Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide

Altres ajuts: This work was supported by Jazz Pharmaceuticals Plc (IST-16-10355 to MDR. and EC); German José Carreras Leukaemia Foundation (Grant 11R/2016 and 03R/2019 to MDR. and EC); [...]. We would like to thank the Proteomics unit staff (CCIT, University of Barcelona) for their support in the proteomic assay performance and analysis, and to the Primary Hemostasis laboratory group for their technical support. We also acknowledge the collaboration of Dr Josep Maria Cruzado of Institut d'Hemodiàlisi Barcelona who collaborated in obtaining the blood samples, the staff of the Maternitat Hospital, in Barcelona, for providing the umbilical cords that made possible some of the current results and to Shook Studio for the visual abstract design.Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT

Acute Graft-vs.-Host Disease-Associated Endothelial Activation in vitro Is Prevented by Defibrotide

Altres ajuts: This study was supported in part by Jazz Pharmaceuticals Plc (IST-16-10355), German Jose Carreras Leukaemia Foundation (11R/2016 and 03R/2019).Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed in vitro studies using endothelial cell (EC) lines. We found that DF significantly and dose-dependently suppressed EC proliferation and notably reduced their ability to form vascular tubes in Matrigel. To explore whether DF administered prophylactically or therapeutically has a significant effect on aGVHD endothelial dysfunction, ECs were exposed to media containing sera from patients with aGVHD (n = 22) in the absence or presence of DF and from patients that did not develop aGVHD (n = 13). ECs upregulated adhesion molecules (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), the adherence junction protein VE-cadherin, von Willebrand factor (VWF), and Akt phosphorylation in response to aGVHD sera. These responses were suppressed upon treatment with DF. In summary, DF inhibits vascular angiogenesis and endothelial activation induced by sera from aGVHD patients. Our results support the view that DF has notable positive effects on endothelial biology during aGVHD

Infection and coinfection by human papillomavirus, Epstein–Barr virus and Merkel cell polyomavirus in patients with squamous cell carcinoma of the larynx: a retrospective study

Background Human papillomavirus (HPV) is recognized as an important risk factor for laryngeal carcinogenesis. Although HPV-16 and 18 have been strongly implicated, the presence of other high-risk HPV (HR-HPV) genotypes or the coinfection with Epstein-Barr virus (EBV) or Merkel cell polyomavirus (MCPV) may increase the risk, but their etiological association has not been definitively established. Methods We characterized the genotype-specific HPV and the frequency of EBV and MCPV infections through the detection of their DNA in 195 laryngeal specimens of squamous cell carcinoma (SCC) histologically confirmed. Results HPV DNA was detected in 93 (47.7%) specimens. HPV-11 was the most frequent with 68 cases (73.1%), and HPV-52 was the most frequently HR-HPV found with 51 cases, which corresponds to 54.8% of all HPV-positive specimens. EBV DNA was detected in 54 (27.7%) tumor tissue specimens of which 25 (46.3%) were in coinfection with HPV. MCPV DNA was detected only in 11 (5.6%) cases of which 5 (45.4%) were in coinfection with an HR-HPV. No association between the presence of DNA of the three examined viruses and the patient smoking habits, alcohol consumption, age, the keratinization status, differentiation grade, or localization of the tumor in the larynx were found. Discussion HPV-52 was the most prevalent HR-HPV, which may suggest that this and other genotypes in addition to HPV-16 and 18 could be considered for prophylaxis. However, further studies including non-cancer larynx cases and the evaluation of other molecular markers and viral co-infection mechanisms are needed to determine the role of the different HR-HPV genotypes, EBV, and MCPV in the etiology of SCC of the larynx

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients

Background and aimsPediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico.MethodsPatients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined.ResultsOverall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1–10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS.ConclusionOutcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes

Red “Universidad, género, docencia e igualdad”

La Red de investigación en docencia universitaria “Universidad, docencia, genero e igualdad” persigue avanzar en la calidad e innovación de las enseñanzas universitarias a partir de la inclusión de la perspectiva de género. Se busca dar cumplimiento a las directrices generales de los nuevos planes de estudio respecto del principio de igualdad de oportunidades entre hombres y mujeres en la formación universitaria (Real Decreto 1393/2007. BOE nº 260, 30 de octubre de 2007). En la quinta edición de la Red, y dada su composición multidisciplinar, se ha trabajado en tres líneas de investigación: 1) mantenimiento del “Portal web con recursos docentes con perspectiva de género”, proyecto financiado por el Instituto de la Mujer (PACUI, 2012) e iniciado en el curso 2012-2013; 2) desarrollo de la primera versión de “iLengUA”, una herramienta informática para un discurso inclusivo e igualitario; y 3) diseño de una Guía de recomendaciones para la inclusión de la perspectiva de género en la docencia universitaria

Interactional pragmatic strategies in the Mexican university classroom

Learning to speak English not only involves knowing the foreign language, but also knowing strategies that help interactants communicate. One aspect of communication refers to strategic behaviour when a breakdown in communication causes misunderstanding (Mauranen 2012) or non-understanding (Cogo and Dewey 2012). Dealing with these kinds of communication problems showcases the different ways in which interactional pragmatic strategies interconnect in order to help interactants reach mutual understanding. Awareness and deliberate use of these strategies may have a positive impact in the workplace that has adquired characteristics of a globalized society (Chiang 2009), in which English is the means of communication most of the time. The language classroom is one of the settings where interaction could be studied in that sense, where the study of English is fundamental to students’ professional development. It is in the classroom where second language is shaped (Walsh 2011); and here different interactional pragmatic strategies such as repetition, rephrasing, repair, and code-switching among others are used to fulfil the teaching and learning processes. Therefore, this thesis examines some interactional pragmatic strategies that help to overcome communicative breakdowns that could hinder understanding within classroom interaction in business English classes. The detailed analysis of classroom interaction – naturally occurring speech – has revealed there is a diverse set of patterns, which go from using one single strategy to more complex patterns that encompass a series of strategies, necessary to reach understanding. In addition, participants have evidenced from their own perceptions that interactional pragmatic strategies are used commonly and confirm both simple and complex classroom interaction patterns, which signals speakers’ awareness of interactional behaviour. In a wider view, students’ and teacher’s perceptions also suggest contradicting issues among English that is used in the workplace (e.g. ELF) and English taught in the classroom (native-like English). This set of findings has implications in language teaching and learning

Antithrombotic and prohemorrhagic actions of different concentrations of apixaban in patients exposed to single and dual antiplatelet regimens

Altres ajuts: Deutsche José Carreras Leukämie-Stifung (03R/ 2019)We evaluated modifications in the hemostatic balance of different concentrations of apixaban (APIX) in 25 healthy donors and 53 patients treated with aspirin (ASA, n = 21), ASA and clopidogrel (ASA + CLOPI, n = 11), or ASA and ticagrelor (ASA + TICA, n = 21). Blood samples from participants were spiked ex vivo with apixaban 0 (APIX0), 40 (APIX40), and 160 ng/mL (APIX160). We assessed the effects of APIX on (1) clot formation, by ROTEM thromboelastometry; (2) thrombin generation primed by platelets; and (3) platelet and fibrin interactions with a thrombogenic surface, in a microfluidic model with circulating blood. APIX caused dose-related prolongations of clotting time with minimal impact on other ROTEM parameters. Thrombin generation was significantly inhibited by APIX160, with ASA + TICA actions showing the strongest inhibition (p < 0.01 vs APIX0). Microfluidic studies showed that APIX160 was more potent at suppressing platelet and fibrin interactions (p < 0.001 vs. APIX0). APIX40 demonstrated a consistent antithrombotic action but with a favorable protective effect on the structural quality of fibrin. APIX potentiated the antithrombotic effects of current antiplatelet regimens. APIX at 40 ng/mL, enhanced the antithrombotic action of single or dual antiplatelet regimens but was more conservative for hemostasis than the 160 ng/mL concentration