12 research outputs found

    Methylation of subtelomeric chromatin modifies the expression of the lncRNA TERRA, disturbing telomere homeostasis

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    The long noncoding RNA (lncRNA) telomeric repeat-containing RNA (TERRA) has been associated with telomeric homeostasis, telomerase recruitment, and the process of chromosome healing; nevertheless, the impact of this association has not been investigated during the carcinogenic process. Determining whether changes in TERRA expression are a cause or a consequence of cell transformation is a complex task because studies are usually carried out using either cancerous cells or tumor samples. To determine the role of this lncRNA in cellular aging and chromosome healing, we evaluated telomeric integrity and TERRA expression during the establishment of a clone of untransformed myeloid cells. We found that reduced expression of TERRA disturbed the telomeric homeostasis of certain loci, but the expression of the lncRNA was affected only when the methylation of subtelomeric bivalent chromatin domains was compromised. We conclude that the disruption in TERRA homeostasis is a consequence of cellular transformation and that changes in its expression profile can lead to telomeric and genomic instability

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

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    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.

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    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

    Methylation of Subtelomeric Chromatin Modifies the Expression of the lncRNA TERRA, Disturbing Telomere Homeostasis

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    The long noncoding RNA (lncRNA) telomeric repeat-containing RNA (TERRA) has been associated with telomeric homeostasis, telomerase recruitment, and the process of chromosome healing; nevertheless, the impact of this association has not been investigated during the carcinogenic process. Determining whether changes in TERRA expression are a cause or a consequence of cell transformation is a complex task because studies are usually carried out using either cancerous cells or tumor samples. To determine the role of this lncRNA in cellular aging and chromosome healing, we evaluated telomeric integrity and TERRA expression during the establishment of a clone of untransformed myeloid cells. We found that reduced expression of TERRA disturbed the telomeric homeostasis of certain loci, but the expression of the lncRNA was affected only when the methylation of subtelomeric bivalent chromatin domains was compromised. We conclude that the disruption in TERRA homeostasis is a consequence of cellular transformation and that changes in its expression profile can lead to telomeric and genomic instability

    Epigenetics, Environment and Asthma

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    Asthma is a chronic in ammatory disease of the respiratory tract with a complex genetic background in uenced by the exposition to a series of environmental factors. Genetic studies can only elucidate part of the heritability and susceptibility of asthma and even though several diseases have an evident genetic etiology, only a fraction of the genes involved in their pathogenicity have been identi ed. The epigenetic regulation of the latter is a fact one should bear in mind in order to explain the major triggers of diseases whose understanding is complicated, such as allergies and asthma. External stimulus such as nourishment, stress, physical activity, atmospheric pollution, tobacco smoking and alcohol drinking can induce either gene silencing or gene expression. In this regard, epigenetics can explain how these environmental factors in u- ence our genetic inheritance. There is growing evidence that backs-up the fact that DNA methylation, histone post-translational modi cation and microRNA expression are in uenced by the environment. This helps explaining how several of the risk factors mentioned contribute to the development and inheritance of asthma. In this review, differ- ent environmental factors and their relation with the main epigenetic regulatory mechanisms will be analyzed, as well as their possible role in the development of asthma

    Proteasome inhibition alters mitotic progression through the upregulation of centromeric α-Satellite RNAs

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    Cell cycle progression requires control of the abundance of several proteins and RNAs over space and time to properly transit from one phase to the next and to ensure faithful genomic inheritance in daughter cells. The proteasome, the main protein degradation system of the cell, facilitates the establishment of a proteome specific to each phase of the cell cycle. Its activity also strongly influences transcription. Here, we detected the upregulation of repetitive RNAs upon proteasome inhibition in human cancer cells using RNA‐seq. The effect of proteasome inhibition on centromeres was remarkable, especially on α‐Satellite RNAs. We showed that α‐Satellite RNAs fluctuate along the cell cycle and interact with members of the cohesin ring, suggesting that these transcripts may take part in the regulation of mitotic progression. Next, we forced exogenous overexpression and used gapmer oligonucleotide targeting to demonstrate that α‐Sat RNAs have regulatory roles in mitosis. Finally, we explored the transcriptional regulation of α‐Satellite DNA. Through in silico analyses, we detected the presence of CCAAT transcription factor‐binding motifs within α‐Satellite centromeric arrays. Using high‐resolution three‐dimensional immuno‐FISH and ChIP‐qPCR, we showed an association between the α‐Satellite upregulation and the recruitment of the transcription factor NFY‐A to the centromere upon MG132‐induced proteasome inhibition. Together, our results show that the proteasome controls α‐Satellite RNAs associated with the regulation of mitosis

