The homeobox gene HLXB9 is upregulated in a morphological subset of poorly differentiated hepatocellular carcinoma

The prognostic outcome for hepatocellular carcinoma (HCC) remains poor. Disease progression is accompanied by dedifferentiation of the carcinoma, a process that is not well understood. The aim of this study was to get more insight into the molecular characteristics of dedifferentiated carcinomas using high throughput techniques. Microarray-based global gene expression analysis was performed on five poorly differentiated HCC cell lines compared with non-neoplastic hepatic controls and a set of three cholangiolar carcinoma (CC) cell lines. The gene with the highest upregulation was HLXB9. HLXB9 is a gene of the homeobox genfamily important for the development of the pancreas. RT-PCR confirmed the upregulation of HLXB9 in surgical specimens of carcinoma tissue, suggesting its biological significance. Interestingly, HLXB9 upregulation was primary observed in poorly differentiated HCC with a pseudoglandular pattern compared with a solid pattern HCC or in moderate or well-differentiated HCC. Additional the expression of translated HLXB9, the protein HB9 (NCBI: NP_001158727), was analyzed by western blotting. Expression of HB9 was only detected in the cytoplasm but not in the nuclei of the HCC cells. For validation CC were also investigated. Again, we found an upregulation of HLXB9 in CC cells accompanied by an expression of HB9 in the cytoplasms of these tumor cells, respectively. In conclusion, homeobox HLXB9 is upregulated in poorly differentiated HCC with a pseudoglandular pattern. The translated HB9 protein is found in the cytoplasm of these HCC and CC. We therefore assume HLXB9 as a possible link in the understanding of the development of HCC and CC, respectivel

The influence of above-ground herbivory on the response of arctic soil methanotrophs to increasing ch4 concentrations and temperatures

Rising temperatures in the Arctic affect soil microorganisms, herbivores, and peatland vegetation, thus directly and indirectly influencing microbial CH4 production. It is not currently known how methanotrophs in Arctic peat respond to combined changes in temperature, CH4 concentration, and vegetation. We studied methanotroph responses to temperature and CH4 concentration in peat exposed to herbivory and protected by exclosures. The methanotroph activity was assessed by CH4 oxidation rate measurements using peat soil microcosms and a pure culture of Methylobacter tundripaludum SV96, qPCR, and sequencing of pmoA transcripts. Elevated CH4 concentrations led to higher CH4 oxidation rates both in grazed and exclosed peat soils, but the strongest response was observed in grazed peat soils. Furthermore, the relative transcriptional activities of different methanotroph community members were affected by the CH4 concentrations. While transcriptional responses to low CH4 concentrations were more prevalent in grazed peat soils, responses to high CH4 concentrations were more prevalent in exclosed peat soils. We observed no significant methanotroph responses to increasing temperatures. We conclude that methanotroph communities in these peat soils respond to changes in the CH4 concentration depending on their previous exposure to grazing. This “conditioning” influences which strains will thrive and, therefore, determines the function of the methanotroph community

Real-life data from standardized preanalytical coding (SPREC) in tissue biobanking and its dual use for sample characterization and process optimization.

The standardized preanalytical code (SPREC) aggregates warm ischemia (WIT), cold ischemia (CIT), and fixation times (FIT) in a precise format. Despite its growing importance underpinned by the European in vitro diagnostics regulation or broad preanalytical programs by the National Institutes of Health, little is known about its empirical occurrence in biobanked surgical specimen. In several steps, the Tissue Bank Bern achieved a fully informative SPREC code with insights from 10,555 CIT, 4,740 WIT, and 3,121 FIT values. During process optimization according to LEAN six sigma principles, we identified a dual role of the SPREC code as a sample characteristic and a traceable process parameter. With this preanalytical study, we outlined real-life data in a variety of organs with specific differences in WIT, CIT, and FIT values. Furthermore, our FIT data indicate the potential to adapt the SPREC fixation toward concrete paraffin-embedding time points and to extend its categories beyond 72 h due to weekend delays. Additionally, we identified dependencies of preanalytical variables from workload, daytime, and clinics that were actionable with LEAN process management. Thus, streamlined biobanking workflows during the day were significantly resilient to workload peaks, diminishing the turnaround times of native tissue processing (i.e. CIT) from 74.6 to 46.1 min under heavily stressed conditions. In conclusion, there are surgery-specific preanalytics that are surgico-pathologically limited even under process optimization, which might affect biomarker transfer from one entity to another. Beyond sample characteristics, SPREC coding is highly beneficial for tissue banks and Institutes of Pathology to track WIT, CIT, and FIT for process optimization and monitoring measurements

