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Δευτέρα, 27 Μαρτίου 2017

Database Independent Protein Sequencing (DiPS) enables full-length de-novo protein and antibody sequence determination [Technology]

Traditional 'bottom-up' proteomics approaches use proteolytic digestion, LC-MS/MS and database searching to elucidate peptide identities and their parent proteins. Protein sequences absent from the database cannot be identified, and even if present in the database, complete sequence coverage is rarely achieved even for the most abundant proteins in the sample. Thus, sequencing of unknown proteins such as antibodies or constituents of metaproteomes remains a challenging problem. To date, there is no available method for full-length protein sequencing, independent of a reference database, in high throughput. Here we present Database Independent Protein Sequencing (DiPS), a method for unambiguous, rapid, database independent, full-length protein sequencing. The method is a novel combination of non-enzymatic, semi-random cleavage of the protein, LC-MS/MS analysis, peptide de novo sequencing, extraction of peptide tags, and their assembly into a consensus sequence using an algorithm named "Peptide Tag Assembler" (pTA). As proof-of-concept, the method was applied to samples of three known proteins representing three size classes and to a previously un-sequenced, clinically relevant, monoclonal antibody. Excluding leucine/isoleucine and glutamic-acid/deamidated glutamine ambiguities, end-to-end, full-length de novo sequencing was achieved with 99-100% accuracy for all benchmarking proteins and the antibody light chain. Accuracy of the sequenced antibody heavy chain, including the entire variable region, was also 100% but there was a 23 residue gap in the constant region sequence.



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Capecitabine in early breast cancer: A meta-analysis of randomised controlled trials

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Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Akina Natori, Josee-Lyne Ethier, Eitan Amir, David W. Cescon
PurposeCapecitabine is an effective therapy for metastatic breast cancer. Its role in early breast cancer is uncertain due to conflicting data from randomised controlled trials (RCTs).MethodsPubMed and major conference proceedings were searched to identify RCTs comparing standard chemotherapy with or without capecitabine in the neoadjuvant or adjuvant setting. Hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS), as well as odds ratios (ORs) for toxicities were extracted or calculated and pooled in a meta-analysis. Subgroup analysis compared triple-negative breast cancer (TNBC) to non-TNBC and whether capecitabine was given in addition to or in place of standard chemotherapy. Meta-regression was used to explore the influence of TNBC on OS.ResultsEight studies comprising 9302 patients were included. In unselected patients, capecitabine did not influence DFS (hazard ratio [HR] 0.99, p = 0.93) or OS (HR 0.90, p = 0.36). There was a significant difference in DFS when capecitabine was given in addition to standard treatment compared with in place of standard treatment (HR 0.92 versus 1.62, interaction p = 0.002). Addition of capecitabine to standard chemotherapy was associated with significantly improved DFS in TNBC versus non-TNBC (HR 0.72 versus 1.01, interaction p = 0.02). Meta-regression showed that adding capecitabine to standard chemotherapy was associated with improved OS in studies with higher proportions of patients with TNBC (R = −0.967, p = 0.007). Capecitabine increased grade 3/4 diarrhoea (odds ratio [OR] 2.33, p < 0.001) and hand-foot syndrome (OR 8.08, p < 0.001), and resulted in more frequent treatment discontinuation (OR 3.80, p < 0.001).ConclusionAdding capecitabine to standard chemotherapy appears to improve DFS and OS in TNBC, but increases adverse events in keeping with its known toxicity profile.



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Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials

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Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Martin D. Berger, Shinichi Yamauchi, Shu Cao, Diana L. Hanna, Yu Sunakawa, Marta Schirripa, Satoshi Matsusaka, Dongyun Yang, Susan Groshen, Wu Zhang, Yan Ning, Satoshi Okazaki, Yuji Miyamoto, Mitsukuni Suenaga, Sara Lonardi, Chiara Cremolini, Alfredo Falcone, Volker Heinemann, Fotios Loupakis, Sebastian Stintzing, Heinz-Josef Lenz
PurposeThe most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF–associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC).Patients and methodsPatients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing.ResultsThe FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2–3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02–0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2–3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14–1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45–4.04; P = 0.60).ConclusionThis is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab.



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MiR-200b and miR-155 as predictive biomarkers for the efficacy of chemoradiation in locally advanced head and neck squamous cell carcinoma

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Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Anne-Katrin Hess, Annika Müer, Fabian Dominik Mairinger, Wilko Weichert, Albrecht Stenzinger, Michael Hummel, Volker Budach, Ingeborg Tinhofer
BackgroundThe predictive value of microRNAs (miRNAs) in tumour cells and infiltrating immune cells for the efficacy of chemoradiation (CRTX) in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated.MethodsFormalin-fixed, paraffin-embedded tumour material was collected from patients with locally advanced HNSCC treated within the ARO-0401 phase III trial with radiotherapy in combination with either 5-fluorouracil/cisplatin (CDDP-CRTX) or 5-fluorouracil/mitomycin C (MMC-CRTX). MiRNA and immune profiles were established in a test cohort of 48 oropharyngeal carcinoma (OPSCC) cases by Affymetrix miRNA microarrays and the nanoString PanCancer Immune Panel, respectively. Expression of miRNA candidates was measured in 149 HNSCC patients by real-time PCR. Interference of miRNA profiles with CRTX efficacy was determined by Kaplan–Meier and Cox regression analysis.ResultsExpression levels of five miRNAs (miR-27b, -130b, -200b, -451 and -532-5p) were significantly associated with overall survival after MMC-CRTX. Six different miRNAs (miR-125b, -146a, -150, -155, -187 and -342-5p) were correlated with overall survival after CDDP-CRTX. Validation by real-time PCR confirmed the predictive value of miR-200b and miR-155 in OPSCC, which was absent in hypopharyngeal carcinomas. MiR-146a was revealed as a prognostic marker for both CRTX regimens. MiR-200b expression was mainly associated with distant metastasis, whereas miR-155 correlated with local recurrence. MiR-155 and miR-146a were identified as surrogate markers for tumour-infiltrating lymphocytes.ConclusionsMiR-200b and miR-155 were established as potential markers for personalised treatment selection of two standard regimens of CRTX. The predictive role of miR-155 deserves further investigation, especially within the framework of clinical trials of CRTX/immune checkpoint inhibitor combinations.



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The difference in association between aspirin use and other thrombocyte aggregation inhibitors and survival in patients with colorectal cancer

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Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): M.A. Frouws, E. Rademaker, E. Bastiaannet, M.P.P. van Herk-Sukel, V.E. Lemmens, C.J.H. Van de Velde, J.E.A. Portielje, G.J. Liefers
BackgroundSeveral studies have suggested that the association between aspirin and improved cancer survival is mediated through the mechanism of aspirin as thrombocyte aggregation inhibitors (TAI). The aim of this study was to provide epidemiological evidence for this mechanism assessing the association between overall survival and the use of aspirin and non-aspirin TAI in patients with colorectal cancer.MethodsIn this observational study, data from the Netherlands Comprehensive Cancer Organisation were linked to PHARMO Database Network. Patients using aspirin or aspirin in combination with non-aspirin TAI (dual users) were selected and compared with non-users. The association between overall survival and the use of (non-)aspirin TAI was analysed using Cox regression models with the use of (non-)aspirin TAI as a time-varying covariate.ResultsIn total, 9196 patients were identified with colorectal cancer and 1766 patients used TAI after diagnosis. Non-aspirin TAI were mostly clopidogrel and dipyridamole. Aspirin use was associated with a significant increased overall survival and hazard ratio (HR) 0.41 (95% confidence interval [CI] 0.37–0.47), and the use of non-aspirin TAI was not associated with survival of HR 0.92 (95% CI 0.70–1.22). Dual users did not have an improved overall survival when compared with patients using solely aspirin.ConclusionsAspirin use after diagnosis of colorectal cancer was associated with significantly lower mortality rates and this effect remained significant after adjusting for potential confounders. No additional survival benefit was observed in patients using both aspirin and another TAI.



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Quality measures of the population-based Finnish Cancer Registry indicate sound data quality for solid malignant tumours

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Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Maarit K. Leinonen, Joonas Miettinen, Sanna Heikkinen, Janne Pitkäniemi, Nea Malila
BackgroundThe Finnish Cancer Registry (FCR) has collected population-based data on cancer incidence for scientific research and statistical purposes since 1953. Our aim was to provide a comprehensive quality assessment of the current cancer registry data in Finland.MethodsWe used established quantitative and semi-quantitative techniques to address four main dimensions of data quality: completeness, comparability, validity and timeliness for the period 1953–2013, with a special focus on cancers diagnosed in 2009–2013. For completeness, hospital admissions and outpatient visits were used as an independent data source.ResultsIn 2009–2013, 153 147 incident tumours were registered in the FCR. Of them, 91% were solid tumours. The completeness for all solid tumours was estimated at 96%, and for non-solid tumours at 86%. Potential underreporting was most prominent for tumours which are not typically histologically verified such as haematological malignancies and non-malignant tumours of the central nervous system. Of all cancers, 93% were morphologically verified, with variation by primary site. The proportion of cancers with uncertain or ill-defined primary site and the proportion of death certificate only registrations were both low at 1.9% and 2.6%, respectively.ConclusionsThe FCR provides overall accurate and close to complete national cancer data for solid malignant tumours. Registration of tumours with no histology is still compromised. This warrants continuous communication with clinicians to ensure undisturbed data flow, and active trace-back using external data sources such as hospital administrative data. In addition, broad diagnosis categories would be less sensitive to diversity of input and data quality when international comparisons are made.



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RE: Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with 131-I-metaiodobenzylguanidine. Huibregtse K et al. European Journal of Cancer 2016. 66:144–152

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Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Cecile M. Ronckers, Lieve Tytgat, Marry M. van den Heuvel-Eibrink, Jop Teepen, Leontine C.M. Kremer, Sarah Clement, Hanneke M. van Santen




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Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician's choice: Results from the randomised phase III BEACON trial

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Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Chris Twelves, Javier Cortés, Joyce O'Shaughnessy, Ahmad Awada, Edith A. Perez, Seock–Ah Im, Patricia Gómez-Pardo, Lee S. Schwartzberg, Véronique Diéras, Denise A. Yardley, David A. Potter, Audrey Mailliez, Alvaro Moreno-Aspitia, Jin-Seok Ahn, Carol Zhao, Ute Hoch, Mary Tagliaferri, Alison L. Hannah, Hope S. Rugo
BackgroundHealth-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL.Patients and methodsHRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m2 every 3 weeks (q3wk)) or single-agent TPC (n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (≥5 points) in HRQoL scores were compared.ResultsDifferences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of −9.4 and −10.8 points, respectively.ConclusionThere was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression.Study numberNCT01492101.



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Improvement of identification methods for honeybee specific Lactic Acid Bacteria; future approaches

by Sepideh Lamei, Yue O. O. Hu, Tobias C. Olofsson, Anders F. Andersson, Eva Forsgren, Alejandra Vásquez

Honeybees face many parasites and pathogens and consequently rely on a diverse set of individual and group-level defenses to prevent disease. The crop microbiota of Apis mellifera, composed of 13 Lactic Acid Bacterial (LAB) species within the genera Lactobacillus and Bifidobacterium, form a beneficial symbiotic relationship with each other and the honeybee to protect their niche and their host. Possibly playing a vital role in honeybee health, it is important that these honeybee specific Lactic Acid Bacterial (hbs-LAB) symbionts can be correctly identified, isolated and cultured, to further investigate their health promoting properties. We have previously reported successful identification to the strain level by culture-dependent methods and we recently sequenced and annotated the genomes of the 13 hbs-LAB. However, the hitherto applied techniques are unfortunately very time consuming, expensive and not ideal when analyzing a vast quantity of samples. In addition, other researchers have constantly failed to identify the 13 hbs-LAB from honeybee samples by using inadequate media and/or molecular techniques based on 16S rRNA gene sequencing with insufficient discriminatory power. The aim of this study was to develop better and more suitable methods for the identification and cultivation of hbs-LAB. We compared currently used bacterial cultivation media and could for the first time demonstrate a significant variation in the hbs-LAB basic requirements for optimal growth. We also present a new bacterial identification approach based on amplicon sequencing of a region of the 16S rRNA gene using the Illumina platform and an error correction software that can be used to successfully differentiate and rapidly identify the 13 hbs-LAB to the strain level.

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Mice lived with us 15,000 years ago even before farming took off

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House mice began to associate with humans when the Natufian people started settling in the eastern Mediterranean, before the advent of farming

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BMA condemns failure to deliver rescue funding to GPs

The BMA has urged NHS England to remedy the “scandalous” failure to deliver resilience funding to struggling general practices that was due be deployed by the end of this financial year.NHS England...
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The BMJ Awards 2017: Anaesthesia

Perioperative medicine drives quality improvementAt West Suffolk Hospital, a 400 bed district general hospital in Bury St Edmunds, anaesthetists have taken the lead in driving a new patient centred...
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Jorgen Kieler

bmj;356/mar27_16/j1530/FAF1faJørgen Kieler was at home in the early hours of 28 April 2013 when he learnt that the Museum of Danish Resistance in central Copenhagen was on fire.1 His first thought...
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Consultant productivity drops as result of poor workforce planning

The productivity of consultants working in NHS acute care hospitals in England has fallen by an average of 2.3% over the past six years, new research has shown.1The think tank the Health Foundation,...
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Generic drugs have lost their profitability

Meeran and colleagues argue that1 Actavis charging around £100 (€116; $125) for a month’s supply of hydrocortisone in the UK is scandalous, compared with its price in Spain (£3.12 a month). I...
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