    El castillo de Consuegra y su alfoz

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    Resumen basado en el del proyecto. Premiado en la convocatoria: Premios para proyectos de innovación concluidos durante el curso 2007-2008, en los centros educativos no universitarios sostenidos con fondos públicos de la Comunidad Autónoma de Castilla-La Mancha (Orden 12-12-2008, de la Consejería de Educación y Ciencia de la Junta de Comunidades de Castilla-La Mancha. Resolución de 5-5-2009, de la Viceconsejería de Educación)El proyecto pretende favorecer líneas de innovación educativa que logren implicar al alumnado y profesorado en el conocimiento de su entorno, el desarrollo de valores, la mejora de los procedimientos, el desarrollo de la competencia lingüística y el uso de las tecnologías de la información y la comunicación. Se da a conocer toda una comarca, el antiguo 'Campo de San Juan', que incluía un vasto territorio controlado por la Orden de San Juan de Jerusalén desde el s. XII, con sede en el castillo de Consuegra, y revalorizar los aspectos básicos del Patrimonio Natural y Cultural de la comarca. Otros objetivos que se persiguen son: comprender y expresar con corrección las conclusiones de la investigación, animando a la lectura como fuente de conocimiento y divertimento; utilizar el conocimiento matemático para identificar los problemas en diversos campos de conocimiento y de la experiencia, para su resolución y para la toma de decisiones; adquirir destrezas y habilidades a partir de conocimientos teóricos; recopilar una memoria fotográfica relacionada con el estudio; respetar la creación musical, identificando y analizando los mensajes que contiene el lenguaje de las distintas manifestaciones musicales (cantigas y folklore popular); utilizar la práctica del deporte para favorecer el desarrollo en lo personal y social, junto a la adquisición de hábitos saludables; utilizar la competencia comunicativa para comprender y expresarse en otros idiomas; confeccionar un proyecto empresarial para la explotación económica del castillo; utilizar los recursos naturales de forma eficaz, respetando el desarrollo sostenible; afianzar el sentido del trabajo en equipo y valorar las perspectivas, experiencias y formas de pensar de los demás, potenciando las relaciones dentro y fuera del contexto educativo como mecanismo de enriquecimiento personal.Castilla La ManchaConsejería de Educación, Ciencia y Cultura. Viceconsejería de Educación y Cultura. Servicio de Documentación; Bulevar del Río Alberche, s. n. - 1 Planta; 45071 Toledo; Tel. +34925286045; Fax +34925247410; [email protected]

    Contemporary use of cefazolin for MSSA infective endocarditis: analysis of a national prospective cohort

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    Objectives: This study aimed to assess the real use of cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) in the Spanish National Endocarditis Database (GAMES) and to compare it with antistaphylococcal penicillin (ASP). Methods: Prospective cohort study with retrospective analysis of a cohort of MSSA IE treated with cloxacillin and/or cefazolin. Outcomes assessed were relapse; intra-hospital, overall, and endocarditis-related mortality; and adverse events. Risk of renal toxicity with each treatment was evaluated separately. Results: We included 631 IE episodes caused by MSSA treated with cloxacillin and/or cefazolin. Antibiotic treatment was cloxacillin, cefazolin, or both in 537 (85%), 57 (9%), and 37 (6%) episodes, respectively. Patients treated with cefazolin had significantly higher rates of comorbidities (median Charlson Index 7, P <0.01) and previous renal failure (57.9%, P <0.01). Patients treated with cloxacillin presented higher rates of septic shock (25%, P = 0.033) and new-onset or worsening renal failure (47.3%, P = 0.024) with significantly higher rates of in-hospital mortality (38.5%, P = 0.017). One-year IE-related mortality and rate of relapses were similar between treatment groups. None of the treatments were identified as risk or protective factors. Conclusion: Our results suggest that cefazolin is a valuable option for the treatment of MSSA IE, without differences in 1-year mortality or relapses compared with cloxacillin, and might be considered equally effective

    Mural Endocarditis: The GAMES Registry Series and Review of the Literature

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

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