Involvement of patients or their representatives in quality management functions in EU hospitals:implementation and impact on patient-centred care strategies

OBJECTIVE: The objective of this study was to describe the involvement of patients or their representatives in quality management (QM) functions and to assess associations between levels of involvement and the implementation of patient-centred care strategies. DESIGN: A cross-sectional, multilevel STUDY DESIGN: that surveyed quality managers and department heads and data from an organizational audit. SETTING: Randomly selected hospitals (n = 74) from seven European countries (The Czech Republic, France, Germany, Poland, Portugal, Spain and Turkey). PARTICIPANTS: Hospital quality managers (n = 74) and heads of clinical departments (n = 262) in charge of four patient pathways (acute myocardial infarction, stroke, hip fracture and deliveries) participated in the data collection between May 2011 and February 2012. MAIN OUTCOME MEASURES: Four items reflecting essential patient-centred care strategies based on an on-site hospital visit: (1) formal survey seeking views of patients and carers, (2) written policies on patients' rights, (3) patient information literature including guidelines and (4) fact sheets for post-discharge care. The main predictors were patient involvement in QM at the (i) hospital level and (ii) pathway level. RESULTS: Current levels of involving patients and their representatives in QM functions in European hospitals are low at hospital level (mean score 1.6 on a scale of 0 to 5, SD 0.7), but even lower at departmental level (mean 0.6, SD 0.7). We did not detect associations between levels of involving patients and their representatives in QM functions and the implementation of patient-centred care strategies; however, the smallest hospitals were more likely to have implemented patient-centred care strategies. CONCLUSIONS: There is insufficient evidence that involving patients and their representatives in QM leads to establishing or implementing strategies and procedures that facilitate patient-centred care; however, lack of evidence should not be interpreted as evidence of no effect

ELM—the database of eukaryotic linear motifs

Linear motifs are short, evolutionarily plastic components of regulatory proteins and provide low-affinity interaction interfaces. These compact modules play central roles in mediating every aspect of the regulatory functionality of the cell. They are particularly prominent in mediating cell signaling, controlling protein turnover and directing protein localization. Given their importance, our understanding of motifs is surprisingly limited, largely as a result of the difficulty of discovery, both experimentally and computationally. The Eukaryotic Linear Motif (ELM) resource at http://elm.eu.org provides the biological community with a comprehensive database of known experimentally validated motifs, and an exploratory tool to discover putative linear motifs in user-submitted protein sequences. The current update of the ELM database comprises 1800 annotated motif instances representing 170 distinct functional classes, including approximately 500 novel instances and 24 novel classes. Several older motif class entries have been also revisited, improving annotation and adding novel instances. Furthermore, addition of full-text search capabilities, an enhanced interface and simplified batch download has improved the overall accessibility of the ELM data. The motif discovery portion of the ELM resource has added conservation, and structural attributes have been incorporated to aid users to discriminate biologically relevant motifs from stochastically occurring non-functional instance

Pretreatment CD4 Cell Slope and Progression to AIDS or Death in HIV-Infected Patients Initiating Antiretroviral Therapy—The CASCADE Collaboration: A Collaboration of 23 Cohort Studies

Analyzing data from several thousand cohort study participants, Marcel Wolbers and colleagues find that the rate of CD4 T cell decline is not useful in deciding when to start HIV treatment

Involvement of patients or their representatives in quality management functions in EU hospitals : Implementation and impact on patient-centred care strategies

The study, "Deepening our Understanding of Quality Improvement in Europe (DUQuE)" has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 241822. Funding to pay the Open Access publication charges for this article was provided by European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 241822.Objective: The objective of this study was to describe the involvement of patients or their representatives in quality management (QM) functions and to assess associations between levels of involvement and the implementation of patient-centred care strategies. Design: A cross-sectional, multilevel study design that surveyed quality managers and department heads and data from an organizational audit. Setting: Randomly selected hospitals (n = 74) from seven European countries (The Czech Republic, France, Germany, Poland, Portugal, Spain and Turkey). Participants: Hospital qualitymanagers (n = 74) and heads of clinical departments (n = 262) in charge of four patient pathways (acute myocardial infarction, stroke, hip fracture and deliveries) participated in the data collection between May 2011 and February 2012. Main Outcome Measures: Four items reflecting essential patient-centred care strategies based on an on-site hospital visit: (1) formal survey seeking views of patients and carers, (2) written policies on patients' rights, (3) patient information literature including guidelines and (4) fact sheets for post-discharge care. The main predictors were patient involvement in QM at the (i) hospital level and (ii) pathway level. Results: Current levels of involving patients and their representatives in QM functions in European hospitals are low at hospital level (mean score 1.6 on a scale of 0 to 5, SD 0.7), but even lower at departmental level (mean 0.6, SD 0.7). We did not detect associations between levels of involving patients and their representatives in QM functions and the implementation of patient-centred care strategies; however, the smallest hospitals were more likely to have implemented patient-centred care strategies. Conclusions: There is insufficient evidence that involving patients and their representatives in QM leads to establishing or implementing strategies and procedures that facilitate patient-centred care; however, lack of evidence should not be interpreted as evidence of no effect

Supportive care for older people with frailty in hospital: An integrative review

BACKGROUND: Growing numbers of older people living with frailty and chronic health conditions are being referred to hospitals with acute care needs. Supportive care is a potentially highly relevant and clinically important approach which could bridge the practice gap between curative models of care and palliative care. However, future interventions need to be informed and underpinned by existing knowledge of supportive care. AIM: To identify and build upon existing theories and evidence about supportive care, specifically in relation to the hospital care of older people with frailty, to inform future interventions and their evaluation. DESIGN: An integrative review was used to identify and integrate theory and evidence. Electronic databases (Cochrane Medline, EMBASE and CIHAHL) were searched using the key term 'supportive care'. Screening identified studies employing qualitative and/or quantitative methods published between January 1990 and December 2015. Citation searches, reference checking and searches of the grey literature were also undertaken. DATA SOURCES: Literature searches identified 2733 articles. After screening, and applying eligibility criteria based on relevance to the research question, studies were subject to methodological quality appraisal. Findings from included articles (n=52) were integrated using synthesis of themes. RESULTS: Relevant evidence was identified across different research literatures, on clinical conditions and contexts. Seven distinct themes of the synthesis were identified, these were: Ensuring fundamental aspects of care are met, Communicating and connecting with the patient, Carer and family engagement, Building up a picture of the person and their circumstances, Decisions and advice about best care for the person, Enabling self-help and connection to wider support, and Supporting patients through transitions in care. A tentative integrative model of supportive care for frail older people is developed from the findings. CONCLUSION: The findings and model developed here will inform future interventions and can help staff and hospital managers to develop appropriate strategies, staff training and resource allocation models to improve the quality of health care for older people

Deciphering the modulation of gene expression by type I and II interferons combining 4sU-tagging, translational arrest and in silico promoter analysis

Interferons (IFN) play a pivotal role in innate immunity, orchestrating a cell-intrinsic anti-pathogenic state and stimulating adaptive immune responses. The complex interplay between the primary response to IFNs and its modulation by positive and negative feedback loops is incompletely understood. Here, we implement the combination of high-resolution gene-expression profiling of nascent RNA with translational inhibition of secondary feedback by cycloheximide. Unexpectedly, this approach revealed a prominent role of negative feedback mechanisms during the immediate (≤60 min) IFNα response. In contrast, a more complex picture involving both negative and positive feedback loops was observed on IFNγ treatment. IFNγ-induced repression of genes associated with regulation of gene expression, cellular development, apoptosis and cell growth resulted from cycloheximide-resistant primary IFNγ signalling. In silico promoter analysis revealed significant overrepresentation of SP1/SP3-binding sites and/or GC-rich stretches. Although signal transducer and activator of transcription 1 (STAT1)-binding sites were not overrepresented, repression was lost in absence of STAT1. Interestingly, basal expression of the majority of these IFNγ-repressed genes was dependent on STAT1 in IFN-naïve fibroblasts. Finally, IFNγ-mediated repression was also found to be evident in primary murine macrophages. IFN-repressed genes include negative regulators of innate and stress response, and their decrease may thus aid the establishment of a signalling perceptive milieu.Fil: Trilling, Mirko. Universitat Duisburg - Essen; AlemaniaFil: Bellora, Nicolás. Parque de Investigación Biomédica de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Patagonia Norte. Instituto de Investigación en Biodiversidad y Medioambiente; ArgentinaFil: Rutkowski, Andrzej J.. University of Cambridge; Reino UnidoFil: de Graaf, Miranda. University of Cambridge; Reino UnidoFil: Dickinson, Paul. University Of Edinburgh; Reino UnidoFil: Robertson, Kevin. University Of Edinburgh; Reino UnidoFil: Da Costa, Olivia Prazeres. Universitat Technical Zu Munich; AlemaniaFil: Ghazal, Peter. University Of Edinburgh; Reino UnidoFil: Friedel, Caroline C.. Ludwig-Maximilians-University Munich; AlemaniaFil: Albà, M. Mar. Institució Catalana de Recerca I Estudis Avancats; España. Parque de Investigación Biomédica de Barcelona; EspañaFil: Dölken, Lars. University of Cambridge; Reino Unid

Towards a better detection of patients at-risk of linezolid toxicity in clinical practice: a prospective study in three Belgian hospital centers

Introduction: Linezolid is a last-resort antibiotic for infections caused by multidrug-resistant microorganisms. It is widely used for off-label indications and for longer than recommended treatment durations, exposing patients at higher risk of adverse drug reactions (ADRs), notably thrombocytopenia. This study aimed to investigate ADR incidence and risk factors, identify thrombocytopenia-related trough levels based on treatment duration, and evaluate the performance of predictive scores for ADR development.Methods: Adult in- and outpatients undergoing linezolid therapy were enrolled in three hospitals and ADRs and linezolid trough levels prospectively monitored over time. A population pharmacokinetic (pop-PK model) was used to estimate trough levels for blood samples collected at varying times.Results: A multivariate analysis based on 63 treatments identified treatment duration ≥10 days and trough levels >8 mg/L as independent risk factors of developing thrombocytopenia, with high trough values correlated with impaired renal function. Five patients treated for >28 days did not develop thrombocytopenia but maintained trough values in the target range (<8 mg/L). The Buzelé predictive score, which combines an age-adjusted Charlson comorbidity index with treatment duration, demonstrated 77% specificity and 67% sensitivity to predict the risk of ADR.Conclusion: Our work supports the necessity of establishing guidelines for dose adjustment in patients with renal insufficiency and the systematic use of TDM in patients at-risk in order to keep trough values ≤8 mg/L. The Buzelé predictive score (if ≥7) may help to detect these at-risk patients, and pop-PK models can estimate trough levels based on plasma samples collected at varying times, reducing the logistical burden of TDM in clinical practice