Methylation deregulation of miRNA promoters identifies miR124-2 as a survival biomarker in Breast Cancer in very young women

MiRNAs are part of the epigenetic machinery, and are also epigenetically modified by DNA methylation. MiRNAs regulate expression of different genes, so any alteration in their methylation status may affect their expression. We aimed to identify methylation differences in miRNA encoding genes in breast cancer affecting women under 35 years old (BCVY), in order to identify potential biomarkers in these patients. In Illumina Infinium MethylationEPIC BeadChip samples (metEPICVal), we analysed the methylation of 9,961 CpG site regulators of miRNA-encoding genes present in the array. We identified 193 differentially methylated CpG sites in BCVY (p-value < 0.05 and methylation differences ±0.1) that regulated 83 unique miRNA encoding genes. We validated 10 CpG sites using two independent datasets based on Infinium Human Methylation 450k array. We tested gene expression of miRNAs with differential methylation in BCVY in a meta-analysis using The Cancer Genome Atlas (TCGA), Clariom D and Affymetrix datasets. Five miRNAs (miR-9, miR-124-2, miR-184, miR-551b and miR-196a-1) were differently expressed (FDR p-value < 0.01). Finally, only miR-124-2 shows a significantly different gene expression by quantitative real-time PCR. MiR-124-hypomethylation presents significantly better survival rates for older patients as opposed to the worse prognosis observed in BCVY, identifying it as a potential specific survival biomarker in BCVY

MicroRNA profile in very young women with breast cancer

BACKGROUND: Breast cancer is rarely diagnosed in very young women (35 years old or younger), and it often presents with distinct clinical-pathological features related to a more aggressive phenotype and worse prognosis when diagnosed at this early age. A pending question is whether breast cancer in very young women arises from the deregulation of different underlying mechanisms, something that will make this disease an entity differentiated from breast cancer diagnosed in older patients. METHODS: We performed a comprehensive study of miRNA expression using miRNA Affymetrix2.0 array on paraffin-embedded tumour tissue of 42 breast cancer patients 35 years old or younger, 17 patients between 45 and 65 years old and 29 older than 65 years. Data were statistically analyzed by t-test and a hierarchical clustering via average linkage method was conducted. Results were validated by qRT-PCR. Putative targeted pathways were obtained using DIANA miRPath online software. RESULTS: The results show a differential and unique miRNA expression profile of 121 miRNAs (p-value <0.05), 96 of those with a FDR-value <0.05. Hierarchical clustering grouped the samples according to their age, but not by subtype nor by tumour characteristics. We were able to validate by qRT-PCR differences in the expression of 6 miRNAs: miR-1228*, miR-3196, miR-1275, miR-92b, miR-139 and miR-1207. Moreover, all of the miRNAs maintained the expression trend. The validated miRNAs pointed out pathways related to cell motility, invasion and proliferation. CONCLUSIONS: The study suggests that breast cancer in very young women appears as a distinct molecular signature. To our knowledge, this is the first time that a validated microRNA profile, distinctive to breast cancer in very young women, has been presented. The miRNA signature may be relevant to open an important field of research in order to elucidate the underlying mechanism in this particular disease, which in a more clinical setting, could potentially help to identify therapeutic targets in this particular set of patients.MPC is funded by the Generalitat Valenciana VALi + d, ACIF/2011/270. MTM is funded by”Rio Hortega Project” (CM12/00264). GR is a FIS “Miquel Servet” Researcher. AB holds a Translational Research Grant awarded by the Spanish Society of Medical Oncology (SEOM). This project was carried out thanks to Fundación LeCadó – proyecto Flor de Vida and co-funded by FIS project PI13/00606 and FEDER. We would like to give thanks to all the patients and volunteers for their participation and also to the INCLIVA Biobank, integrated into the Spanish Hospital Biobanks Network (ReTBioH) and supported by the Instituto de Salud Carlos III/FEDER (grant number: RD09/0076/00132). We also wish to thank several private Breast cancer associations that funded this study and the Unit for Multigenic Analysis from the Central Unit for Medical Research (UCIM/INCLIVA) for the performance of the Affymetrix microRNA profiles.S

