and a blocked regulation. During systemic applications, “Ozone peroxides” are able to replace H2O2 in its specific function of regulation, restore redox signaling, and improve the antioxidant capacity. Two different mechanisms have to be understood. Firstly, there is the direct mechanism, used in topical treatments, mostly via radical reactions. In systemic treatments, the indirect, ionic mechanism is to be discussed: “ozone peroxide” will be directly reduced by the glutathione system, informing the nuclear factors to start the regulation. The GSH/GSSG balance outlines the ozone dose and concentration limiting factor. Antioxidants are regulated, and in the case of inflammatory diseases up-regulated; cytokines are modulated, here downregulated. Rheumatoid arthritis RA as a model for chronic inflammation: RA, in preclinical and clinical trials, reflects the pharmacology of ozone in a typical manner: SOD (superoxide dismutase), CAT (catalase) and finally GSH (reduced glutathione) increase, followed by a significant reduction of oxidative stress. Inflammatory cytokines are downregulated. Accordingly, the clinical status improves. The pharmacological background investigated in a remarkable number of cell experiments, preclinical and clinical trials is well documented and published in internationally peer reviewed journals. This should encourage clinicians to set up clinical trials with chronic inflammatory diseases integrating medical ozone as a complement

Antioxidant therapy in human immunodeficiency virus-infection

El estrés oxidativo juega un papel importante como cofactor en la patogénesis del virus de la inmunodeficiencia humana (VIH). Los individuos infectados con VIH desarrollan además deficiencia en micronutrientes antioxidantes que recrudecen aún más el estado redox. En la era actual de la terapia antirretroviral altamente efectiva, nos propusimos una revisión del estado del conocimiento sobre los mecanismos moleculares oxidativos involucrados con la infección y el uso de los antioxidantes en estos individuos. Las combinaciones de suplementación de antioxidantes empleadas, resultan variadas, así como controvertidas en cuanto a los resultados sobre su eficacia. El empleo de los antioxidantes en individuos seropositivos al VIH resulta una alternativa terapéutica con reducido efecto tóxico, que pudiera repercutir en la supresión viral con restauración de las funciones inmunológicas.Antioxidant therapy in human immunodeficiency virus-infection. Oxidative stress may play an important role as cofactor in human immunodeficiency virus (HIV) pathogenesis. HIV infected individuals are known to be deficient in antioxidant micronutrients that exacerbates the loose of redox status. At the actual date of highly active antiretroviral therapies era we propose the revision about knowledge of oxidative molecular mechanisms involved and the use of antioxidants in HIV-seropositive patients. The combinations for antioxidants supplementation used are diverse as much as controversial the results about its efficacy. The option for its use in HIV seropositive individuals could be an alternative that seeks to both suppresses HIV and restore immune functions with less toxic side effects.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Antioxidant therapy in human immunodeficiency virus-infection

El estrés oxidativo juega un papel importante como cofactor en la patogénesis del virus de la inmunodeficiencia humana (VIH). Los individuos infectados con VIH desarrollan además deficiencia en micronutrientes antioxidantes que recrudecen aún más el estado redox. En la era actual de la terapia antirretroviral altamente efectiva, nos propusimos una revisión del estado del conocimiento sobre los mecanismos moleculares oxidativos involucrados con la infección y el uso de los antioxidantes en estos individuos. Las combinaciones de suplementación de antioxidantes empleadas, resultan variadas, así como controvertidas en cuanto a los resultados sobre su eficacia. El empleo de los antioxidantes en individuos seropositivos al VIH resulta una alternativa terapéutica con reducido efecto tóxico, que pudiera repercutir en la supresión viral con restauración de las funciones inmunológicas.Antioxidant therapy in human immunodeficiency virus-infection. Oxidative stress may play an important role as cofactor in human immunodeficiency virus (HIV) pathogenesis. HIV infected individuals are known to be deficient in antioxidant micronutrients that exacerbates the loose of redox status. At the actual date of highly active antiretroviral therapies era we propose the revision about knowledge of oxidative molecular mechanisms involved and the use of antioxidants in HIV-seropositive patients. The combinations for antioxidants supplementation used are diverse as much as controversial the results about its efficacy. The option for its use in HIV seropositive individuals could be an alternative that seeks to both suppresses HIV and restore immune functions with less toxic side effects.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Atenuación del efecto hepatotóxico del tetracloruro de carbono en ratas tratadas con Polypodium polypodiodes

Se comprobó experimentalmente en ratas la utilidad del Polypodium polypodiodes en la atenuación del efecto hepatotóxico provocado por el tetracloruro de carbono, que origina un incremento del nivel de los peróxidos lipídicos y las transaminasas sanguíneas. Se logró una disminución de la transaminasa glutamicopirúvica por debajo de los niveles normales con la administración del extracto de la planta a una dosis de 300 mg/kg de peso corporal. Los peróxidos lipídicos y la transaminasa glutamicooxalacética reducen su actividad, pero no notablemente, lo cual evidencia que el daño hepático persiste a pesar de la recuperación parcial. Los resultados fueron confirmados por un estudio anatomopatológico. Se determinó la toxicidad aguda por vía oral del extracto de la planta y se observó que la DL50 se encuentra por encima de 1 g/kg, por lo que puede considerarse esta preparación como relativamente inocua en los animales de experimentación.<br>The benefits of Polypodium polypodiodes in reducing hepatotoxic effects caused by carbon tetrachloride which gives rise to increased level of lipid peroxides and blood transaminase were tested in rats under lab conditions. Glutamicpiruvic trnnsaminane level was lower tham the normal lavels due to the administration of a 300 mg/kg dosege of the plant extract. The activities of both lipid peroxides and glutamicoxalacetic transaminase were reduced but not in a remarkable way showing that the hepatic damage is still present despite the partial recovery. The results were confirmed using and anatomytological study. Lidewise, acute toxicity resulted from oral administration of plant extrac was determined. It was observed that DL50 level was over 1g/kg, so this preparation may be considered relatively harmless in lab animals