Role of DGKα and DGKζ in the control of lipid metabolism in breast cancer: implications for therapeutic intervention

Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 21-09-2012. Tesis doctoral con mención europe

Complexity of Puiseux solutions of differential and qq-difference equations of order and degree one

We relate the complexity of both differential and $q$-difference equations of order one and degree one and their solutions. Our point of view is to show that if the solutions are complicated, the initial equation is complicated too. In this spirit, we bound from below an invariant of the differential or $q$-difference equation, the height of its Newton polygon, in terms of the characteristic factors of a solution. The differential and the $q$-difference cases are treated in a unified way.Comment: 27 pages, 2 figure

Validez de predicción de un cuestionario de conocimientos y actitudes hacia la medicina familiar

ResumenObjetivoconocer la validez de predicción de un cuestionario que evalúa los conocimientos y las actitudes de los estudiantes de medicina hacia la medicina familiar (mf).Material y métodoestudio de cohorte; los sujetos de estudio fueron estudiantes matriculados en una asignatura de Atención Primaria (ap) entre 2005 y 2006, que se graduaron en 2010 y eligieron especialidad en 2011. Se diseñó un cuestionario con 34 preguntas cerradas. A los estudiantes se les invitó a contestar antes y después de cursar ap, así como a los matriculados en el sexto curso (2009-2010). Se registró la especialidad que eligieron; para calcular la validez predictiva del cuestionario se estimó su sensibilidad y especificidad, analizando las curvas cor (características operativas del receptor).Resultadosrespondieron el cuestionario 44 estudiantes antes de cursar la asignatura y 79 después. Al final del sexto curso contestaron 76. El área bajo la curva cor fue, respectivamente, 0.299 (ic 95%: 0.094-0.504), 0.482 (ic 95%: 0.280-0.684) y 0.688 (ic 95%: 0.282-1.093). Solamente en el último caso la curva cor estaba por encima de la diagonal. El mejor punto de corte en este caso fue 31, con sensibilidad=0.75 y especificidad=0.714.Conclusionesel cuestionario tiene una deficiente validez de predicción en relación con la elección de la mf. Sólo mejora en el último curso de la licenciatura.SummaryObjectiveto learn about the validity of prediction of a questionnaire that assesses knowledge and attitudes of students of medicine towards Family Medicine (fm).Material and methodscohort study; the studied individuals were students enrolled in a Primary Care course (pc) between 2005 and 2006, who graduated in 2010 and chose a specialty in 2011. It was designed a questionnaire with 34 closed questions. Students were invited to answer before and after taking the pc course, as well as those students enrolled in the sixth course (2009-2010). The specialty chosen was registered; to calculate the predictive validity of the questionnaire, their sensitivity and specificity was estimated, analyzing the roc (receiver operating characteristic) curves.Resultsthe questionnaire was answered by 44 students before studying the course and 79 after studying it. At the end of the sixth course, 76 students answered the questionnaire. The area under the roc curve was, respectively, 0.299 (ic 95%: 0.094-0.504), 0.482 (ic 95%: 0.280-0.684) and 0.688 (ic 95%: 0.282-1.093). Only in the latter case the curve roc was above the diagonal. The best cut-off point was 31, with sensitivity=0.75 and specifcity=0.714.Conclusionsthe questionnaire has a poor validity of prediction concerning the choice of fm. It only improves during the last year of the degree

The Recovery Umbrella in the World of Elite Sport: Do Not Forget the Coaching and Performance Staff

In the field of sports science, the recovery umbrella is a trending topic, and even more so in the world of elite sports. This is evidenced by the significant increase in scientific publications during the last 10 years as teams look to find a competitive edge. Recovery is recognized to be an integral component to assist athlete preparation in the restoration of physical and psychological function, and subsequently, performance in elite team sports athletes. However, the importance of recovery in team staff members (sports coaches and performance staff) in elite sports appears to be a forgotten element. Given the unrelenting intense nature of daily tasks and responsibilities of team staff members, the elite sports environment can predispose coaches to increased susceptibility to psycho-socio physiological fatigue burden, and negatively affect health, wellbeing, and performance. Therefore, the aim of this opinion was to (1) develop an educational recovery resource for team staff members, (2) identify organizational task-specific fatigue indicators and barriers to recovery and self-care in team staff members, and (3) present recovery implementation strategies to assist team staff members in meeting their organizational functions. It is essential that we do not forget the coaching and performance staff in the recovery process

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

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Combing the Cancer Genome for Novel Kinase Drivers and New Therapeutic Targets

Protein kinases are critical regulators of signaling cascades that control cellular proliferation, growth, survival, metabolism, migration, and invasion. Deregulation of kinase activity can lead to aberrant regulation of biological processes and to the onset of diseases, including cancer. In this review, we focus on oncogenic kinases and the signaling pathways they regulate that underpin tumor development. We highlight genomic biomarker-based precision medicine intervention strategies that match kinase inhibitors alone or in combination to mutationally activated kinase drivers, as well as progress towards implementation of these treatment strategies in the clinic. We also discuss the challenges for identification of novel protein kinase cancer drivers in the genomic era

Diacylglycerol kinase α promotes 3D cancer cell growth and limits drug sensitivity through functional interaction with Src

Diacylglycerol kinase (DGK)α converts diacylglycerol to phosphatidic acid. This lipid kinase sustains survival, migration and invasion of tumor cells, with no effect over untransformed cells, suggesting its potential as a cancer-specific target. Nonetheless the mechanisms that underlie DGKα specific contribution to cancer survival have not been elucidated. Using three-dimensional (3D) colon and breast cancer cell cultures, we demonstrate that DGKα upregulation is part of the transcriptional program that results in Src activation in these culture conditions. Pharmacological or genetic DGKα silencing impaired tumor growth in vivo confirming its function in malignant transformation. DGKα-mediated Src regulation contributed to limit the effect of Src inhibitors, and its transcriptional upregulation in response to PI3K/Akt inhibitors resulted in reduced toxicity. Src oncogenic properties and contribution to pharmacological resistance have been linked to its overactivation in cancer. DGKα participation in this central node helps to explain why its pharmacological inhibition or siRNA-mediated targeting specifically alters tumor viability with no effect on untransformed cells. Our results identify DGKα-mediated stabilization of Src activation as an important mechanism in tumor growth, and suggest that targeting this enzyme, alone or in combination with other inhibitors in wide clinical use, could constitute a treatment strategy for aggressive forms of cancer.PTA holds a FPU fellowship from the Spanish Ministry of Education, AAF was supported by the Spanish AntiCancer Association (AECC) and the Madrid regional government. This work was supported in part by grants from the Spanish Ministry of Economy and Competitivity (BFU2010-21138), Spanish Ministry of Health (Instituto de Salud Carlos III; RD12/0036/0059), and the Madrid regional government (IMMUNOTHERCAN S2010/BMD-2326) to IM.Peer Reviewe

Diacylglycerol Kinase Malfunction in Human Disease and the Search for Specific Inhibitors

The diacylglycerol kinases (DGKs) are master regulator kinases that control the switch from diacylglycerol (DAG) to phosphatidic acid (PA), two lipids with important structural and signaling properties. Mammalian DGKs distribute into five subfamilies that regulate local availability of DAG and PA pools in a tissue- and subcellular-restricted manner. Pharmacological manipulation of DGK activity holds great promise, given the critical contribution of specific DGK subtypes to the control of membrane structure, signaling complexes, and cell-cell communication. The latest advances in the DGK field have unveiled the differential contribution of selected isoforms to human disease. Defects in the expression/activity of individual DGK isoforms contribute substantially to cognitive impairment, mental disorders, insulin resistance, and vascular pathologies. Abnormal DGK overexpression, on the other hand, confers the acquisition of malignant traits including invasion, chemotherapy resistance, and inhibition of immune attack on tumors. Translation of these findings into therapeutic approaches will require development of methods to pharmacologically modulate DGK functions. In particular, inhibitors that target the DGKα isoform hold particular promise in the fight against cancer, on their own or in combination with immune-targeting therapies