Differential contribution of n-and c-terminal regions of hif1α and hif2α to their target gene selectivity

Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional Vhl-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as CAIX (CAR9) and BNIP3, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier SLC7A5. The HIF selectivity for some genes in WT8 cells is conserved in Vhl-deficient lung and liver tissue, whereas other genes like Glut1 (Slc2a1) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed.This work was supported by grants from Ministerio de Economia y Competitividad (SAF2016-76815-R and SAF2017-90794-REDT), Ministerio de Ciencia e Innovación (PID2019-106371RB-I00) and Fundació La Marató de TV3 (534/C/2016). A.A.U is supported by the CAM “Atracción de Talento” program and Universidad Autónoma de Madrid, grant SI1/PJI/2019-0039

Entropy and canonical ensemble of hybrid quantum classical systems

In this work we generalize and combine Gibbs and von Neumann approaches to build, for the first time, a rigorous definition of entropy for hybrid quantum-classical systems. The resulting function coincides with the two cases above when the suitable limits are considered. Then, we apply the MaxEnt principle for this hybrid entropy function and obtain the natural candidate for the hybrid canonical ensemble (HCE). We prove that the suitable classical and quantum limits of the HCE coincide with the usual classical and quantum canonical ensembles since the whole scheme admits both limits, thus showing that the MaxEnt principle is applicable and consistent for hybrid systems

Entropy and canonical ensemble of hybrid quantum classical systems

We generalize von Neumann entropy function to hybrid quantum-classical systems by considering the principle of exclusivity of hybrid events. For non-interacting quantum and classical subsystems, this entropy function separates into the sum of the usual classical (Gibbs) and quantum (von Neumann) entropies, whereas if the two parts do interact, it can be properly separated into the classical entropy for the marginal classical probability, and the conditional quantum entropy. We also deduce the hybrid canonical ensemble (HCE) as the one that maximizes this entropy function, for a fixed ensemble energy average. We prove that the HCE is additive for non-interacting systems for all thermodynamic magnitudes, and reproduces the appropriate classical- and quantum-limit ensembles. Furthermore, we discuss how and why Ehrenfest dynamics does not preserve the HCE and does not yield the correct ensemble averages when time-averages of simulations are considered -- even if it can still be used to obtain correct averages by modifying the averaging procedure.Comment: 6 pages + 4 pages Supp. Ma

About the computation of finite temperature ensemble averages of hybrid quantum-classical systems with molecular dynamics

Molecular or condensed matter systems are often well approximated by hybrid quantum-classical models: the electrons retain their quantum character, whereas the ions are considered to be classical particles. We discuss various alternative approaches for the computation of equilibrium (canonical) ensemble averages for observables of these hybrid quantum-classical systems through the use of molecular dynamics (MD)-i.e. by performing dynamics in the presence of a thermostat and computing time-averages over the trajectories. Often, in classical or ab initio MD, the temperature of the electrons is ignored and they are assumed to remain at the instantaneous ground state given by each ionic configuration during the evolution. Here, however, we discuss the general case that considers both classical and quantum subsystems at finite temperature canonical equilibrium. Inspired by a recent formal derivation for the canonical ensemble for quantum classical hybrids, we discuss previous approaches found in the literature, and provide some new formulas

LAT-1 and GLUT-1 Carrier Expression and Its Prognostic Value in Gastroenteropancreatic Neuroendocrine Tumors

Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and correlate them with tumor malignancy and progression. LAT-1, GLUT-1, and pVHL expression was analyzed in 116 GEP-NETs and 48 peritumoral tissue samples by immunohistochemistry. LAT-1 was stably silenced using specific shRNA in the human NET BON cell line. LAT-1 expression was significantly increased in tumor tissue compared to non-tumor tissue in both gastrointestinal (67% vs. 44%) and pancreatic NETs (54% vs. 31%). Similarly, GLUT-1 was substantially elevated in gastrointestinal (74% vs. 19%) and pancreatic (58% vs. 4%) NETs. In contrast, pVHL expression was decreased (85% vs. 58%) in pancreatic NETs. Tumors with metastases at diagnosis displayed increased LAT-1 and GLUT-1 and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. These markers might be related to the proliferation and metastatic capacity of these tumors

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Niños hospitalizados por gripe An H1N1en el período agosto-diciembre de 2009en un hospital terciario

