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Plasmid-Mediated Quinolone Resistance in Different Diarrheagenic Escherichia coli Pathotypes Responsible for Complicated, Noncomplicated, and Traveler's Diarrhea Cases

  • Herrera-Leon, Silvia
  • LLorente, Maria Teresa
  • Sanchez-Prieto, Sergio
This work was supported by grants MPY-1042/14 and PI14CIII/00051 from the Fondo de Investigaciones Sanitarias from the Spanish Ministry of Economy and Competitiveness. Sergio Sánchez acknowledges the Miguel Servet Programme of the Fondo de Investigaciones Sanitarias, Spanish Ministry of Economy and Competitiveness, for his research contract (CP13/00237)., Sí

Influence of glutathione availability on cell damage induced by human immunodeficiency virus type 1 viral protein R

  • Monroy, Noemí
  • Herrero-Romero, Laura
  • Carrasco, Luis
  • Gonzalez, Maria Eugenia
The human immunodeficiency virus type 1 (HIV-1) encodes for accessory viral protein R (Vpr), which arrests the cell cycle of host cells at G2 and causes mitochondrial dysfunction and alterations in glycolysis. High-level expression of Vpr protein correlates with increased viral production and disease progression. Vpr causes structural and functional injury in many types of eukaryotic cells, whether or not they are permissive for viral replication; among them is the budding yeast Saccharomyces cerevisiae. We hypothesized that the dramatic Vpr-induced injuries in yeast could be prevented by strengthening their redox response capacity. We show that exogenous addition of glutathione (GSH) or its prodrug, N-acetylcysteine (NAC), protected budding yeasts from Vpr-induced cytopathic effects. Moreover, addition of adenosine triphosphate (ATP) to growing cultures of Vpr-producing yeast returned cellular growth to control levels, whereas the addition dehydroascorbic acid (DHA) had only a minor protective effect. The diminished protein levels of Cox2p and Cox4p in wild typeVpr-producing yeasts together with the acute sensitivity of petite yeasts to Vpr activity may have been caused by low intracellular ATP levels. As a consequence of this energy deficit, eukaryotic cells would be unable to synthetize adequate supplies of GSH or to signal the mitochondrial retrograde response. Our findings strongly suggest that the cytopathogenic effect of Vpr protein in eukaryotic cells can be prevented by increasing intracellular antioxidant stores or, alternatively, supplying external ATP. Furthermore, these results support a potentially promising future for S. cerevisiae expression as a modality to search for Vpr-targeted inhibitors., We acknowledge the technical support of Maite Rejas and the members of the electron microscopy unit of the CBMSO (Universidad Autónoma, Madrid). This study was supported by Grant PI08/0912 from Acción Estratégica en Salud and by Programa Intramural de Formación from Instituto de Salud Carlos III., Sí

First detection of Aspergillus fumigatus azole-resistant strain due to Cyp51A TR46/Y121F/T289A in an azole-naive patient in Spain

  • Pelaez, T
  • Monteiro, Catia
  • Garcia-Rubio, R
  • Gomez-Lopez, Alicia
  • Bouza, E
  • Mellado, Emilia
We report the first isolation of a voriconazole-resistant Aspergillus fumigatus strain harbouring the azole resistance mechanism TR46/Y121F/T289A, recovered from an azole-naive patient in Spain with chronic obstructive pulmonary disease. This new finding in Spain suggests the spread of this resistance mechanism and reinforces the need for antifungal susceptibility surveillance., EM is supported by a Project from the Spanish Fondo de Investigación Sanitaria (FIS) (PI12_02376). MCM is funded by FIS by a Sara Borrell Fellowship (CD13/00198). TP is supported by a FIS project (PI14_02376).

NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation

  • García-Carpizo, Verónica
  • Sarmentero, Jacinto
  • Han, Bomie
  • Graña Castro, Osvaldo
  • Ruiz-Llorente, Sergio
  • Pisano, David G
  • Serrano Marugan, Manuel
  • Brooks, Harold B
  • Campbell, Robert M
  • Barrero, Maria Jose
The histone methyltransferase NSD2/WHSC1/MMSET is overexpressed in a number of solid tumors but its contribution to the biology of these tumors is not well understood. Here, we describe that NSD2 contributes to the proliferation of a subset of lung cancer cell lines by supporting oncogenic RAS transcriptional responses. NSD2 knock down combined with MEK or BRD4 inhibitors causes co-operative inhibitory responses on cell growth. However, while MEK and BRD4 inhibitors converge in the downregulation of genes associated with cancer-acquired super-enhancers, NSD2 inhibition affects the expression of clusters of genes embedded in megabase-scale regions marked with H3K36me2 and that contribute to the RAS transcription program. Thus, combinatorial therapies using MEK or BRD4 inhibitors together with NSD2 inhibition are likely to be needed to ensure a more comprehensive inhibition of oncogenic RAS-driven transcription programs in lung cancers with NSD2 overexpression., This work was supported by Eli Lilly and Company. We would like to thank the Genomics and Flow Cytometry units at the CNIO for technical help, C. Pantoja and the CNIO-Lilly Cell Signaling Therapies Laboratory for sharing protocols and reagents., Sí

New insulin delivery devices and glycemic outcomes in young patients with type 1 diabetes: a protocol for a systematic review and meta-analysis

  • Dos Santos, Tiago Jeronimo
  • Donado Campos, Juan de Mata
  • Fraga-Medín, Cristina A
  • Argente, Jesús
  • Rodríguez-Artalejo, Fernando
BACKGROUND: Optimal type 1 diabetes mellitus (T1D) care requires lifelong appropriate insulin treatment, which can be provided either by multiple daily injections (MDI) of insulin or by continuous subcutaneous insulin infusion (CSII). An increasing number of trials and previous systematic reviews and meta-analyses (SRMA) have compared both CSII and MDI but have provided limited information on equity and fairness regarding access to, and the effect of, those insulin devices. This study protocol proposes a clear and transparent methodology for conducting a SRMA of the literature (1) to assess the effect of CSII versus MDI on glycemic and patient-reported outcomes (PROs) among young patients with T1D and (2) to identify health inequalities in the use of CSII. METHODS: This protocol was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P), the PRISMA-E (PRISMA-Equity 2012 Guidelines), and the Cochrane Collaboration Handbook. We will include randomized clinical trials and non-randomized studies published between January 2000 and June 2019 to assess the effectiveness of CSII versus MDI on glycemic and PROs in young patients with T1D. To assess health inequality among those who received CSII, we will use the PROGRESS framework. To gather relevant studies, a search will be conducted in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews, and the Health Technology Assessment (HTA) database. We will select studies that compared glycemic outcomes (the glycosylated hemoglobin values, severe hypoglycemia episodes, diabetic ketoacidosis events, and/or time spent in range or in hyper-hypoglycemia), and health-related quality of life, as a PRO, between therapies. Screening and selection of studies will be conducted independently by two researchers. Subgroup analyses will be performed according to age group, length of follow-up, and the use of adjunctive technological therapies that might influence glycemic outcomes. DISCUSSION: Studies of the average effects of CSII versus MDI may have not assessed their impact on health equity, as some intended populations have been excluded. Therefore, this study will address health equity issues when assessing effects of CSII. The results will be published in a peer-review journal. Ethics approval will not be needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018116474.

Association Between Western and Mediterranean Dietary Patterns and Mammographic Density

  • Castello, Adela
  • Ascunce, Nieves
  • Salas-Trejo, Dolores
  • Vidal, Carmen
  • Sánchez-Contador, Carmen
  • Santamariña, Carmen
  • Pedraz-Pingarrón, Carmen
  • Moreno, Maria Pilar
  • Perez-Gomez, Beatriz
  • Lope, Virginia
  • Aragones, Nuria
  • Vioque, Jesús
  • Pollan-Santamaria, Marina
OBJECTIVE: To examine the association between two dietary patterns (Western and Mediterranean), previously linked to breast cancer risk, and mammographic density. METHODS: This cross-sectional study included 3,584 women attending population-based breast cancer screening programs and recruited between October 7, 2007, and July 14, 2008 (participation rate 74.5%). Collected data included anthropometric measurements; demographic, obstetric, and gynecologic characteristics; family and personal health history; and diet in the preceding year. Mammographic density was blindly assessed by a single radiologist and classified into four categories: less than 10%, 10-25%, 25-50%, and greater than 50%. The association between adherence to either a Western or a Mediterranean dietary pattern and mammographic density was explored using multivariable ordinal logistic regression models with random center-specific intercepts. Models were adjusted for age, body mass index, parity, menopause, smoking, family history, hormonal treatment, and calorie and alcohol intake. Differences according to women's characteristics were tested including interaction terms. RESULTS: Women with a higher adherence to the Western dietary pattern were more likely to have high mammographic density (n=242 [27%]) than women with low adherence (n=169 [19%]) with a fully adjusted odds ratio (ORQ4vsQ1) of 1.25 (95% confidence interval [CI] 1.03-1.52). This association was confined to overweight-obese women (adjusted ORQ4vsQ1 [95% CI] 1.41 [1.13-1.76]). No association between Mediterranean dietary pattern and mammographic density was observed. CONCLUSION: The Western dietary pattern was associated with increased mammographic density among overweight-obese women. Our results might inform specific dietary recommendations for women with high mammographic density., Sí