Interacción entre clima y ocupación humana en la configuración del paisaje vegetal del Parque Nacional de Aigüestortes i Estany de Sant Maurici a lo largo de los últimos 15.000 años

The vegetation of the National Park of Aigüestortes i Estany de St Maurici is the result of an interaction between climate, plant community dynamics and the human occupation of the territory. The OCUPAproject aimed to reconstruct this interaction across the last millennia combining methods from palaeoecology and archaeology. The study focused primarily on the Sant Nicolau valley and built on the multidisciplinary analysis of the sedimentary archive of two lakes (Llebreta and Redó) and a number of archaeological sites located in shelters and outdoors. There is archaeological evidence of human presencesince 9000 yr cal BP, and a continuous record since 7500 yr cal BP. At early stages, humans transformed the surroundings of the shelters occupied and lithic tools indicate contacts with locations far away (i.e.,the Ebro plains). Since more than 3000 years ago, there has been human impact on the vegetation withoutinterruption until present. Initially, the impacts were mostly related to livestock: use of fire to open grazing lands, soil erosion and, during the medieval period, forestry and eutrophication of lakes. The agriculture impact in the lower part of the valley (e.g., Llebreta) occurred about 2100 yr ago, although some cereal grains and tools for harvesting have been found for the Neolithic. In the medieval period, the impact was higher than during the last centuries. In general, the changes in the human land use approximately follow the major changes in climate, but the specific causal link is likely related to the social and cultural dynamics of a broader territory since the Neolithic

Interacción entre clima y ocupación humana en la configuración del paisaje vegetal del Parque Nacional de Aigüestortes i Estany de Sant Maurici a lo largo de los últimos 15.000 años

The vegetation of the National Park of Aigüestortes i Estany de St Maurici is the result of an interaction between climate, plant community dynamics and the human occupation of the territory. The OCUPA project aimed to reconstruct this interaction across the last millennia combining methods from palaeoecology and archaeology. The study focused primarily on the Sant Nicolau valley and built on the multidisciplinary analysis of the sedimentary archive of two lakes (Llebreta and Redó) and a number of archaeological sites located in shelters and outdoors. There is archaeological evidence of human presence since 9000 yr cal BP, and a continuous record since 7500 yr cal BP. At early stages, humans transformed the surroundings of the shelters occupied and lithic tools indicate contacts with locations far away (i.e., the Ebro plains). Since more than 3000 years ago, there has been human impact on the vegetation without interruption until present. Initially, the impacts were mostly related to livestock: use of fire to open grazing lands, soil erosion and, during the medieval period, forestry and eutrophication of lakes. The agriculture impact in the lower part of the valley (e.g., Llebreta) occurred about 2100 yr ago, although some cereal grains and tools for harvesting have been found for the Neolithic. In the medieval period, the impact was higher than during the last centuries. In general, the changes in the human land use approximately follow the major changes in climate, but the specific causal link is likely related to the social and cultural dynamics of a broader territory since the Neolithic.Para el sondeo y estudio mineralógico se ha contado con la colaboración de financiación adicional a través del proyecto «Multidisciplinary research consortium on gradual and abrupt climate changes, and their impacts on the environment (GRACCIE), CSD2007-00067, Programa Consolider 2007»Peer Reviewe

Interacció entre clima i ocupació humana en la configuració del paisatge vegetal del Parc Nacional d’Aigüestortes i Estany de Sant Maurici

The vegetation of the National Park of Aigüestortes and Lake of Sant Maurici is the result of an interaction process between climate, plant community dynamics and the human occupation of the territory. The OCUPA project aims to reconstruct this interaction ovar the last millennia using methods of palaeoecolagy and archaeology. Here, we describe the main features of the project and summarize the results obtained so far. The study focuses primarily on the Sant Nicolau valley and bases on the multidisciplinary analysis of the sedimentary archive of two lakes (LLebreta and Redó) and a number of archaeological sites located in shelters and outdoors. There is archaaological evidence of human presence since 9.000 yr cal BP. and a continuous record since 7.500 yr cal BP. At early stages, they transformad the surroundings of the shelters occupied and lithic tools indicate contacts with areas as lar as the Ebro plains. Since the Bronze Age (ca. 4,300 yr cal BP) there has been human impact on the vegetation without interruption until present. Initialty, the impacts were mostly related to livestock: use of fire to open grassing areas, soil erosion and, during the medieval period, forestry and water eutrophication of lakes. The agricultura impact in lhe lower part of the valley (e.g., Llebreta) occurred about 2,100 yr ago, although some cereal grains and tools for harvesting have been found from the Neolithic. In the medieval period, the impact was much higher than during the last centurias. In general, it can be concluded that changes in the human land use approximately follow the major changes in climate, but the specific causal link is likely to be related to the social and cultural dynamics of a broader territory since the Neoliihic

Interacció entre clima i ocupació humana en la configuració del paisatge vegetal del Parc Nacional d'Aigüestortes i Estany de Sant Maurici

[EN] The vegetation of the National Park of Aigüestortes and Lake of Sant Maurici is the result of an interaction process between climate, plant community dynamics and the human occupation of the territory. The OCUPA project aims to reconstruct this interaction ovar the last millennia using methods of palaeoecolagy and archaeology. Here, we describe the main features of the project and summarize the results obtained so far. The study focuses primarily on the Sant Nicolau valley and bases on the multidisciplinary analysis of the sedimentary archive of two lakes (LLebreta and Redó) and a number of archaeological sites located in shelters and outdoors. There is archaaological evidence of human presence since 9.000 yr cal BP. and a continuous record since 7.500 yr cal BP. At early stages, they transformad the surroundings of the shelters occupied and lithic tools indicate contacts with areas as lar as the Ebro plains. Since the Bronze Age (ca. 4,300 yr cal BP) there has been human impact on the vegetation without interruption until present. Initialty, the impacts were mostly related to livestock: use of fire to open grassing areas, soil erosion and, during the medieval period, forestry and water eutrophication of lakes. The agricultura impact in lhe lower part of the valley (e.g., Llebreta) occurred about 2,100 yr ago, although some cereal grains and tools for harvesting have been found from the Neolithic. In the medieval period, the impact was much higher than during the last centurias. In general, it can be concluded that changes in the human land use approximately follow the major changes in climate, but the specific causal link is likely to be related to the social and cultural dynamics of a broader territory since the Neoliihic.[CA] El paísatge vegetal del Parc Nacional d'Aigüestortes i Estany do Sant Mauríci és el resultat d'un procés d'interacció entre el clima, els components de la mateixa vegetació i l'ocupació humana del territori. El projecte OCUPA té per objectiu reconstruir aquesta interacció al llarg deis darrers mil·lennis fent ús de métodes de la paleoecologia i l'arqueologia. Presentem aquí les característiques del projecte i fem un resum dels principals resultats obtinguts fins ara. L'estudi se centra sobretot en la vall de Sant Nicolau i es basa en l'análisi multidisciplinària del registre sedimentari de dos estanys (Llebreta i Rodó) i d'un bon nombre de jaciments arqueològics situats tant en abrics i balmes com a l'aire lliure. Hi ha evidències arqueològiques de presència humana des de 9.000 anys cal BP, i més continuadament des de 7.000 anys cal BP. Hi ha indicis que aquesta presència modifica l'entorn deis abrics, i de l'estudi de les eines lítiques es poden deduir contactes habituals amb zones tan allunyades com les planes de l'Ebre. Des de l'edat del bronze (ca. 4.300 anys cal BP) hi ha ocupació i impacte sobre el paisatge sense interrupció fins a l'actualitat. La influéncia va lligada sobrotot a lo ramaderia: utilització del foc per obrir espais de pastura; erosió del sòl, i, en periode medieval, explotació forestal i eutrofització de l'aigua dels estanys. L'impacte en el paisatge de l'agrlcultura de fons de vall (p. e., Llebreta) es produeix des de fa uns 2.100 anvs. encara que en els jaciments arqueològics es troben alguns grans de cereals i eines per segar tiges seques des del neolític. Durant el periode medieval l'impacte és molt superior al dels darrers segles i l'actualitat. En general, es pot concloure que el canvis en la forma de l'ocupació coincideixen a grans trets amb els principals canvis en el clima, però el lligam causal precís és probable que, ja des del neolític, estigui relacional amb la dinàmica cultural i social d'un territorl força més ampli, que també es veu condicionada pel clima.Peer reviewe

Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Background: Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications. Methods: We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged ≥18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients' preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARRadj). This study is registered with ClinicalTrials.gov, number NCT01865513. Findings: Between June 16, 2014, and April 29, 2015, data from 22 803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7·6%] of 21 694); ORadj 1·86, 95% CI 1·53–2·26; ARRadj −4·4%, 95% CI −5·5 to −3·2). Only 2·3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1·31, 95% CI 1·15–1·49; ARRadj −2·6%, 95% CI −3·9 to −1·4) and the administration of reversal agents (1·23, 1·07–1·41; −1·9%, −3·2 to −0·7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1·03, 95% CI 0·85–1·25; ARRadj −0·3%, 95% CI −2·4 to 1·5) nor extubation at a train-of-four ratio of 0·9 or more (1·03, 0·82–1·31; −0·4%, −3·5 to 2·2) was associated with better pulmonary outcomes. Interpretation: We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications. Funding: European Society of Anaesthesiology

Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Background Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications.Methods We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged &gt;= 18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients' preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARR(adj)). This study is registered with ClinicalTrials. gov, number NCT01865513.Findings Between June 16, 2014, and April 29, 2015, data from 22 803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7.6%] of 21 694); ORadj 1.86, 95% CI 1.53-2.26; ARR(adj) -4.4%, 95% CI -5.5 to -3.2). Only 2.3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1.31, 95% CI 1.15-1.49; ARR(adj) -2.6%, 95% CI -3.9 to -1.4) and the administration of reversal agents (1.23, 1.07-1.41; -1.9%, -3.2 to -0.7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1.03, 95% CI 0.85-1 center dot 25; ARR(adj) -0.3%, 95% CI -2.4 to 1.5) nor extubation at a train-of-four ratio of 0.9 or more (1.03, 0.82-1.31; -0.4%, -3.5 to 2.2) was associated with better pulmonary outcomes.Interpretation We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications

Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Background Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications. Methods We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged ≥18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients’ preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARRadj). This study is registered with ClinicalTrials.gov, number NCT01865513. Findings Between June 16, 2014, and April 29, 2015, data from 22803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7·6%] of 21694); ORadj 1·86, 95% CI 1·53–2·26; ARRadj –4·4%, 95% CI –5·5 to –3·2). Only 2·3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1·31, 95% CI 1·15–1·49; ARRadj –2·6%, 95% CI –3·9 to –1·4) and the administration of reversal agents (1·23, 1·07–1·41; –1·9%, –3·2 to –0·7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1·03, 95% CI 0·85–1·25; ARRadj –0·3%, 95% CI –2·4 to 1·5) nor extubation at a train-of-four ratio of 0·9 or more (1·03, 0·82–1·31; –0·4%, –3·5 to 2·2) was associated with better pulmonary outcomes. Interpretation We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications