Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.

Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer. Objectives: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors. Methods: FHIT immunostaining was performed on 305 tumor samples. Themethylation status of FHIT promoterwas assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples ofwhich a subset of 187 patients had available normal/tumorDNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers. Measurements and Main Results: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7%of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was presentwhenmethylation and LOHwere analyzed together (P5 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P , 0.0001) and in smokers (P5 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P 5 0.0415). Conclusions:Our results indicate thatdifferentmolecularmechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease

Virtual Multidisciplinary Tumor Boards: A Narrative Review Focused on Lung Cancer

To date, the virtual multidisciplinary tumor boards (vMTBs) are increasingly used to achieve high-quality treatment recommendations across health-care regions, which expands and develops the local MTB team to a regional or national expert network. This review describes the process of lung cancer-specific MTBs and the transition process from face-to-face tumor boards to virtual ones. The review also focuses on the project organization's description, advantages, and disadvantages. Semi-structured interviews identified five major themes for MTBs: current practice, attitudes, enablers, barriers, and benefits for the MTB. MTB teams exhibited positive responses to modeled data feedback. Virtualization reduces time spent for travel, allowing easier and timely patient discussions. This process requires a secure web platform to assure the respect of patients’ privacy and presents the same unanswered problems. The implementation of vMTB also permits the implementation of networks especially in areas with geographical barriers facilitating interaction between large referral cancer centers and tertiary or community hospitals as well as easier access to clinical trial opportunities. Studies aimed to improve preparations, structure, and conduct of MTBs, research methods to monitor their performance, teamwork, and outcomes are also outlined in this article. Analysis of literature shows that MTB participants discuss 5–8 cases per meeting and that the use of a vMTB for lung cancer and in particular stage III NSCLC and complex stage IV cases is widely accepted by most health professionals. Despite still-existing gaps, overall vMTB represents a unique opportunity to optimize patient management in a patient-centered approach

Genomic signatures of selection associated with benzimidazole drug treatments in Haemonchus contortus field populations

Genome-wide methods offer a powerful approach to detect signatures of drug selection. However, limited availability of suitable reference genomes and the difficulty of obtaining field populations with well-defined, distinct drug treatment histories mean there is little information on the signatures of selection in parasitic nematodes and on how best to detect them. This study addresses these knowledge gaps by using field populations of Haemonchus contortus with well-defined benzimidazole treatment histories, leveraging a recently completed chromosomal-scale reference genome assembly. We generated a panel of 49,393 genomic markers to genotype 20 individual adult worms from each of four H. contortus populations: two from closed sheep flocks with an approximate 20 year history of frequent benzimidazole treatment, and two populations with a history of little or no treatment. Sampling occurred in the same geographical region to limit genetic differentiation and maximise the detection sensitivity. A clear signature of selection was detected on chromosome I, centred on the isotype-1 β-tubulin gene. Two additional, but weaker, signatures of selection were detected; one near the middle of chromosome I spanning 3.75 Mbp and 259 annotated genes, and one on chromosome II spanning a region of 3.3 Mbp and 206 annotated genes, including the isotype-2 β-tubulin locus. We also assessed how sensitivity was impacted by sequencing depth, worm number, and pooled versus individual worm sequence data. This study provides the first known direct genome-wide evidence for any parasitic nematode, that the isotype-1 β-tubulin gene is quantitatively the single most important benzimidazole resistance locus. It also identified two additional genomic regions that likely contain benzimidazole resistance loci of secondary importance. This study provides an experimental framework to maximise the power of genome-wide approaches to detect signatures of selection driven by anthelmintic drug treatments in field populations of parasitic nematodes

The genome and transcriptome of Haemonchus contortus, a key model parasite for drug and vaccine discovery

<p>Background: The small ruminant parasite Haemonchus contortus is the most widely used parasitic nematode in drug discovery, vaccine development and anthelmintic resistance research. Its remarkable propensity to develop resistance threatens the viability of the sheep industry in many regions of the world and provides a cautionary example of the effect of mass drug administration to control parasitic nematodes. Its phylogenetic position makes it particularly well placed for comparison with the free-living nematode Caenorhabditis elegans and the most economically important parasites of livestock and humans.</p> <p>Results: Here we report the detailed analysis of a draft genome assembly and extensive transcriptomic dataset for H. contortus. This represents the first genome to be published for a strongylid nematode and the most extensive transcriptomic dataset for any parasitic nematode reported to date. We show a general pattern of conservation of genome structure and gene content between H. contortus and C. elegans, but also a dramatic expansion of important parasite gene families. We identify genes involved in parasite-specific pathways such as blood feeding, neurological function, and drug metabolism. In particular, we describe complete gene repertoires for known drug target families, providing the most comprehensive understanding yet of the action of several important anthelmintics. Also, we identify a set of genes enriched in the parasitic stages of the lifecycle and the parasite gut that provide a rich source of vaccine and drug target candidates.</p> <p>Conclusions: The H. contortus genome and transcriptome provides an essential platform for postgenomic research in this and other important strongylid parasites. </p&gt

Substantial and sustained reduction in under-5 mortality, diarrhea, and pneumonia in Oshikhandass, Pakistan : Evidence from two longitudinal cohort studies 15 years apart

