Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance

The Impact of Ischemia Assessed by Magnetic Resonance on Functional, Arrhythmic, and Imaging Features of Hypertrophic Cardiomyopathy

Funding: LL is supported by an MRC UK clinical academic partnership award (CARP) MR/T005181/1.publishersversionpublishe

A Structural Equations Modeling Approach

COVID-19 vaccine hesitancy (VH) has caused concerns due to the possible fluctuations that may occur directly impacting the control of the pandemic. In this study, we aimed to estimate the prevalence and factors associated with COVID-19 VH in Portuguese-speaking countries. We developed a web survey (N:6,843) using an online, structured, and validated questionnaire. We used Measurement Models, Exploratory Factor Analysis, Exploratory Structural Equation Models, and Confirmatory Factor Analysis for the data analysis. The overall prevalence of COVID-19 VH in Portuguese-speaking countries was 21.1%. showed a statistically significant direct effect for VH: vaccine-related conspiracy beliefs (VB) (β = 0.886), perceived stress (PS) (β = 0.313), COVID-19 Misinformation (MIS) (β = 0.259) and individual responses to COVID-19 (CIR) (β = −0.122). The effect of MIS and CIR for VH was greater among men and of PS and VB among women; the effect of PS was greater among the youngest and of VB and CIR among the oldest. No discrepant differences were identified in the analyzed education strata. In conclusion, we found that conspiracy beliefs related to the vaccine strongly influence the decision to hesitate (not to take or to delay the vaccine). Specific characteristics related to gender, age group, social and cognitive vulnerabilities, added to the knowledge acquired, poorly substantiated and/or misrepresented about the COVID-19 vaccine, need to be considered in the planning of vaccination campaigns. It is necessary to respond in a timely, fast, and accurate manner to the challenges posed by vaccine hesitancy.publishersversionpublishe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

práticas artísticas no ensino básico e secundário

Educação Artística: integrar a inovação. A educação artística apresenta-se como um território a re-cartografar, numa atualização tão rápida quanto aquela que ocorre no campo artístico. As propostas publicadas neste número 11 da Revista Matéria-Prima trazem essa diversidade de abordagens, com novidades conceptuais que estabelecem as devidas relações entre educação e cidadania, participação, sustentabilidade, cultura visual, e também com alguma atenção sobre os debates pós-coloniais e as questões de género. Os 16 artigos reunidos neste 11º número da Revista Matéria-Prima trazem a realidade operativa quer na formação de professores e quer na formulação dos discursos pedagógicos, suas justificações e suas propostas alternativas.As propostas apresentadas devolvem o debate ao terreno, e alargam-no. Provocam as periferias, convocam abordagens diferenciadas sobre o tema da arte e da educação. Em todas elas a proposta de crescimento através da arte, que hoje implica cada vez mais cidadania, crítica, criatividade, interligação, comprometimento, participação.info:eu-repo/semantics/publishedVersio

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Estudios de Caso sobre Ciencias Agropecuarias y Rurales en el siglo XXI.

Libro científico sobre estudios de casos en el medio agropecuario y ruralCon el advenimiento del siglo XXI y el avance de los procesos de globalización, el medio rural presenta diversos cambios económicos, sociales, políticos y culturales. Lo anterior significa que el campo es un objeto de estudio altamente dinámico, complejo e inasible. las ciencias agropecuarias y rurales, en la actualidad, requieren de un abordaje sistémico e interdisciplinario que den cuenta de la heterogeneidad de situaciones y contextos que enfrenta el campo mexicano. La presente obra agrupa 18 estudios de caso, que capturan algunas fotografías de las diversas problemáticas de la ruralidad mexicana, con lo cual se pretende dar cuenta tanto de los objetivos de estudio como de la perspectiva teórico metodológico desde que estos son abordados. lo anterior tiene que ver con el hecho de que las ciencias agropecuarias y rurales manifiestan un alto grado de observación empírica, motivo por el que los estudios de caso se convierten en la perspectiva metodológica idónea que permite ir y venir de la realidad a la teoría y viceversa para la construcción de objetos de estudio. En este volumen se aborda una gran diversidad de casos, que sintetizan la heterogeneidad de enfoques y perspectivas mediante las cuales los fenómenos agropecuarios y rurales han sido abordados en el Instituto de Ciencias Agropecuarias y Rurales de la Universidad Autónoma del Estado de México, en los últimos 30 años

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat