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Patients with Fontan circulation (FC) have a high incidence of clinical complications. However, no biomarker is able to accurately stratify risk. The aim of this study was to analyze the relationship between biomarkers and clinical complications, including carbohydrate antigen 125 (CA125) for the first time, and to propose a risk estimation based on a combination of biomarkers.Cross-sectional study of patients with FC. The clinical endpoint was the combination of heart failure, atrial arrhythmias, veno-venous fistulae, protein-losing enteropathy, or plastic bronchitis. Demographic, clinical, and laboratory variables were analyzed, including CA125, NT-proBNP, renal and liver function, and red cell distribution width (RDW). We performed univariate and multivariate analyses of the relationship between these variables and the composite endpoint. Cutoff values were calculated by ROC curves.We included 56 patients (27.4±7.8 years). A total of 34% showed the composite endpoint, with significantly higher CA125 levels (30.1 IU/mL vs 12.6 IU/mL; P=.001). In the multivariate model, the biomarkers related to the endpoint were LnCA125 (OR, 5.1; 95%CI, 1.2-22), RDW (OR, 1.8; 95%CI, 1.1-3.1), and FIB4 (OR, 38, 95%CI, 1.7-855). The cutoff points were CA125 ≥ 20 U/mL, FIB4 ≥ 0.75, and RDW ≥ 14.5%, and the probability of the occurrence of the endpoint was 81% if ≥ 2 biomarkers were elevated.CA125 elevation is associated with a higher prevalence of complications in patients with Fontan-type circulation. CA125 levels ≥ 20U/mL, FIB4 ≥ 0.75 and RDW ≥ 14.5% identify with a high probability the clinical failure of FC.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease that typically affects middle-aged men with ulcerative colitis (UC). However, recent studies point out to epidemiological changes. Our aim was to determine if the epidemiology, clinical course and outcome of patients with PSC followed at a reference hepatology center resemble what is described in the literature.Retrospective search of patients with a diagnosis of PSC treated in our center between 2000 and 2019.Cohort of 55 patients (mean age: 37 years), 44% women. Most were large duct type (79%). Most diagnoses were made after 2011. At time of diagnosis, 63% of patients were asymptomatic. The median time from suspicion to diagnosis was 2 years. After a mean follow-up time of 7 years, one third developed cirrhosis, and 25% required liver transplantation (LT); among these, the disease recurred in almost half. Inflammatory bowel disease (IBD) was present in 45%, especially UC. Although statistical significance was not reached, PSC in women was characterized by higher rate of asymptomatic presentation and more frequent association with UC versus other forms of IBD. Women also had more frequently cirrhosis at diagnosis and required LT more often than men.The epidemiology of PSC is changing. The number of women affected is greater than what was expected from the literature, with a recent increase in incidence. There seems to be differences between sexes in the form of presentation and disease course that should be confirmed in subsequent studies.

Resumen Introduccion y objetivos La colangitis esclerosante primaria (CEP) es una enfermedad hepatica colestasica rara, que tipicamente afecta a varones de mediana edad con colitis ulcerosa (CU). No obstante, estudios recientes apuntan a cambios epidemiologicos. Nuestro objetivo es determinar si la epidemiologia, presentacion clinica y curso evolutivo de pacientes con CEP seguidos en un centro de referencia se asemejan a lo descrito en la literatura. Pacientes y metodos Busqueda retrospectiva de pacientes con diagnostico de CEP atendidos en nuestro centro entre los anos 2000 y 2019. Resultados Cohorte de 55 pacientes (media de edad: 37 anos), el 44% mujeres, afectos de CEP, el 79% de ducto grande. Casi dos tercios fueron diagnosticados a partir de 2011. En el momento del diagnostico, un 63% de los pacientes se encontraba asintomatico. La mediana de tiempo desde la sospecha hasta el diagnostico fue de 2 anos. Un 34% desarrollo cirrosis en el seguimiento, y un 25% requirio trasplante hepatico (TH) tras una media de tiempo de 7 anos; entre estos, la enfermedad recurrio en un 46%. Un 45% presentaba una enfermedad inflamatoria intestinal (EII), sobre todo CU. Si bien no se alcanzo significacion estadistica, la CEP en mujeres se caracterizo por mayor tasa de presentacion asintomatica, mayor asociacion con CU frente a otras formas de EII, asi como cirrosis al diagnostico y necesidad de TH con mayor frecuencia que los varones. Conclusiones La epidemiologia de la CEP esta cambiando. El numero de mujeres afectas es mayor al descrito previamente, objetivandose un aumento reciente de la incidencia. Podrian existir diferencias entre sexos en la forma de presentacion y evolucion que deberan confirmarse en estudios posteriores.

espanolEste articulo presenta la evolucion en la contratacion publica local en el ambito de los servicios de atencion a las personas en Barcelona, a partir de los cambios introducidos en la legislacion y codigos de buenas practicas que pretenden acciones positivas hacia la contratacion socialmente responsable. En este contexto, se describe la evolucion de la naturaleza juridica de los licitantes y los adjudicatarios, diferenciando entre empresas mercantiles y entidades del tercer sector, para examinar el posible vinculo entre los cambios mencionados y el tipo de licitador y adjudicatario. Para ello, se analizan los contratos en el ambito de los servicios de atencion a las personas realizados entre 2017 y 2019 por el ayuntamiento de Barcelona, institucion pionera en la introduccion de clausulas sociales, y se compara con otros siete municipios de Catalunya. Si bien los resultados no identifican una relacion positiva entre la introduccion de clausulas sociales con el aumento de las entidades del tercer sector entre los licitadores o los adjudicatarios en Barcelona, si que se aprecia una mayor exito de las entidades del tercer sector social en los casos que compiten con las empresas mercantiles. Ademas, el analisis identifico algunos factores que podrian mejorar las posibilidades de exito de estas entidades sin fines de lucro en los procesos de adjudicacion de estos servicios. EnglishThis article presents the evolution of local public procurement in the services to people in Barcelona, ​​based on the changes introduced in the legislation and codes of good practices that seek positive actions towards socially responsible procurement. In this context, the article examines the evolution of the legal nature of the bidders and the successful bidders, differentiating between capitalist enterprises and third-sector social entities, to determine possible linkage between the changes in the public procurmenent and the type of bidder and successful bidder. For this purpose all contracts in the field of services to people carried out from 2017 to 2019 by the Barcelona city council are analysed and we compare them with seven other municipalities of Catalonia. Despite the fact the results do not find a positive relationship between the introduction of social clauses and the increase in third sector entities among bidders or successful bidders, the third sector entities are more succesful when they compite against capitalist enterpreises in Barcelona. Moreover, the analysis identified some factors that could improve the chances of these non-profit entities to be a successful bidder.

Drug-induced liver injury (DILI) is an adverse toxic hepatic clinical reaction associated to the administration of a drug that can occur both at early clinical stages of drug development, as well after normal clinical usage of approved drugs. Because of its unpredictability and clinical relevance, it is of medical concern. Three DILI phenotypes (hepatocellular, cholestatic, and mixed) are currently recognized, based on serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values. However, this classification lacks accuracy to distinguish among the many intermediate mixed types, or even to estimate the magnitude and progression of the injury. It was found desirable to have additional elements for better evaluation criteria of DILI. With this aim, we have examined the serum metabolomic changes occurring in 79 DILI patients recruited and monitored using established clinical criteria, along the course of the disease and until recovery. Results revealed that free and conjugated bile acids, and glycerophospholipids were among the most relevant metabolite classes for DILI phenotype characterization. Using an ensemble of PLS–DA models, metabolomic information was integrated into a ternary diagram to display the disease phenotype, the severity of the liver damage, and its progression. The modeling implemented and the use of such compiled information in an easily understandable and visual manner facilitates a straightforward DILI phenotyping and allow to monitor its progression and recovery prediction, usefully complementing the concise information drawn out by the ALT and ALP classification. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03114-z.

A new coronavirus emerged in 2019 in Wuhan, China named Severe Acute Respiratory Syndrome type 2 coronavirus (SARS-CoV-2). Later, this virus spread worldwide, causing a disease called coronavirus disease (COVID-19). To control the outbreak, many countries announced mandatory quarantine; thus, people changed their lifestyles and started engaging in most activities from home. This review explains how some dermatological pathologies may be precipitated by prolonged stays at home, considering that quarantine was a widely used public health measure during 2020. Most of these dermatoses had to be seen, diagnosed, and treated through tele-dermatology, a remote health care system that took force during the COVID-19 pandemic because of its ease and efficiency in connecting health care professionals and their patients; therefore, reducing the risk of contagion and costs associated to medical care. This review of the principal dermatologic conditions during confinement could allow for a better preparation of health professionals.

Carbapenems are antibiotics of the cephalosporin family with a good penetrance into the central nervous system. Neurotoxicity is a rare adverse effect, most often associated with imipenem (0.4-10 %) and unusual with ertapenem. It usually presents as seizures, although encephalopathy or hallucinations may develop. However, a recent large study (n = 544) found neurotoxicity associated to the use of ertapenem with an incidence of 4.6 %. There were associated factors such as advanced age or renal dysfunction (ertapenem has a renal metabolism level of 80 %).

A transformação digital é um conceito cada vez mais presente nas instituições, não apenas como um processo que permite usar recursos tecnológicos para aumentar o desempenho organizacional, mas também como uma mudança cultural. O propósito deste estudo é analisar que transformações organizacionais, administrativas, tecnológicas e pedagógicas resultam da transformação digital das escolas e que impacto teve a pandemia de Covid-19 neste processo. Tendo em conta a complexidade e amplitude do tema, decidimos focar a investigação num estudo de caso num agrupamento de escolas. A recolha de dados baseou-se num modelo de triangulação, sendo a informação recolhida através de análise documental, de uma entrevista semiestruturada à diretora do agrupamento e de questionários aos docentes. A transformação digital no agrupamento em estudo já vinha a acontecer de forma gradual, na área administrativa e no apoio ao ensino nas salas de aula, com a necessidade de suspensão das atividades letivas devido à pandemia de Covid-19 a tecnologia ganhou um papel de destaque. Foi necessário organizar, reinventar e encontrar recursos para que escola não parasse e para que os alunos continuassem a aprender. O ensino remoto de emergência foi a alternativa possível, deixando em aberto para o futuro da escola possibilidades, experiências e conhecimento para um ensino mais digital. A capacitação do corpo docente é fundamental para uma atuação competente neste novo caminho. Este caminho da transformação digital está a ser feito, todavia ainda falta investimento tecnológico em equipamentos adequados e eficazes e formação de professores que dê resposta a este desafio. Digital transformation is a concept increasingly present in institutions, not only as a process that allows using technological resources to increase organizational performance, but also as a cultural change. The purpose of this study is to analyze what organizational, administrative, technological, and pedagogical transformations result from the digital transformation of schools and what impact the Covid-19 pandemic has had on this process. Given the complexity and breadth of the topic, we decided to focus the research on a case study in one school cluster. Data collection was based on a triangulation model, with information collected through document analysis, a semi-structured interview with the cluster's director, and questionnaires to teachers. The digital transformation in the school cluster under study was already happening gradually, in the administrative area and in supporting teaching in the classrooms, but with the need to suspend school activities due to the Covid-19 pandemic, technology gained a prominent role. It was necessary to organize, reinvent, and find resources so that school would not stop and students would continue to learn. Emergency remote teaching was the possible alternative, leaving open for the future of the school possibilities, experiences, and knowledge for a more digital education. Training the teaching staff is essential to perform competently on this new path. This path of digital transformation is being taken, however, there is still a lack of technological investment in adequate and effective equipment and teacher training to meet this challenge.

Anabolic–androgenic steroids are testosterone derivatives, used by body-builders to increase muscle mass. Epistane (EPI) is an orally administered 17α-alkylated testosterone derivative with 2a-3a epithio ring. We identified four individuals who, after EPI consumption, developed long-lasting cholestasis. The bile acid (BA) profile of three patients was characterized, as well the molecular mechanisms involved in this pathology. The serum BA pool was increased from 14 to 61-fold, basically on account of primary conjugated BA (cholic acid (CA) conjugates), whereas secondary BA were very low. In in vitro experiments with cultured human hepatocytes, EPI caused the accumulation of glycoCA in the medium. Moreover, as low as 0.01 μM EPI upregulated the expression of key BA synthesis genes (CYP7A1, by 65% and CYP8B1, by 67%) and BA transporters (NTCP, OSTA and BSEP), and downregulated FGF19. EPI increased the uptake/accumulation of a fluorescent BA analogue in hepatocytes by 50–70%. Results also evidenced, that 40 μM EPI trans-activated the nuclear receptors LXR and PXR. More importantly, 0.01 μM EPI activated AR in hepatocytes, leading to an increase in the expression of CYP8B1. In samples from a human liver bank, we proved that the expression of AR was positively correlated with that of CYP8B1 in men. Taken together, we conclude that EPI could cause cholestasis by inducing BA synthesis and favouring BA accumulation in hepatocytes, at least in part by AR activation. We anticipate that the large phenotypic variability of BA synthesis enzymes and transport genes in man provide a putative explanation for the idiosyncratic nature of EPI-induced cholestasis.

[Background & Aims] Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period., [Methods] Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected., [Results] A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974–0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994–0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy’s law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%)., [Conclusions] AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management., [Lay summary] Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes., The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, PI18/00901, PI18/01804, PI-0285-2016, PI-0274-2016, PI-0310-2018, PT17/0017/0020) and Agencia Española del Medicamento. CIBERehd and Plataforma ISCIII Ensayos Clinicos are funded by Instituto de Salud Carlos III. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) and JSC a Rio Hortega (CM17/00243) research contract from ISCIII and Consejería de Salud de Andalucía.

[Abstract] A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions. Ministerio de Economía y Empresa; IDI-20151125 Ministerio de Ciencia, Innovación y Universidades; SAF SAF 2017-87846-R

BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100-mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. At 100 &mu, M, BOLD-100 significantly reduced cell proliferation and expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gamma-H2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER&minus, ) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gamma-H2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER&minus, breast cancer.

Oestrogen receptor (ER)-positive breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of any targeted therapy often results in resistance to the therapy. Our ultimate goal is to use mathematical modelling to optimize alternating therapies that not only decrease proliferation but also stave off resistance. Toward this end, we measured levels of key proteins and proliferation over a 7-day time course in ER+ MCF-7 breast cancer cells. Treatments included endocrine therapy, either oestrogen deprivation, which mimics the effects of an aromatase inhibitor, or fulvestrant, an ER degrader. These data were used to calibrate a mathematical model based on key interactions between ER signalling and the cell cycle. We show that the calibrated model is capable of predicting the combination treatment of fulvestrant and oestrogen deprivation. Further, we show that we can add a new drug, palbociclib, to the model by measuring only two key proteins, cMyc and hyperphosphorylated RB1, and adjusting only parameters associated with the drug. The model is then able to predict the combination treatment of oestrogen deprivation and palbociclib. We illustrate the model's potential to explore protocols that limit proliferation and hold off resistance by not depending on any one therapy. Public Health Service grantUnited States Public Health Service [R01-CA201092, 1P30-CA-51008] This work was partly supported by Public Health Service grant R01-CA201092 to W.T.B. and A.N.S.-H. Technical services were provided by shared resources at Georgetown University Medical Center, including the Tissue Culture Core Shared Resource, that were funded through Public Health Service award 1P30-CA-51008 (Lombardi Comprehensive Cancer Center Support Grant).

Obeticholic acid (OCA) was recently approved as the only on-label alternative for patients with primary biliary cholangitis (PBC) with intolerance or suboptimal response to ursodeoxycholic acid (UDCA). However, few data are available outside clinical trials.To assess the effectiveness and safety of OCA in a real-world cohort of patients with non-effective UDCA therapy.Open-label, prospective, real-world, multicentre study, enrolling consecutive patients who did not meet Paris II criteria, from 18 institutions in Spain and Portugal. Effectiveness was assessed by the changes in GLOBE and UK-PBC scores from baseline. POISE and Paris II criteria were evaluated after 12 months of OCA . Liver fibrosis was evaluated by FIB-4 and AST to platelet ratio index (APRI).One hundred and twenty patients were eligible, median time since PBC diagnosis 9.3 (4.0-13.8) years, 21.7% had cirrhosis, and 26.7% received had previous or concomitant treatment with fibrates. Seventy-eight patients completed at least 1 year of OCA. The Globe-PBC score decreased to 0.17 (95% CI 0.05 to 0.28; P = 0.005) and the UK-PBC score decreased to 0.81 (95% CI -0.19 to 1.80; P = 0.11). There was a significant decrease in alkaline phosphatase of 81.3 U/L (95% CI 42.5 to 120; P 0.001), ALT 22.1 U/L (95% CI 10.4 to 33.8; P 0.001) and bilirubin 0.12 mg/dL (95% CI 0 to 0.24; P = 0.044). FIB-4 and APRI remained stable. According to the POISE criteria, 29.5% (23 out of 78) achieved response. The adverse events rate was 35%; 11.67% discontinued (8.3% due to pruritus).This study supports data from phase III trials with significant improvement of PBC-Globe continuous prognostic marker score among OCA-treated patients with good tolerability.

Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiovascular agents, steroids, and other miscellaneous drugs. The molecular mechanisms of DIC have been investigated since the 1980s but they remain debatable. It is recognised that altered expression and/or function of hepatobiliary membrane transporters underlies some forms of cholestasis, and this and other concomitant mechanisms are very likely in DIC. Deciphering these processes may pave the ways for diagnosis, prognosis and prevention, for which currently major gaps and caveats exist. In this review, we summarise recent advances in the field of DIC, including clinical aspects, the potential mechanisms postulated so far and the in vitro systems that can be useful to investigate and identify new cholestatic drugs.

La bibliométrica mide variables de la literatura científica que se describen de forma cuantitativa por medio de análisis estadístico; con esta herramienta se busca evidenciar el impacto de los trasplantes de células madre hematopoyéticas en la literatura de los últimos 45 años. Objetivo: Descripción de la literatura médica indexada en MEDLINE desde 1970 hasta 2015 sobre trasplantes de células madre hematopoyéticas. Metodología: Se realizó una búsqueda en la base de datos MEDLINE a través de GoPubMed y Fabumed. La estrategia de búsqueda fue: "Hematopoietic Stem Cell Transplantation"[Majr] AND "1970:2015"[dp]. Las variables analizadas fueron el número de publicaciones por año, revistas, países y porcentaje de publicaciones sobre trasplantes de células madre hematopoyéticas. Resultados: Se recuperaron 23,295 referencias sobre trasplantes de células madre hematopoyéticas. Se identificaron 1,844 revistas diferentes, el mayor número de publicaciones se encontró en Bone Marrow Transplantation con 2,443 publicaciones, seguida de Blood con 1,375 y Biology of Bone Marrow Transplantation con 1,319 referencias. Estados Unidos fue el país con mayor número de publicaciones con 7,491 (32.15%); en Latinoamérica fueron publicados 324 (1.39%). Los descriptores de la literatura más investigados relacionados con el tema fueron: Trasplante de células madre hematopoyéticas con 23,345 publicaciones, humanos con 22,019 y células madre con 17,564. Conclusiones: Las publicaciones sobre trasplantes de células madre hematopoyéticas han incrementado de forma progresiva durante los 45 años estudiados. Los países desarrollados son los que han realizado mayor investigación del tema, en contraste con el número de publicaciones en total. [Rios-Moreno JV, Bueno-Florez SJ, Conde-Hurtado DI, Tarazona N, Sossa-Melo Claudia Lucía. Estudio bibliométrico: 45 años de literatura biomédica en trasplante de células madre hematopoyéticas. MedUNAB 2017-2018; 20(3): 319-326]. Bibliometric measures variables from the scientific literature that are described quantitatively by means of statistical analysis; this tool seeks to demonstrate the impact of hematopoietic stem cell transplants in the literature throughout the last 45 years. Objective: To describe the indexed medical literature in MEDLINE from 1970 to 2015 on hematopoietic stem cell transplants. Methodology: A search of the MEDLINE database through GoPubMed and Fabumed was performed. The search strategy was: Hematopoietic Stem Cell Transplantation [Majr] and 1970:2015 [dp]. The variables analyzed were the number of publications per year, journals, countries and percentage of publications on hematopoietic stem cell transplants. Results: 23,295 references were recovered on hematopoietic stem cell transplants. 1,844 different journals were identified, the largest number of publications was found in Bone Marrow Transplantation with 2,443 publications, followed by Blood with 1,375 and Biology of Bone Marrow Transplantation with 1,319 references. The United States was the country with the highest number of publications with 7,491 (32.15%), in Latin America 324 (1.39%) were published. The most researched descriptors of literature related to the topic were: Transplantation of hematopoietic stem cells with 23,345 publications, humans with 22,019 and stem cells with 17,564. Conclusions: The publications on hematopoietic stem cell transplants have increased progressively during the 45 years studied. The developed countries are the ones that have done more research on the subject, in contrast to the number of publications in total. [Rios-Moreno JV, Bueno-Florez SJ, Conde-Hurtado DI, Tarazona N, Sossa-Melo Claudia Lucía. A Bibliometric Study: 45 Years of Biomedical Literature in Hematopoietic Stem Cell Transplantation. MedUNAB 2017-2018; 20(3): 319-326].

Reseña de: Paredes, Juan, Ensayos de literaturas románicas, Granada, Universidad de Granada, 2018, 422 pp.

Anabolic-androgenic steroids are testosterone derivatives, used by body-builders to increase muscle mass. Epistane (EPI) is an orally administered 17α-alkylated testosterone derivative with 2a-3a epithio ring. We identified four individuals who, after EPI consumption, developed long-lasting cholestasis. The bile acid (BA) profile of three patients was characterized, as well the molecular mechanisms involved in this pathology. The serum BA pool was increased from 14 to 61-fold, basically on account of primary conjugated BA (cholic acid (CA) conjugates), whereas secondary BA were very low. In in vitro experiments with cultured human hepatocytes, EPI caused the accumulation of glycoCA in the medium. Moreover, as low as 0.01 μM EPI upregulated the expression of key BA synthesis genes (CYP7A1, by 65% and CYP8B1, by 67%) and BA transporters (NTCP, OSTA and BSEP), and downregulated FGF19. EPI increased the uptake/accumulation of a fluorescent BA analogue in hepatocytes by 50-70%. Results also evidenced, that 40 μM EPI trans-activated the nuclear receptors LXR and PXR. More importantly, 0.01 μM EPI activated AR in hepatocytes, leading to an increase in the expression of CYP8B1. In samples from a human liver bank, we proved that the expression of AR was positively correlated with that of CYP8B1 in men. Taken together, we conclude that EPI could cause cholestasis by inducing BA synthesis and favouring BA accumulation in hepatocytes, at least in part by AR activation. We anticipate that the large phenotypic variability of BA synthesis enzymes and transport genes in man provide a putative explanation for the idiosyncratic nature of EPI-induced cholestasis.

Drug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.

Resumen La infeccion cronica por el virus de la hepatitis C (VHC) afecta a cerca de 150 millones de personas. Es una de las principales causas de morbimortalidad asociadas al higado por su relacion con el desarrollo de fibrosis hepatica, cirrosis y complicaciones por enfermedad hepatica avanzada. Los nuevos tratamientos basados en antivirales de accion directa han supuesto una nueva era en el tratamiento de la cirrosis por virus C. Estos permiten la erradicacion del virus, sin apenas efectos secundarios, en la gran mayoria de los pacientes cirroticos, consiguiendo asi una reduccion del riesgo de hepatocarcinoma, descompensacion hepatica y mortalidad. Este articulo, una actualizacion en la cirrosis por VHC, se centra en la relevancia de esta enfermedad y en los principales avances en el diagnostico, el seguimiento y el tratamiento de este subgrupo de pacientes.

Background & Aims: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. Methods: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. Results: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevirtr +dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p

High resolution LC-MS untargeted lipidomics using data independent acquisition (DIA) has the potential to increase lipidome coverage, as it enables the continuous and unbiased acquisition of all eluting ions. However, the loss of the link between the precursor and the product ions combined with the high dimensionality of DIA data sets hinder accurate feature annotation. Here, we present LipidMS, an R package aimed to confidently identify lipid species in untargeted LC-DIA-MS. To this end, LipidMS combines a coelution score, which links precursor and fragment ions with fragmentation and intensity rules. Depending on the MS evidence reached by the identification function survey, LipidMS provides three (ii) "fatty acyl level", e.g., PG(16:0_18:1); and (iii) "fatty acyl with freely available data dependent acquisition (DDA) and more accurate and structural informative lipid identifications. function survey, LipidMS provides three levels of structural annotations: (i) "subclass level", e.g., PG(34:1); (ii) "fatty acyl level", e.g., PG(16:0_18:1); and (iii) "fatty acyl position level", e.g., PG(16:0/18:1). The comparison of LipidMS with freely available data dependent acquisition (DDA) and DIA identification tools showed that LipidMS provides significantly more accurate and structural informative lipid identifications. Finally, to exemplify the utility of LipidMS, we investigated the lipidomic serum profile of patients diagnosed with nonalcoholic steatohepatitis (NASH), which is the progressive form of nonalcoholic fatty liver disease, a disorder underlying a strong lipid dysregulation. As previously published, a significant decrease in lysophosphatidylcholines, phosphatidylcholines and cholesterol esters and an increase in phosphatidylethanolamines were observed in NASH patients. Remarkably, LipidMS allowed the identification of a new set of lipids that may be used for NASH diagnosis. Altogether, LipidMS has been validated as a tool to assist lipid identification in the LC-DIA-MS untargeted analysis of complex biological samples.

In‐vitro studies suggest that electromagnetic interference can occur under specific conditions involving proximity between electronic dental equipment and pacemakers. At present, in‐vivo investigations to verify the effect of using electronic dental equipment in clinical conditions on patients with pacemakers are scarce. This study aimed to evaluate, in vivo, the effect of three commonly used electronic dental instruments – ultrasonic dental scaler, electric pulp tester, and electronic apex locator – on patients with different pacemaker brands and configurations. Sixty‐six consecutive non‐pacemaker‐dependent patients were enrolled during regular electrophysiology follow‐up visits. Electronic dental tools were operated while the pacemaker was interrogated, and the intracardiac electrogram and electrocardiogram were recorded. No interferences were detected in the intracardiac electrogram of any patient during the tests with dental equipment. No abnormalities in pacemaker pacing and sensing function were observed, and no differences were found with respect to the variables, pacemaker brands, pacemaker configuration, or mode of application of the dental equipment. Electromagnetic interferences affecting the surface electrocardiogram, but not the intracardiac electrogram, were found in 25 (37.9%) patients, especially while using the ultrasonic dental scaler; the intrinsic function of the pacemakers was not affected. Under real clinical conditions, none of the electronic dental instruments tested interfered with pacemaker function.

Liver biopsy is currently the only reliable method to establish nonalcoholic fatty liver disease (NAFLD) severity. However, this technique is invasive and occasionally associated with severe complications. Thus, non-invasive diagnostic markers for NAFLD are needed. Former studies have postulated 18 different serum microRNA biomarkers with altered levels in NAFLD patients. In the present study, we have re-examined the predictive value of these serum microRNAs and found that 9 of them (miR-34a, -192, -27b, -122, -22, -21, -197, -30c and -16) associated to NAFLD severity in our independent cohort. Moreover, miR-192, -27b, -22, -197 and -30c appeared specific for NAFLD, when compared with patients with drug-induced liver injury. Preliminary serum RNAseq analysis allowed identifying novel potential miRNA biomarkers for nonalcoholic steatohepatitis (NASH). The classification performance of validated miRNAs (and their ratios) for NASH was better than that reached by AST, whereas for advanced fibrosis prediction miRNAs did not perform better than the FIB-4 algorithm. Cross-validated models combining both clinical and miRNA variables showed enhanced predictivity. In conclusion, the circulating microRNAs validated demonstrate a better diagnostic potential than conventional serum markers to identify NASH patients and could complement and improve current fibrosis prediction algorithms. The research in this field is still open.

Background A reliable population screening strategy for hepatitis C virus (HCV) infection may be based in easy-to-use point-of-care (POC) tests for HCV antibodies, but validation data is needed before their potential widespread use in primary care or outreach practice. Besides, the sensitivity of these POC tests in patients with spontaneous or treatment-induced viral clearance is unknown. Objectives To test the performance of a non-invasive POC anti-HCV test (OraQuick HCV rapid test) in oral mucosal transudate (OMT) and fingerstick blood from patients with known anti-HCV serostatus and with or without active viremia (after treatment-induced clearance). Study design A risk factor questionnaire was collected from 317 consecutive patients (anti-HCV positive/HCV-RNA positive n = 107; anti-HCV positive/HCV-RNA negative after antiviral treatment n = 107; anti-HCV negative with other liver diseases n = 109) before performing the OraQuick HCV rapid test in OMT (n = 317) and fingerstick blood (n = 251). We calculated the sensitivity and specificity of the test by using anti-HCV serostatus as the reference gold-standard. Results Among all anti-HCV seropositive patients, the clinical sensitivity and specificity of the OraQuick HCV rapid test in OMT was 89.9% and 100%, respectively. In fingerstick blood, the sensitivity improved to 98.8%. The sensitivity was higher in OMT (97.2%) in anti-HCV seropositive patients who were viremic as compared to that in non-viremic individuals (82.2%). In contrast, there were no significant differences in sensitivity between viremic and non-viremic individuals when testing fingerstick blood. Finally, extension of the read time to 40 min enhanced the sensitivity, especially in OMT (up to 94.7%) and in the subgroup of non-viremic, anti-HCV-positive patients (up to 90.1%). Conclusions The OraQuick HCV rapid test in OMT has a high sensitivity and specificity for detecting active HCV infection that decreases substantially in anti-HCV positive/HCV-RNA negative patients with treatment-induced viral clearance. For these individuals, extension of read times and testing fingerstick blood showed improved sensitivity.

The association between cytomegalovirus (CMV) reactivation and cardiovascular risk has been reported in solid organ transplant populations; however, it has yet to be assessed in liver transplantation (LT). We aim to evaluate whether CMV reactivation is associated with cardiovascular events (CVE) in HCV-LT patients. LT patients (2010 and 2014) due to HCV cirrhosis were included. Clinically significant CMV (CS-CMV) was defined as viral load (VL) >5000 copies/ml, need of therapy or CMV disease. Baseline variables and endpoint measures (CVE, survival, severe recurrent hepatitis C, de novo tumors, and diabetes) were collected. One hundred and forty patients were included. At LT, a history of AHT was present in 23%, diabetes 22%, tobacco use 45%, obesity 20%, and renal impairment (eGFR < 60 ml/min) in 26.5%. CS-CMV reactivation occurred in 25% of patients. Twenty-six patients (18.5%) developed a CVE. Cox regression analysis revealed two factors significantly associated with CVE: Pre-LT DM [HR = 4.6 95% CI (1.6, 13), P = 0.004] and CS-CMV [HR = 4.7 95% CI (1.8, 12.5), P = 0.002]. CS-CMV was not independently associated with the remaining endpoints except for survival (P = 0.03). In our series, CS-CMV reactivation was associated with a greater risk of developing CVE, thus confirming data from other solid organ transplant populations and emphasizing the need for adequate CMV control.

About 70% of all breast cancer tumors are estrogen receptor positive (ER+) and are treated with antiestrogen therapies. While the inevitability of developing resistance to these therapies remains uncontested, little is known about the mechanism and prevention of resistance. Our ultimate goal is to use mathematical modeling to optimize dynamic therapies that decrease proliferation and stave off resistance. In this initial study, we used MCF7 cells as a model of ER+ breast cancer and estrogen deprivation as a surrogate for aromatase inhibitors. We developed long-term estrogen deprived MCF7s (LTEDs) that proliferate similarly to untreated MCF7s but are resistant to antiestrogens. We collected time-course data for simultaneous gene expression and protein levels (NanoString Pan Cancer panel, a non-amplification based digital method) over 6 weeks to capture early molecular adaptations of deprived MCF7s and compare them to those present in LTEDs. PCA analysis of the mRNA and protein data shows a dramatic change in the first component due to estrogen deprivation, and a dramatic change in the second component associated with long-term resistance. Correlation analysis shows a large number of cell cycle genes that are similarly regulated, decreasing with estrogen deprivation and increasing with the onset of resistance. There is also a highly-correlated group of genes associated with resistance. This knowledge allowed us to hypothesize a molecular mechanism for resistance that can be tested experimentally. To begin building a dynamic model, we measured a 7-day time course of estrogen related proteins. The model is built around ER signaling and the cell cycle, and simulates protein and proliferation changes in response to deprivation and antiestrogen (ICI182,780; ICI) treatment. To determine which treatments to model in addition to estrogen deprivation and ICI, we looked for a promising sequential therapy to limit proliferation and, hopefully, stave off resistance compared to a single non-stop therapy. We found that alternating the targeting of CDK4/6 using Palbociclib (clinical anti-cancer therapy) with targeting of RUNX1 (gene that is increased at the onset of resistance in our model), could be a plausible strategy to inhibit endocrine resistance. Future work will involve extending the model to longer time scales and using it for treatment optimization. Citation Format: Wei He, Diane M. Demas, Isabel Conde, Yassi Fallah, William T. Baumann, Ayesha N. Shajahan-Haq. Predicting cellular response to therapy in breast cancer using mathematical modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 674.

Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug induced steatosis. Methods: Human HepG2 cells were treated with drugs and changes in miRNA levels were measured by microarray and qRT-PCR. Drug-induced fat accumulation in HepG2 was analyzed by high-content screening and enzymatic methods, miRNA biomarkers were also analyzed in the sera of 44 biopsy proven NAFLD patients and in 10 controls. Results: We found a set of 10 miRNAs [miR-22-5p, -3929, -24-2-5p, -663a, -29a-3p, -21 (5p and 3p), -27a-5p, -1260 and -202-3p] that were induced in human HepG2 cells and secreted to the culture medium upon incubation with model steatotic drugs (valproate, doxycycline, cyclosporin A and tamoxifen). Moreover, cell exposure to 17 common drugs for NAFLD patients showed that some of them (e.g., irbesartan, fenofibrate, and omeprazole) also induced these miRNAs and increased intracellular triglycerides, particularly in combinations. Finally, we found that most of these miRNAs (60%) were detected in human serum, and that NAFLD patients under fibrates showed both induction of these miRNAs and a more severe steatosis grade. Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development. Moreover, most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis.

Understanding central mechanisms underlying drug-induced toxicity plays a crucial role in drug development and drug safety. However, a translation of cellular in vitro findings to an actual in vivo context remains challenging. Here, physiologically based pharmacokinetic (PBPK) modeling was used for in vivo contextualization of in vitro toxicity data (PICD) to quantitatively predict in vivo drug response over time by integrating multiple levels of biological organization. Explicitly, in vitro toxicity data at the cellular level were integrated into whole-body PBPK models at the organism level by coupling in vitro drug exposure with in vivo drug concentration–time profiles simulated in the extracellular environment within the organ. PICD was exemplarily applied on the hepatotoxicant azathioprine to quantitatively predict in vivo drug response of perturbed biological pathways and cellular processes in rats and humans. The predictive accuracy of PICD was assessed by comparing in vivo drug response predicted for rats with observed in vivo measurements. To demonstrate clinical applicability of PICD, in vivo drug responses of a critical toxicity-related pathway were predicted for eight patients following acute azathioprine overdoses. Moreover, acute liver failure after multiple dosing of azathioprine was investigated in a patient case study by use of own clinical data. Simulated pharmacokinetic profiles were therefore related to in vivo drug response predicted for genes associated with observed clinical symptoms and to clinical biomarkers measured in vivo. PICD provides a generic platform to investigate drug-induced toxicity at a patient level and thus may facilitate individualized risk assessment during drug development. Electronic supplementary material The online version of this article (doi:10.1007/s00204-016-1723-x) contains supplementary material, which is available to authorized users.

Recent studies indicated a role of microRNAs (miRNAs, small non-coding RNAs which regulate the expression of target genes by acting on mRNAs) in several neural processes, in the pathogenetic mechanisms of neuropsychiatric diseases and in the action of psychotropic drugs. A modulation induced by the antidepressant drug escitalopram on the expression levels of 30 miRNAs was highlighted in the blood of patients suffering from major depressive disorder. With the aim to investigate the effects of escitalopram in an in vitro model, we performed an analysis of the effects produced by escitalopram on the profiles of the 6 miRNAs found to be more significantly modulated in the above-mentioned study (miR-130b, miR-26a and -26b, let-7f, miR-770-5p, miR-34c-5p) in human U87 glioblastoma cells. Cells were treated with the drug for 24, 48 and 72h. The obtained results confirmed a significant increase of let-7f, both after 48 (p=0.031) and 72h (p=0.022), and of miR-26a after 48h (p=0.032). On the same experimental model, a transcriptome analysis was conducted after 72h, highlighting a drug-induced modulation of 1184 protein-coding genes, 207 of which represent let-7f targets. Particularly interesting was the downregulation of BCOR, CCND1 and ATR, validated let-7f targets, which play a key role in the mechanisms of neurogenesis, neuroplasticity and protection from oxidative stress in the brain, indicating that escitalopram could exert downstream effects on gene expression through the regulation of specific miRNAs.

Chronic hepatitis C virus (HCV) infection affects around 150 million people. It is a leading cause of liver related morbidity and mortality through its predisposition to liver fibrosis, cirrhosis and end-stage liver complications. New treatments based on direct-acting antivirals have opened a new era in the management of HCV cirrhosis. They allow for HCV eradication without substantial side effects in almost all cirrhotic patients, reducing the risk of hepatocellular carcinoma, liver decompensation and mortality. This review provides an update on HCV cirrhosis. The paper focuses on the disease burden and major progresses in the diagnosis, follow-up and treatment of this patient subgroup.

IT-139 is a novel small-molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity as a monotherapy in a phase I clinical trial. A high affinity for albumin and unique chemistry allow increased uptake and activation of IT-139 within tumor cells, respectively. To date, IT-139 has been reported to inhibit the endoplasmic reticulum stress-sensing protein GRP78. However, different cancer cells show disparate responses to IT-139 and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that IT-139 induces cytostatic rather than cytotoxic effects as a monotherapy. In this study, to understand IT-139 mediated signaling mechanism in breast cancer cells, we used estrogen receptor-positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models following IT-139 treatment (10 or 100 μM for 72 h). Our data showed that IT-139 significantly reduced expression of genes involved in the DNA repair pathway, including BRCA1 and RAD51, following treatment with IT-139 in MCF7 cells. Validation of our findings in other breast cancer cell lines including MDA-MB-175 (ER+), MDA-MB-231 and MDA-MB-468 (both ER-) cells also showed increased phosphorylation of H2AX (Ser139) following IT-139 treatment, suggesting lack of proper DNA surveillance and subsequent accumulation of DNA double-stranded breaks (DSB). Consequently, we investigated the effects of combination treatment approaches with IT-139 and other clinical anticancer therapies that interfere with nucleotide synthesis or DNA damage repair pathways, particularly in ER- breast cancers. Our data showed additive effects of IT-139 in combination with capecitabine (5-FU prodrug) or olaparib (PARP inhibitor) and a synergistic effect with carboplatin in ER- breast cancer cell lines. Further analysis of IT-139 mediated signal transduction in breast cancer cells will reveal whether it can be combined with aforementioned chemotherapies to circumvent resistance. Citation Format: Isabel Conde, Yassi Fallah, Diane Demas, Suzanne Bakewell, Filipa Lynce, Ayesha N. Shajahan-Haq. Inhibition of DNA repair pathways in breast cancer is a potential mechanism of action of IT-139 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2862.

22 p.-7 fig., Megakaryocytic differentiation of myelogenous leukemia cell lines induced by a number of chemical compounds mimics, in part, the physiological process that takes place in the bone marrow in response to a variety of stimuli. We have investigated the involvement of mitogen-activated protein kinases (MAPKs) [extracellular signal-regulated protein kinase (ERK1/2) and p38] and phosphoinositide 3-kinase (PI3K) signaling pathways in the differentiated phenotypes of K562 cells promoted by phorbol 12-myristate 13-acetate, staurosporine (STA), and the p38 MAPK inhibitor SB202190. In our experimental conditions, only STA-treated cells showed the phenotype of mature megakaryocytes (MKs) including GPIbα expression, DNA endoreduplication, and formation of platelet-like structures. We provide evidence supporting that basal activity, but not sustained activation, of ERK1/2 is required for expression of MK surface markers. Moreover, ERK1/2 signaling is not involved in cell endomitosis. The PI3K pathway exerts dual regulatory effects on K562 cell differentiation: it is intimately connected with ERK1/2 cascade to stimulate expression of surface markers and it is also necessary, but not sufficient, for polyploidization. Finally, apoptosis and megakaryocytic differentiation exhibit different sensitivity to p38 down-regulation: it is required for expression of early specific markers but is not involved in cell apoptosis. The present work with K562 cells provides new insights into the molecular mechanisms regulating MK differentiation. The results indicate that a precise orchestration of signals, including ERK1/2 and p38 MAPKs as well as PI3K pathway, is necessary for acquisition of features of mature MKs., This work was supported by grants from the Dirección General de Investigación del Ministerio de Educación y Ciencia (BMC2003-01409 and BFU2006-00914). A. Jayo was recipient of a fellowship from the Ministerio de Educación y Ciencia. I. Conde holds a research contract from the Consejo Superior de Investigaciones Científicas