Funding Information: Study 1 was funded through the Applied Diarrheal Disease Research Program at Harvard Institute for International Development with a grant from USAID (Project 936–5952, Cooperative Agreement # DPE-5952-A-00-5073-00), and the Aga Khan Health Service, Northern Areas and Chitral, Pakistan. Study 2 was funded by the Pakistan US S&T Cooperative Agreement between the Pakistan Higher Education Commission (HEC) (No.4–421/PAK-US/HEC/2010/955, grant to the Karakoram International University) and US National Academies of Science (Grant Number PGA-P211012 from NAS to the Fogarty International Center). The funding bodies had no role in the design of the study, data collection, analysis, interpretation, or writing of the manuscript. Publisher Copyright: © 2020 The Author(s).Peer reviewedPublisher PD

Tratamientos Psicológicos Empíricamente Apoyados Para Adultos: Una Revisión Selectiva [Evidence-Based Psychological Treatments for Adults: A Selective Review]

Antecedentes: los tratamientos psicológicos han mostrado su efi cacia, efectividad y efi ciencia para el abordaje de los trastornos mentales; no obstante, considerando el conocimiento científi co generado en los últimos años, no se dispone de trabajos de actualización en español sobre cuáles son los tratamientos psicológicos con respaldo empírico. El objetivo fue realizar una revisión selectiva de los principales tratamientos psicológicos empíricamente apoyados para el abordaje de trastornos mentales en personas adultas. Método: se recogen niveles de evidencia y grados de recomendación en función de los criterios propuestos por el Sistema Nacional de Salud de España (en las Guías de Práctica Clínica) para diferentes trastornos psicológicos. Resultados: los resultados sugieren que los tratamientos psicológicos disponen de apoyo empírico para el abordaje de un amplio elenco de trastornos psicológicos. El grado de apoyo empírico oscila de bajo a alto en función del trastorno psicológico analizado. La revisión sugiere que ciertos campos de intervención necesitan una mayor investigación. Conclusiones: a partir de esta revisión selectiva, los profesionales de la psicología podrán disponer de información rigurosa y actualizada que les permita tomar decisiones informadas a la hora de implementar aquellos procedimientos psicoterapéuticos empíricamente fundamentados en función de las características de las personas que demandan ayuda. // Evidence-Based Psychological Treatments for Adults: A Selective Review. Background: Psychological treatments have shown their effi cacy, effectiveness, and effi ciency in dealing with mental disorders. However, considering the scientifi c knowledge generated in recent years, in the Spanish context, there are no updating studies about empirically supported psychological treatments. The main goal was to carry out a selective review of the main empirically supported psychological treatments for mental disorders in adults. Method: Levels of evidence and degrees of recommendation were collected based on the criteria proposed by the Spanish National Health System (Clinical Practice Guidelines) for different psychological disorders. Results: The results indicate that psychological treatments have empirical support for the approach to a wide range of psychological disorders. These levels of empirical evidence gathered range from low to high depending on the psychological disorder analysed. The review indicates the existence of certain fi elds of intervention that need further investigation. Conclusions: Based on this selective review, psychology professionals will be able to have rigorous, up-to-date information that allows them to make informed decisions when implementing empirically based psychotherapeutic procedures based on the characteristics of the people who require help

Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile

© 2016 The Author(s)The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation. This phenomenon reduces many unique hepatocyte functions, limiting their use in drug disposition and toxicity assessment. The aetiology of dedifferentiation has not been well defined, and further understanding of the process would allow the development of novel strategies for sustaining the hepatocyte phenotype in culture or for improving protocols for maturation of hepatocytes generated from stem cells. We have therefore carried out the first proteomic comparison of primary human hepatocyte differentiation. Cells were cultured for 0, 24, 72 and 168 h as a monolayer in order to permit unrestricted hepatocyte dedifferentiation, so as to reveal the causative signalling pathways and factors in this process, by pathway analysis. A total of 3430 proteins were identified with a false detection rate of <1 %, of which 1117 were quantified at every time point. Increasing numbers of significantly differentially expressed proteins compared with the freshly isolated cells were observed at 24 h (40 proteins), 72 h (118 proteins) and 168 h (272 proteins) (p < 0.05). In particular, cytochromes P450 and mitochondrial proteins underwent major changes, confirmed by functional studies and investigated by pathway analysis. We report the key factors and pathways which underlie the loss of hepatic phenotype in vitro, particularly those driving the large-scale and selective remodelling of the mitochondrial and metabolic proteomes. In summary, these findings expand the current understanding of dedifferentiation should facilitate further development of simple and complex hepatic culture systems

The motivations for the adoption of management innovation by local governments and its performance effects

This article analyses the economic, political and institutional antecedents and performance effects of the adoption of shared Senior Management Teams (SMTs) – a management innovation (MI) that occurs when a team of senior managers oversees two or more public organizations. Findings from statistical analysis of 201 English local governments and interviews with organizational leaders reveal that shared SMTs are adopted to develop organisational capacity in resource‐challenged, politically risk‐averse governments, and in response to coercive and mimetic institutional pressures. Importantly, sharing SMTs may reduce rather than enhance efficiency and effectiveness due to redundancy costs and the political transaction costs associated with diverting resources away from a high‐performing partner to support their lower‐performing counterpart