Breakdown of anomalous channeling with ion energy for accurate strain determination in gan-based heterostructures

The influence of the beam energy on the determination of strain state with ion channeling in GaN-based heterostructures (HSs) is addressed. Experimental results show that anomalous channeling may hinder an accurate analysis due to the steering effects at the HS interface, which are more intense at lower ion energies. The experimental angular scans have been well reproduced by Monte Carlo simulations, correlating the steering effects with the close encounter probability at the interface. Consequently, limitations in the determination of the strain state by ion channeling can be overcome by selecting the adequate beam energy

Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

New water soluble, enantiopure arene ruthenium compound SRuSN-(1R, 4S)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}Cl]Cl (Bn = benzyl, 1a') has been synthesized. The novel compound along with that previously described RRuRN-(1S, 4R)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a' was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a' induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a' towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells

La violencia contra las mujeres enfermeras en la pareja. Primeros resultados de un estudio en Andalucía

Aim. To Identify intimate partner violence (IPV) against female nurses in a sample of nurses in Cordoba, Spain.Design. Descriptive, cross-sectional study.Setting. Hospitals and primary health care in Cordoba, Spain.Participants. One hundred and two female nurses working in urban or rural, public or private health centers in Cordoba, Spain.Measures. Social-demographic characteristics and presence of abuse (psychological, physical and sexual).Results. A) A stricter recoding of the parameters of abuse: overall, 47.1% had experienced some type of IPV, of which 41.2% was psychological. B) A more permissible recoding of the parameters of abuse: 25.5% had experienced some type of IPV, of which 19.6% was psychological. C) Both recodings: 2.9% had suffered three types of abuse together (psychological, physical and sexual) and both psychological and sexual IPV; likewise, 11,8% reported more severe or more serious abuse.Conclusion. The existence of intimate partner violence in female nurses was established and it was confirmed that this was expressed through psychological aspects.Objetivo. Identificar violencia contra las mujeres enfermeras en la pareja a partir de una muestra de profesionales que prestan sus servicios en la Provincia de Córdoba.Diseño. Estudio descriptivo transversal.Emplazamiento. Hospitales y distritos sanitarios de la Provincia de Córdoba.Participantes. Mujeres enfermeras que desarrollaban sus actividades profesionales en cualquiera de los sistemas de salud, público o privado, rural o urbano, en la Provincia de Córdoba.Mediciones Principales. Características sociodemográficas y presencia de malos tratos (psíquico, físico y sexual), con el cuestionario validado por Delgado y colaboradores (2006).Resultados. La Recodificación de las variables del maltrato más estricta muestra que el 47,1% del total de enfermeras en la muestra tuvo algún tipo de maltrato, del que el 41,2% fue exclusivamente psicológico. Una Recodificación del maltrato más permisiva indica que el 25,5% tuvo algún tipo de maltrato del que 19,6% fue psicológico. Considerando ambas se puede ver que el 2,9% presentaron los tres tipos juntos (psicológico, físico y sexual) y psicológico acompañado del sexual; así como que el 11,8% presentó un maltrato más severo o de mayor gravedad.Conclusiones. Establecida la existencia de malos tratos en la mujer enfermera se constata que las manifestaciones van referidas al aspecto psicológic

The diacylglycerol kinase α/Atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells

Pretransplant CMV-Specific T-Cell Immunity But Not Dose of Antithymocyte Globulin Is Associated With Recovery of Specific Immunity After Kidney Transplantation

