Hernandez-Perez S.,Hospital Universitario Of Canarias
Oncogene | Year: 2017
Correct control of DNA replication is crucial to maintain genomic stability in dividing cells. Inappropriate re-licensing of replicated origins is associated with chromosomal instability (CIN), a hallmark of cancer progression that at the same time provides potential opportunities for therapeutic intervention. Geminin is a critical inhibitor of the DNA replication licensing factor Cdt1. To properly achieve its functions, Geminin levels are tightly regulated through the cell cycle by ubiquitin-dependent proteasomal degradation, but the de-ubiquitinating enzymes (DUBs) involved had not been identified. Here we report that DUB3 and USP7 control human Geminin. Overexpression of either DUB3 or USP7 increases Geminin levels through reduced ubiquitination. Conversely, depletion of DUB3 or USP7 reduces Geminin levels, and DUB3 knockdown increases re-replication events, analogous to the effect of Geminin depletion. In exploring potential clinical implications, we found that USP7 and Geminin are strongly correlated in a cohort of invasive breast cancers (P<1.01E−08). As expected, Geminin expression is highly prognostic. Interestingly, we found a non-monotonic relationship between USP7 and breast cancer-specific survival, with both very low or high levels of USP7 associated with poor outcome, independent of estrogen receptor status. Altogether, our data identify DUB3 and USP7 as factors that regulate DNA replication by controlling Geminin protein stability, and suggest that USP7 may be involved in Geminin dysregulation during breast cancer progression.Oncogene advance online publication, 13 March 2017; doi:10.1038/onc.2017.21. © 2017 Macmillan Publishers Limited, part of Springer Nature.
Dominguez-Rodriguez A.,Hospital Universitario Of Canarias |
Abreu-Gonzalez P.,University of La Laguna |
Avanzas P.,Hospital Central Of Asturias
Frontiers in Bioscience | Year: 2012
Melatonin, a circadian hormone with marked antioxidant properties, has been shown to protect against ischemia-reperfusion myocardial damage, especially when administered during reperfusion period. Melatonin has cardioprotective properties via its direct free radical scavenging and its indirect antioxidant activity. Melatonin efficiently interacts with various reactive oxygen and reactive nitrogen species and it also upregulates antioxidant enzymes and downregulates pro-oxidant enzymes. In addition, melatonin demonstrated blood pressure lowering, lipid profile normalizing and anti-inflammatory properties. The lack of these cardioprotective effects due to insufficient melatonin levels might be associated with several cardiovascular pathologies including ischemic heart disease. Patients with acute coronary syndrome or after myocardial infarction were shown to have reduced nighttime melatonin levels and 6-sulfatoxymelatonin urinary excretion. These alterations might translate to increased cardiovascular risk observed in acute myocardial infarction patients with low melatonin levels; and a mutation in melatonin receptors might augment the risk for acute myocardial infarction. Therefore, it is expected that melatonin administration could play a clinically relevant role in the pharmacotherapy of ischemic heart disease; an assumption supported by low toxicity and high safety of melatonin.
Kakarougkas A.,University of Sussex |
Ismail A.,University of Sussex |
Katsuki Y.,University of Sussex |
Freire R.,Hospital Universitario Of Canarias |
And 2 more authors.
Nucleic Acids Research | Year: 2013
In G2 phase cells, DNA double-strand break repair switches from DNA non-homologous end-joining to homologous recombination. This switch demands the promotion of resection. We examine the changes in 53BP1 and RAP80 ionizing radiation induced foci (IRIF) in G2 phase, as these are factors that restrict resection. We observed a 2-fold increase in the volume of 53BP1 foci by 8 h, which is not seen in G1 cells. Additionally, an IRIF core devoid of 53BP1 arises where RPA foci form, with BRCA1 IRIF forming between 53BP1 and replication protein A (RPA). Ubiquitin chains assessed using α-FK2 antibodies are similarly repositioned. Repositioning of all these components requires BRCA1's BRCT but not the ring finger domain. 53BP1, RAP80 and ubiquitin chains are enlarged following POH1 depletion by small interfering RNA, but a devoid core does not form and RPA foci formation is impaired. Co-depletion of POH1 and RAP80, BRCC36 or ABRAXAS allows establishment of the 53BP1 and ubiquitin chain-devoid core. Thus, the barriers posed by 53BP1 and RAP80 are relieved by BRCA1 and POH1, respectively. Analysis of combined depletions shows that these represent distinct but interfacing barriers to promote loss of ubiquitin chains in the IRIF core, which is required for subsequent resection. We propose a model whereby BRCA1 impacts on 53BP1 to allow access of POH1 to RAP80. POH1-dependent removal of RAP80 within the IRIF core enables degradation of ubiquitin chains, which promotes loss of 53BP1. Thus, POH1 represents a novel component regulating the switch from non-homologous end-joining to homologous recombination. © 2013 The Author(s).
Lorente L.,Hospital Universitario Of Canarias |
Blot S.,Ghent University |
Rello J.,Hospital Vall DHebron
American Journal of Respiratory and Critical Care Medicine | Year: 2010
In the past 2 years, American, Canadian, and European scientific societies have published their new evidence-based guidelines for ventilator-associated pneumonia (VAP) prevention. However, these guidelines did not review some potentially useful strategies, such as the use of an endotracheal tube with an ultrathin cuff membrane, an endotracheal tube with a low-volume/low-pressure cuff, a device for continuous monitoring of the endotracheal tube cuff pressure, a device to remove biofilm from the inner site of the endotracheal tube, and saline instillation before tracheal suctioning. Only a few guidelines analyze the time of tracheostomy, and so no firm recommendations can be made regarding its importance. In addition, the guidelines diverge on the use of heat and moisture exchangers or heated humidifiers and on the use of an endotracheal tube coated with antimicrobial agents. The current review focuses on measures of VAP prevention for which there is no clear recommendation, or the use of which is controversial. A review of the literature suggests that the use of an endotracheal tube with an ultrathin and tapered-shape cuffmembrane and coated in antimicrobial agents may reduce the risk of VAP. These features offer an attractive way to optimize the VAP prevention capacity of endotracheal tubeswitha lumenfor subglottic secretion drainage. We believe that early tracheostomy should be considered, based on the length reduction of mechanical ventilation and intensive care unit stay, reduction of mortality, and on patient comfort, although early tracheostomy has not yet been shown to favorably impact the incidence of VAP. We believed that heat and moisture exchangers should be considered based on the benefits in terms of cost savings. More research is necessary to clarify the role of continuous cuff pressure monitoring, removal of biofilm formation in the endotracheal tubes, and routine saline instillation before tracheal suctioning.
Bello A.P.,Hospital Universitario Of Canarias |
Masip T.C.,Hospital Universitario Of Canarias
Archivos Espanoles de Urologia | Year: 2014
Objectives: The aim of this study is to provide an evidence-based analysis of the epidemiological situation of prostate cancer today and its future perspectives. Method: A literature review on Medline has been made of the most relevant papers related to the epidemiology of prostate cancer and their etiological factors. We selected for review those manuscripts with the highest level of evidence. RESULTS: Prostate cancer is the second most common neoplasia in men worldwide. The increasing trend in the incidente counteracted by an overall decrease in mortality from this disease have made prostate cancer an important health problem because of its high prevalence. There are significant geographic differences in terms of incidence and mortality. Age, ethnicity and family history are risk factors demonstrated but there are other factors related to the environment that play an important role in the biology of prostate cancer and tumor genesis. Conclusions: In the last 20 years there has been a progressive increase in the global incidence of this disease probably secondary to a progressive aging population, the improvement in diagnostic techniques and a higher intensity screening of prostate cancer. Though mortality has been reduced prostate cancer is the sixth cause of cancer-specific death worldwide. The combination of genetic and environmental factors may explain the ethnic and geographical variations in the incidence and mortality from prostate cancer.
Nicolas-Perez D.,Hospital Universitario Of Canarias
Gastroenterologia y Hepatologia | Year: 2012
Endoscopic submucosal dissection (ESD) can be applied to early gastrointestinal cancers. This technique was developed to achieve radical curative resection and to reduce unnecessary surgical interventions. ESD was designed in eastern countries and is not widely used in the West.Although ESD represents a major therapeutic advance in endoscopy and is performed with curative intent, the complication rate (hemorrhage, perforation) is higher than reported in other techniques, requiring from endoscopists the acquirement of technical skill and experience through a structured and progressive training program to reduce the morbidity associated with this technique and increase its potential benefits. Although there is substantial published evidence on the applications and results of ESD, there are few publications on training in this technique and a standardized training program is lacking. The current article aims to describe the various proposals for training, as well as the basic principles of the technique, its indications, and the results obtained, since theoretical knowledge that would guide endoscopists during the clinical application of ESD is advisable before training begins. Training in an endoscopic technique has a little value without knowledge of the technique's aims, the situations in which it should be applied, and the results that can be expected. © 2011 Elsevier España, S.L. and AEEH y AEG.
Perez-Castro A.J.,Hospital Universitario Of Canarias |
Freire R.,Hospital Universitario Of Canarias
Journal of Cell Science | Year: 2012
The complex formed by Rad9, Rad1 and Hus1 (9-1-1) protects against genomic instability by activating DNA damage checkpoint and DNA damage repair pathways, mainly in response to replication fork collapse and UV lesions. Here we compare the role of Rad9A (also known as Rad9) with the human paralogue Rad9B. Unlike Rad9A, overexpression of Rad9B delays cells in G1 phase. Moreover, Rad9B migrates to nucleoli after nucleolar stress in an ATR- and JNK-dependent manner, in a newly described nucleolar domain structure containing p21. Analysis of chimeras of Rad9A and Rad9B demonstrate that localisation to nucleoli and the block in G1 phase upon overexpression crucially depend on the Rad9B C-terminal tail. Taken together, data presented here show a relationship between Rad9B and pathways for checkpoints, stress response and nucleolar function. © 2012.
Gonzalez Gonzalez N.L.,Hospital Universitario Of Canarias
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians | Year: 2013
To find the best early predictor model for fetal growth and large for gestational age (LGA) infants considering clinical, ultrasonographic and biochemical variables. In 2097 singleton pregnancies at first trimester, we evaluated maternal characteristics, PAPP-A and ß-HCG proteins, fetal nuchal translucency thickness and uterine artery pulsatility index (UtA-PI). At second trimester fetal ultrasound biometry and UtA-PI were then measured. The relationships between birth weight and LGA and maternal characteristics, first and second trimester variables, and all variables combined, were studied. The performance of screening was determined by receiver operating characteristic curves analysis. Stepwise regression analysis showed that in the prediction of birthweight percentile there were significant contributions from all maternal factors, PAPP-A and Ut-A PI in the first trimester, and fetal biometric variables in the second trimester. Maternal charateristics combined with PAPP-A, β-hCG, fetal NT and uterine artery PI identified 30.2 % LGA (FPR 10%). The combined model reached a sensitivity of 41.2% (FPR 10%) and 56.2% (FPR 20%). Sensitivity of the screening for LGA improves significantly after addition of second trimester ultrasound measurements to first trimester variables and maternal characteristics.
Cabrera E.,Hospital Universitario Of Canarias
Oncogene | Year: 2016
Stresses such as hypoxia, nutrient deprivation and acidification disturb protein folding in the endoplasmic reticulum (ER) and activate the Unfolded Protein Response (UPR) to trigger adaptive responses through the effectors, PERK, IRE1 and ATF6. Most of these responses relate to ER homoeostasis; however, here we show that the PERK branch of the UPR also controls DNA replication. Treatment of cells with the non-genotoxic UPR agonist thapsigargin led to a rapid inhibition of DNA synthesis that was attributable to a combination of DNA replication fork slowing and reduced replication origin firing. DNA synthesis inhibition was dependent on the UPR effector PERK and was associated with phosphorylation of the checkpoint adaptor protein Claspin and activation of the Chk1 effector kinase, both of which occurred in the absence of detectable DNA damage. Remarkably, thapsigargin did not inhibit bulk DNA synthesis or activate Chk1 in cells depleted of Claspin, or when Chk1 was depleted or subject to chemical inhibition. In each case thapsigargin-resistant DNA synthesis was due to an increase in replication origin firing that compensated for reduced fork progression. Taken together, our results unveil a new aspect of PERK function and previously unknown roles for Claspin and Chk1 as negative regulators of DNA replication in the absence of genotoxic stress. Because tumour cells proliferate in suboptimal environments, and frequently show evidence of UPR activation, this pathway could modulate the response to DNA replication-targeted chemotherapies.Oncogene advance online publication, 4 July 2016; doi:10.1038/onc.2016.239. © 2016 Macmillan Publishers Limited
Gomez-Oliveira G.,Hospital Universitario Of Canarias
Medicina oral, patología oral y cirugía bucal | Year: 2010
Removal of an impacted superior third molar is usually a simple and uncomplicated procedure for an Oral and Maxillofacial Surgeon. Nevertheless, complications are possible and include infection, facial swallowing, trismus, wound dehiscence, root fracture or even orosinusal fistula. Iatrogenic displacement into the infratemporal fossa is frequently mentioned but rarely reported. This anatomical fossa includes several important structures such as the internal maxillary artery, the venous pterygoid plexus, the sphenopalatine nerve, the coronoid process of the mandible and the pterygoid muscles. Recommended treatment includes immediate surgical removal if possible or initial observation and secondary removal, as necessary, because of infection, limited mandibular movement, inability to extract the tooth, or the patient's psychological unease. Sometimes, the displaced tooth may spontaneously migrate inferiorly and becomes accessible intraorally. This report describes the location and secondary surgical removal of a left maxillary third molar displaced into the infratemporal fossa, two weeks after first attempt at extraction.