The Differential Impact of SRC Expression on the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma

Aberrant SRC expression and activation is frequently detected in multiple cancers, and hence, targeting SRC has emerged as a promising therapeutic strategy. Different SRC inhibitors have demonstrated potent anti-tumor activity in preclinical models, although they largely lack clinical efficacy as monotherapy in late-stage solid tumors, including head and neck squamous cell carcinomas (HNSCC). Adequate selection and stratification of patients who may respond to and benefit from anti-SRC therapies is therefore needed to guide clinical trials and treatment efficacy. This study investigates the prognostic significance of active SRC expression in a homogeneous cohort of 122 human papillomavirus (HPV)-negative, surgically treated HNSCC patients. Immunohistochemical evaluation of the active form of SRC by means of anti-SRC Clone 28 monoclonal antibody was specifically performed and subsequently correlated with clinical data. The expression of p-SRC (Tyr419), total SRC, and downstream SRC effectors was also analyzed. Our results uncovered striking differences in the prognostic relevance of SRC expression in HNSCC patients depending on the tumor site. Active SRC expression was found to significantly associate with advanced disease stages, presence of lymph node metastasis, and tumor recurrences in patients with laryngeal tumors, but not in the pharyngeal subgroup. Multivariate Cox analysis further revealed active SRC expression as an independent predictor of cancer-specific mortality in patients with laryngeal carcinomas. Concordantly, expression of p-SRC (Tyr419) and the SRC substrates focal adhesion kinase (FAK) and the Arf GTPase-activating protein ASAP1 also showed specific associations with poor prognosis in the larynx. These findings could have important implications in ongoing Src family kinase (SFK)-based clinical trials, as these new criteria could help to improve patient selection and develop biomarker-stratified trials

Cambio Climático en el Mediterráneo Español

Semi-enclosed and bounded by three continents, the Mediterranean sea is a region highly vulnerable to human activities, i.e.: the population surge along the coasts, the tourism pressure, the maritime traffic, the agriculture and the fishery exploitation, all have a potential impact on the Mediterranean environment. In addition, effective initiatives against the Global Climate Change need to be attempted in order to preserve our marine environment and to achieve a sustainable development of its resources. Prevention and adaptation to this new threat must be based on the rigorous and scientific knowledge accomplished through the systematic and continuous observation of the sea, and through the collection of multidisciplinary time-series and the subsequent analysis. This report responds to this necessity. The main goals of the Instituto Español de Oceanografía (IEO) are to generate scientific knowledge, as well as to assess and to inform the public about the state of the sea. The IEO is primary focussed on the study of the variety of phenomena influencing spanish coasts, including the process of Climate Change. To meet these objectives, a large set of actions have been planned. Some of them are already being implemented, such as a multidisciplinary observation system in the shelf and continental slope waters, or periodic scientific reports dealing with the detection and quantification of Climate Change effects and of other possible environmental impacts. The present report is the first of a series of future contributions. Besides the IEO, other Spanish institutions such as the ICM (CSIC), Puertos del Estado (PE), the IMEDEA (CSIC), the UMA, the UIB and the INM, involved in the monitoring, analysis and modelling of the Mediterranean sea, have also participated in it. The results show clear evidences of the effect of Climate Change in the physical properties of the mediterranean waters since 1948; in particular, the temperature and salinity increase of the deep waters, the accelerated rise of sea level since the early 1990s, and the air and sea surface temperature increase during the second half of the XX century.Versión del edito

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Cambio climático en el Mediterráneo español. Segunda edición actualizada

The first edition of the report “Climate Change in the Spanish Mediterranean” acknowledged the necessity of monitoring environmental conditions within the Mediterranean Sea and it stated that initiatives aimed at preserving and achieving a sustainable development of its resources should be based on a rigorous and scientific knowledge. The first edition of this report attempted to establish the basis for future works and detected and quantified the sea level rise of waters surrounding the Mediterranean Spanish coasts, the temperature and salinity increase of deep waters, and the warming of the air and sea surface waters. The study of these and other man-made threats on the marine environment is an open question and requires a continuous monitoring effort. Thanks to the collaboration with other Spanish institutions such as ICM (CSIC), Puertos del Estado (PE), IMEDEA (CSIC), UMA, UIB and AEMET, as well as the own monitoring programs from the Instituto Español de Oceanografía (RADMED program), this second edition continues the previous report, analyzing time series extended to July 2008 and evidencing the persistence of the above mentioned warming trends in the Spanish Mediterranean. This and future updated reports, the activities of the IEO Mediterranean Group on Climate Change, and the collaboration with the already mentioned institutions intend to be a tool for the continuous surveillance of the Mediterranean Spanish waters and the assessment for its sustainable exploitation.Versión del edito

Climate and Oceanographic Change in the Atlantic of northern Spain

Esta obra ofrece una síntesis de la información recogida en las series temporales de observaciones oceánicas del IEO en la región atlántica del norte de España iniciadas en 1943 con el registro mareográfico; muestra evidencias de cambios interanuales en la física, la química y la biología del océano en relación con los factores climáticos, y estima los impactos más probables del clima en el océano futuro. Este volumen continúa la serie de estudios de la influencia del cambio climático en el mar iniciada con el Cambio climático en el Mediterráneo español (Vargas Yánez et al., 2010). En este caso, el enfoque es multidisciplinar, empleando, por primera vez, series de observaciones recogidas de forma coordinada y simultánea. A lo largo de sus ochos capítulos, se analiza la variabilidad climática atmosférica reciente y su influencia sobre las condiciones oceanográficas de la región, especialmente en relación con la intensidad y frecuencia del afloramiento de aguas profundas que determina, en gran medida, el aporte estacional de nutrientes a la superficie y, por tanto, la producción biológica. Se describen las tendencias en el nivel del mar a partir de las medidas de los mareógrafos de la zona con una estimación de los niveles extremos esperados a largo plazo. Se realiza un análisis comparativo –entre Galicia y el Cantábrico– de la variabilidad en los nutrientes inorgánicos y se determinan los elementos limitantes de la producción primaria en cada zona. Finalmente, se analizan las variaciones en las comunidades de fitoplancton, picoplancton y zooplancton como indicadoras de cambios en el ecosistema pelágico, destacando las fluctuaciones en la biomasa y producción primaria, base de la red trófica pelágica de la región, y la presencia de medusas y salpas y su relación con el clima.This book presents a synthesis of the oceanic time-series observations of IEO in the Atlantic region of northern Spain. These series, starting in 1943 with tide-gauges, reveal evidence of interanual changes in physical, chemical and biological properties of the ocean that were related to climatic factors, allowing to estimate future impacts of climate on the ocean. The volume continues the series started with “Climate Change in the Spanish Mediterranean” (Vargas Yánez et al., 2010). In this case the study is multidisciplinary, including for the first time series obtained in coordinated and simultaneous observational programs. The eight chapters first analyse recent climatic variability and its influence on the regional oceanography, particularly in relation to the intensity and frequency of the deep-water upwelling that largely determines the seasonal inputs of nutrients and primary production in this region. Next, the main trends in sea level revealed by tidal gauges along with the estimates of expected extreme levels are described. The variability in inorganic nutrients and the identification of limiting elements for primary production were presented as a comparative analysis between Galicia (in the West) and the Mar Cantábrico (in the east). Finally, the variability in the composition of the plankton communities, including phytoplankton, picoplankton and zooplankton, is analysed as indicative of changes in the pelagic ecosystem. Particular attention is given to the fluctuations in primary biomass and production and to the presence of salps and jellyfish in relation to climate.Versión del edito

Switching TNF antagonists in patients with chronic arthritis: An observational study of 488 patients over a four-year period

The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34-0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97-2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13-4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications. © 2006 Gomez-Reino and Loreto Carmona; licensee BioMed Central Ltd