Background: This is a prospective, multicenter, observational study in cytomegalovirus (CMV)-seropositive kidney transplant recipients with pretransplant CMV-specific cell-mediated immunity (CMV-CMI) receiving antithymocyte globulin (ATG). We aimed to investigate posttransplant CMV-CMI over time and the impact of the dose-dependent ATG. Methods: CMV-CMI was assessed at days +30, +45, +60, and +90 after transplantation with the QuantiFERON-CMV assay. A reactive result (interferon-? [IFN-?] ? 0.2 IU/mL) indicated a positive CMV-CMI. Results: A total of 78 positive CMV-CMI patients were enrolled in the study, of which 59.5% had a positive CMV-CMI at day +30 and 82.7% at day +90. Multivariate logistic regression analysis showed that ATG dose was not associated with positive CMV-CMI at any point. However, pretransplant IFN-? level (>12 IU/mL vs ?12 IU/mL) was associated with positive CMV-CMI at day +30 (odds ratio, 12.9; 95% confidence interval, 3.1-53.3; P < .001). In addition, all the patients who did not recover CMV-CMI at day +90 had a pretransplant IFN-? level ?12 IU/mL. Conclusions: More than half of CMV-seropositive kidney transplant recipients receiving ATG recover (or maintain) CMV-CMI by the first month after transplantation. The pretransplant IFN-? level, but not the ATG dose, shows a strong association with the kinetics of this recovery.This work was supported by the Fundación Progreso y Salud, Consejería de Salud y Familias, Junta de Andalucía (grant number PI-0294-2014); Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (grant number CP 18/00073 to M. F. R.); Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia e Innovación, Spanish Network for Research in Infectious Diseases (grant numbers REIPI RD16/0016/0002, RD16/0016/0003, RD16/0016/0007, RD16/0016/0008, RD16/0016/0009 and RD16/0016/0012); cofinanced by European Development Regional Fund “A way to achieve Europe,” Operative Program Intelligent Growth 2014- 2020; Spanish Network for Research in Renal Diseases (grant numbers RD16/0009/0006, RD16/0009/0008, RD16/0009/0013, RD16/0009/0014, RD16/0009/0019, RD16/0009/0034); Centro de Investigación Biomédica en Red Enfermedades Respiratorias (grant number CB06/06/0058); and Spanish Group for the Study of Infection in Transplantation and the Immunocompromised Host of the Spanish Society of Infectious Diseases and Clinical Microbiolog

Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple e ects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients’ data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data.This research was funded by the Instituto de Salud Carlos III (DTS15/00174; PIE16-00045), by the Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucía and European Regional Development Fund (ERDF), references SOMM17/6109/UGR (UCE-PP2017-3) and (PI-0441-2014), and by the Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963). This research was also funded partially by RTI2018-098983-B-I00

Pre-exposure prophylaxis with hydroxychloroquine for COVID-19 : a double-blind, placebo-controlled randomized clinical trial

Background: Pre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period. Methods: We conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400 mg of hydroxychloroquine daily for the first four consecutive days and subsequently, 400 mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets. Results: 52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one participant in each group was diagnosed with COVID-19. The trial was stopped due to futility and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. Both groups showed a similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041). Conclusions: Although the efficacy of PrEP with hydroxychloroquine for preventing COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low doses is safe. Trial registration: ClinicalTrials.govNCT04331834. Registered on April 2, 2020

Molecular basis of engineered meganuclease targeting of the endogenous human RAG1 locus

Homing endonucleases recognize long target DNA sequences generating an accurate double-strand break that promotes gene targeting through homologous recombination. We have modified the homodimeric I-CreI endonuclease through protein engineering to target a specific DNA sequence within the human RAG1 gene. Mutations in RAG1 produce severe combined immunodeficiency (SCID), a monogenic disease leading to defective immune response in the individuals, leaving them vulnerable to infectious diseases. The structures of two engineered heterodimeric variants and one single-chain variant of I-CreI, in complex with a 24-bp oligonucleotide of the human RAG1 gene sequence, show how the DNA binding is achieved through interactions in the major groove. In addition, the introduction of the G19S mutation in the neighborhood of the catalytic site lowers the reaction energy barrier for DNA cleavage without compromising DNA recognition. Gene-targeting experiments in human cell lines show that the designed single-chain molecule preserves its in vivo activity with higher specificity, further enhanced by the G19S mutation. This is the first time that an engineered meganuclease variant targets the human RAG1 locus by stimulating homologous recombination in human cell lines up to 265 bp away from the cleavage site. Our analysis illustrates the key features for à la carte procedure in protein–DNA recognition design, opening new possibilities for SCID patients whose illness can be treated ex vivo

Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis.

PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.We apologize to those authors whose work could not be cited due to size limitations. We thank Dr. Eduard Serra, Dr. Conxi Lázaro and Dr. David Lyden for their support in the project. We also thank Héctor Tejero for his help in analyzing RNA-seq data. Dr. Peinado laboratory is funded by US Department of Defense (W81XWH-16-1-0131), Agencia Estatal de Investigación/Ministerio de Ciencia e Innovación (AEI/MCIN) (PID2020-118558RB-I00/AEI/10.13039/501100011033), Fundación Proyecto Neurofibromatosis, European Union’s Horizon 2020 research and innovation programme “proEVLifeCycle” under the Marie Skłodowska-Curie grant agreement No 860303, and Fundación Científica AECC. We are also grateful for the support of the Ministerio de Universidades (Programa de Formación de Profesorado Universitario (FPU)) for the fellowship FPU016/05356 awarded to T. González-Muñoz and to the Translational NeTwork for the CLinical application of Extracellular VesicleS (TeNTaCLES) RED2018-102411-T(AEI/10.13039/501100011033). A. Di Giannatale was supported during this work by a research gran Nuovo-Soldati Foundation. The CNIO, certified as Severo Ochoa Excellence Centre, is supported by the Spanish Government through the Instituto de Salud Carlos III.N

Estudio de cohortes en atención primaria sobre la evolución de sujetos con prediabetes (PREDAPS). Fundamentos y metodología

El estudio PREDAPS pretende determinar el riesgo de desarrollo de diabetes y aparición de complicaciones vasculares en sujetos con prediabetes e identificar los factores asociados. Se trata de un estudio observacional de seguimiento de una cohorte de 1.184 sujetos con prediabetes y otra cohorte de 838 sujetos sin alteraciones en el metabolismo de la glucosa. Los datos de la etapa basal se obtuvieron de pacientes que acudieron a centros de Atención Primaria en España a lo largo del año 2012. Los sujetos con prediabetes fueron clasificados en tres grupos: aquellos que sólo tenían alteradas las cifras de glucemia en ayunas -entre 100 y 125 mg/dl-, aquellos que sólo tenían alterado el nivel de HbA1c -entre 5,7 y 6,4%- y aquellos que tenían alterados ambos parámetros. La información sobre sus características sociodemográficas, antecedentes familiares y personales, estilos de vida y tratamiento farmacológico se obtuvo de la historia clínica y de la entrevista realizada en la consulta por el médico. Se realizó un examen físico para determinar peso, talla, perímetro de la cintura y presión arterial y se realizaron análisis de sangre y orina. El estudio PREDAPS puede contribuir a disminuir la incertidumbre en las estrategias individuales de prevención en los sujetos con prediabetes. El seguimiento anual durante cinco años de los participantes posibilitará conocer el riesgo de desarrollo de diabetes mellitus tipo 2 y el de complicaciones macro y microvasculares en los tres grupos de sujetos con prediabetes, así como averiguar los posibles factores asociados a esos riesgos. The PREDAPS study aims to determine the risk of developing diabetes and the risk of vascular complications in patients with prediabetes and identify factors associated with those risks. It is a prospective observational study of a cohort of 1184 subjects with prediabetes and another cohort of 838 subjects with no alterations in glucose metabolism. The data at baseline were obtained from patients attending primary care centers in Spain throughout 2012. Subjects with prediabetes were classified into three groups: those who had only altered the fasting blood glucose levels -between 100 and 125mg/dl-, those who had only altered the HbA1c level -between 5.7 and 6.4% - and those who had altered both parameters. Information on sociodemographic characteristics, personal and family history, lifestyle and drug therapy was obtained from medical records and the interview with the doctor in the consultation. It was also performed a physical examination to determine weight, height, waist circumference and blood pressure were performed and blood and urine analysis. The PREDAPS study may help to reduce uncertainty in individual prevention strategies in subjects with prediabetes. Annual monitoring of patients recruited for five years will enable to know the risk of developing diabetes type 2 and the risk of macro-and microvascular complications in the three groups of subjects with prediabetes and determine the factors associated with those risks