Introduction:Following the detection of the first cases of influenza An H1N1 in California in April 2009,the virus has rapidlyspread throughout the world.The World Health Organization raised the pandemic alert to phase six in June 2009.Materialsand methods:From August 1 to December 31, 2009, 47 cases in children younger than 15 years hospitalized of novelinfluenza An H1N1 were reported.Results:The most cases hospitalized were in children younger than 5 years, withmaximum incidence in the first half of November 2009.The most common underlying pathology was asthma, present in25% of patients,47% received treatment with Oseltamivir.The only complication observed was pneumoniae (47%),that wasassociated with pleural effusion with positive pneumococcal antigen in 3 cases. No patient required admission to IntensiveCare Unit o were exitus.Discusion:Despite the alarm arising from the declaration of an influenza An H1N1 pandemic byWHO, in our setting, the number of hospitalizations and severity of the disease were similar to those found in seasonalinfluenza.Introducción: En abril de 2009 se detecta el primer caso de gripe An H1N1 en California, siendo un mes despuéscuando se declara el primer caso en España. En pocos meses, el virus se extiende de forma global declarándosenivel de pandemia 6 por la OMS en junio de 2009.Material y métodos:Se estudian de manera prospectiva 47pacientes pediátricos menores de 15 años de edad con diagnóstico de gripe An H1N1 confirmado por PCR eingresados entre agosto y diciembre de 2009.Resultados:De 47 casos incluidos en el estudio, el grupo de edad conmayor tasa de hospitalización fue el de los menores de 5 años, sin encontrarse diferencias significativas en relaciónal sexo, con un pico máximo en la primera quincena de noviembre de 2009. La patología de base más frecuentefue el asma, que estaba presente en el 25% de los pacientes. El 47% de los ingresados recibió tratamiento conOseltamivir.La única complicación encontrada fue la neumonía (47%),que se asoció a derrame paraneumónico conantígeno neumocócico positivo en 3 casos. Ningún paciente precisó ingreso en Unidad de Cuidados Intensivos nifue exitus.Conclusiones:A pesar de la alarma surgida por la declaración de pandemia de gripe An H1N1 por la OMS,el número de hospitalizaciones, la gravedad de la enfermedad y sus complicaciones fueron similares a lasencontradas en la gripe estacional

Estudio epidemiológico y clínico de las infecciones pulmonares por Mycoplasma pneumoniae

Introduction:Due to the high prevalence of M. pneumoniaeinfection in the etiology of childhood pneumonia a retrospectivestudy of an outbreak of pneumonia due to this organism occurred in children under 14 years and admitted to Hospital InfantilUniversitario Miguel Servet is performed in order to describe their epidemiological and clinical characteristics.Material andmethods:Medical records of hospitalized patients treated in the period from May to August 2010 were reviewed. 21 casesof pneumonia were caused by M. pneumoniaeand diagnosed by Mycoplasma InmnunoCard EIA with positive IgM.Results:There was a higher incidence in females (66.6%) and children older than 5 years (76%). Fever, cough and rhinitis were thesymptoms more frequently found. In the chest x-ray, the consolidation was the image more predominant (90.5%), multifocalpresentation was found in 33.3% of patients. The analytical results showed neutrophilia of >70% in 47% of cases.Conclusions:Pneumonia caused by M. pneumoniaewas observed mainly in female and older than 5 years.The clinic wasvery variable but fever and cough were prevalent. Radiological studies showed consolidation and laboratory data were nonspecific. For diagnosis it is important to consider the cases of pneumonia not responding to a previous antibiotic therapy.Introducción:Debido a la alta prevalencia de la infección por Mycoplasma pneumoniaeen la etiología de la neumoníainfantil se realiza un estudio retrospectivo de un brote de neumonía debido a este microorganismo ocurrido enmenores de 14 años e ingresados en el Hospital Universitario Infantil Miguel Servet con el objetivo de describirsus características epidemiológicas y clínicas.Material y métodos:Se realiza un estudio retrospectivo mediante larevisión de las historias clínicas de los pacientes ingresados atendidos en el período de mayo a agosto de 2010.Fueron diagnosticados 21 casos de neumonía por M. pneumoniaediagnosticados mediante EIA InmnunoCard My-coplasma con IgM positiva.Resultados:Se observó una mayor incidencia en el sexo femenino (66,6%) y en mayoresde 5 años (76%). Fiebre, tos y rinitis fueron los síntomas más frecuentemente encontrados. En la radiografía detórax la consolidación fue la imagen predominante (90,5%). La presentación multifocal se encontró en el 33,3% delos casos. Los resultados analíticos mostraron una neutrofilia >70% en el 47% de los casos.Conclusiones:Laneumonía por M.pneumoniaese observó fundamentalmente en el sexo femenino y en mayores de 5 años.La clínicafue muy variable y fueron prevalentes la fiebre y la tos, radiológicamente predominaron las formas consolidativas ylos resultados analíticos fueron inespecíficos. Para el diagnóstico es importante valorar los casos de neumonía queno responden a la antibioterapia