Spanish Mediterranean diet and other dietary patterns and breast cancer risk: case-control EpiGEICAM study

  • Castello, Adela
  • Pollan-Santamaria, Marina
  • Buijsse, B
  • Ruiz, A
  • Casas, A M
  • Baena-Cañada, José Manuel
  • Lope, Virginia
  • Antolín, Silvia
  • Ramos, M
  • Muñoz, Mercedes
  • Lluch, A
  • de Juan-Ferré, A
  • Jara, C
  • Jimeno, M A
  • Rosado, P
  • Díaz, E
  • Guillem, V
  • Carrasco, E
  • Perez-Gomez, Beatriz
  • Vioque, J
  • Boeing, H
  • Martín, M
BACKGROUND: Although there are solid findings regarding the detrimental effect of alcohol consumption, the existing evidence on the effect of other dietary factors on breast cancer (BC) risk is inconclusive. This study aimed to evaluate the association between dietary patterns and risk of BC in Spanish women, stratifying by menopausal status and tumour subtype, and to compare the results with those of Alternate Healthy Index (AHEI) and Alternate Mediterranean Diet Score (aMED). METHODS: We recruited 1017 incident BC cases and 1017 matched healthy controls of similar age (±5 years) without a history of BC. The association between 'a priori' and 'a posteriori' developed dietary patterns and BC in general and according to menopausal status and intrinsic tumour subtypes (ER+/PR+ and HER2-; HER2+; and ER-/PR- and HER2-) was evaluated using logistic and multinomial regression models. RESULTS: Adherence to the Western dietary pattern was related to higher risk of BC (OR for the top vs the bottom quartile 1.46 (95% CI 1.06-2.01)), especially in premenopausal women (OR=1.75; 95% CI 1.14-2.67). In contrast, the Mediterranean pattern was related to a lower risk (OR for the top quartile vs the bottom quartile 0.56 (95% CI 0.40-0.79)). Although the deleterious effect of the Western pattern was similarly observed in all tumour subtypes, the protective effect of our Mediterranean pattern was stronger for triple-negative tumours (OR=0.32; 95% CI 0.15-0.66 and Pheterogeneity=0.04). No association was found between adherence to the Prudent pattern and BC risk. The associations between 'a priori' indices and BC risk were less marked (OR for the top vs the bottom quartile of AHEI=0.69; 95% CI 0.51-0.94 and aMED=0.74; 95% CI 0.46-1.18)). CONCLUSIONS: Our results confirm the harmful effect of a Western diet on BC risk, and add new evidence on the benefits of a diet rich in fruits, vegetables, legumes, oily fish and vegetable oils for preventing all BC subtypes, and particularly triple-negative tumours., This work was supported by the Fundación Científica Asociación Española Contra el Cáncer (AECC) (Scientific Foundation of the Spanish Association Against Cancer); Fundación Cerveza y Salud 2005 (Beer and Health Foundation 2005); Sociedad Española de Oncología Médica (SEOM) (Spanish Society of Medical Oncology); Federación de Mujeres con Cáncer de Mama (FECMA) (Association of Women with Breast Cancer) and Fondo de Investigación Sanitaria (FIS) (Health Research Fund) CD110/00018.

Digitaldlsorter: Deep-Learning on scRNA-Seq to Deconvolute Gene Expression Data

  • Torroja, Carlos
  • Sanchez-Cabo, Fatima
The development of single cell transcriptome sequencing has allowed researchers the possibility to dig inside the role of the individual cell types in a plethora of disease scenarios. It also expands to the whole transcriptome what before was only possible for a few tenths of antibodies in cell population analysis. More importantly, it allows resolving the permanent question of whether the changes observed in a particular bulk experiment are a consequence of changes in cell type proportions or an aberrant behavior of a particular cell type. However, single cell experiments are still complex to perform and expensive to sequence making bulk RNA-Seq experiments yet more common. scRNA-Seq data is proving highly relevant information for the characterization of the immune cell repertoire in different diseases ranging from cancer to atherosclerosis. In particular, as scRNA-Seq becomes more widely used, new types of immune cell populations emerge and their role in the genesis and evolution of the disease opens new avenues for personalized immune therapies. Immunotherapy have already proven successful in a variety of tumors such as breast, colon and melanoma and its value in other types of disease is being currently explored. From a statistical perspective, single-cell data are particularly interesting due to its high dimensionality, overcoming the limitations of the "skinny matrix" that traditional bulk RNA-Seq experiments yield. With the technological advances that enable sequencing hundreds of thousands of cells, scRNA-Seq data have become especially suitable for the application of Machine Learning algorithms such as Deep Learning (DL). We present here a DL based method to enumerate and quantify the immune infiltration in colorectal and breast cancer bulk RNA-Seq samples starting from scRNA-Seq. Our method makes use of a Deep Neural Network (DNN) model that allows quantification not only of lymphocytes as a general population but also of specific CD8+, CD4Tmem, CD4Th and CD4Tregs subpopulations, as well as B-cells and Stromal content. Moreover, the signatures are built from scRNA-Seq data from the tumor, preserving the specific characteristics of the tumor microenvironment as opposite to other approaches in which cells were isolated from blood. Our method was applied to synthetic bulk RNA-Seq and to samples from the TCGA project yielding very accurate results in terms of quantification and survival prediction., This work was supported by the European Union’s Horizon 2020 research and innovation program under grant agreement number 633592 (Project APERIM: Advanced bioinformatics platform for personalized cancer immunotherapy). We thank Francesca Finotello and Zlatko Trajanoski for fruitful discussions and to the CNIC Bioinformatics Unit members for continuous support and work. The CNIC is supported by MEIC and the ProCNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505)., Sí

Convocatorias de proyectos, sexenios y premios: cómo pueden los investigadores localizar su producción científica y los datos que se solicitan

  • Maseda, Irene
Curso de formación del Instituto de Salud Carlos III, Preparación de la producción científica y métricas necesarias para la presentación de CV para proyectos, sexenios y premios de investigación. Métricas para las convocatorias. Localización de la producción científica en WoS y Scopus. CVN y CVA. Perfiles científicos., No

Atrial Myopathy

  • Shen, Mark J.
  • Arora, Rishi
  • Jalife, Jose
This paper discusses the evolving concept of atrial myopathy by presenting how it develops and how it affects the properties of the atria. It also reviews the complex relationships among atrial myopathy, atrial fibrillation (AF), and stroke. Finally, it discusses how to apply the concept of atrial myopathy in the clinical setting—to identify patients with atrial myopathy and to be more selective in anticoagulation in a subset of patients with AF. An apparent lack of a temporal relationship between episodes of paroxysmal AF and stroke in patients with cardiac implantable electronic devices has led investigators to search for additional factors that are responsible for AF-related strokes. Multiple animal models and human studies have revealed a close interplay of atrial myopathy, AF, and stroke via various mechanisms (e.g., aging, inflammation, oxidative stress, and stretch), which, in turn, lead to fibrosis, electrical and autonomic remodeling, and a pro-thrombotic state. The complex interplay among these mechanisms creates a vicious cycle of everworsening atrial myopathy and a higher risk of more sustained AF and strokes. By highlighting the importance of atrial myopathy and the risk of strokes independent of AF, this paper reviews the methods to identify patients with atrial myopathy and proposes a way to incorporate the concept of atrial myopathy to guide anticoagulation in patients with AF., Sí

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