National Health Service NHS Blood and Transplant

Cambridge, United Kingdom

National Health Service NHS Blood and Transplant

Cambridge, United Kingdom
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Caputo M.,University of Tuscia | Balzerano A.,University of Tuscia | Arisi I.,European Brain Research Institute EBRI Rita Levi Montalcini | D'Onofrio M.,European Brain Research Institute EBRI Rita Levi Montalcini | And 6 more authors.
PLoS ONE | Year: 2017

The DNA repair protein Cockayne syndrome group B (CSB) has been recently identified as a promising anticancer target. Suppression, by antisense technology, of this protein causes devastating effects on tumor cells viability, through a massive induction of apoptosis, while being non-toxic to non-transformed cells. To gain insights into the mechanisms underlying the pro-apoptotic effects observed after CSB ablation, global gene expression patterns were determined, to identify genes that were significantly differentially regulated as a function of CSB expression. Our findings revealed that response to endoplasmic reticulum stress and response to unfolded proteins were ranked top amongst the cellular processes affected by CSB suppression. The major components of the endoplasmic reticulum stressmediated apoptosis pathway, including pro-apoptotic factors downstream of the ATF3-CHOP cascade, were dramatically up-regulated. Altogether our findings add new pieces to the understanding of CSB mechanisms of action and to the molecular basis of CS syndrome. © 2017 Caputo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Oakland K.,National Health Service NHS Blood and Transplant | Oakland K.,Imperial College London | Jairath V.,University of Western Ontario | Uberoi R.,University of Oxford | And 6 more authors.
The Lancet Gastroenterology and Hepatology | Year: 2017

Background Acute lower gastrointestinal bleeding is a common reason for emergency hospital admission, and identification of patients at low risk of harm, who are therefore suitable for outpatient investigation, is a clinical and research priority. We aimed to develop and externally validate a simple risk score to identify patients with lower gastrointestinal bleeding who could safely avoid hospital admission. Methods We undertook model development with data from the National Comparative Audit of Lower Gastrointestinal Bleeding from 143 hospitals in the UK in 2015. Multivariable logistic regression modelling was used to identify predictors of safe discharge, defined as the absence of rebleeding, blood transfusion, therapeutic intervention, 28 day readmission, or death. The model was converted into a simplified risk scoring system and was externally validated in 288 patients admitted with lower gastrointestinal bleeding (184 safely discharged) from two UK hospitals (Charing Cross Hospital, London, and Hammersmith Hospital, London) that had not contributed data to the development cohort. We calculated C statistics for the new model and did a comparative assessment with six previously developed risk scores. Findings Of 2336 prospectively identified admissions in the development cohort, 1599 (68%) were safely discharged. Age, sex, previous admission for lower gastrointestinal bleeding, rectal examination findings, heart rate, systolic blood pressure, and haemoglobin concentration strongly discriminated safe discharge in the development cohort (C statistic 0·84, 95% CI 0·82–0·86) and in the validation cohort (0·79, 0·73–0·84). Calibration plots showed the new risk score to have good calibration in the validation cohort. The score was better than the Rockall, Blatchford, Strate, BLEED, AIMS65, and NOBLADS scores in predicting safe discharge. A score of 8 or less predicts a 95% probability of safe discharge. Interpretation We developed and validated a novel clinical prediction model with good discriminative performance to identify patients with lower gastrointestinal bleeding who are suitable for safe outpatient management, which has important economic and resource implications. Funding Bowel Disease Research Foundation and National Health Service Blood and Transplant. © 2017 Elsevier Ltd

Cvejic A.,University of Cambridge | Cvejic A.,Wellcome Trust Sanger Institute | Haer-Wigman L.,Sanquin Research | Haer-Wigman L.,University of Amsterdam | And 71 more authors.
Nature Genetics | Year: 2013

The blood group Vel was discovered 60 years ago, but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel. To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 × 10-15). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors. © 2013 Nature America, Inc. All rights reserved.

Ghevaert C.,National Health Service NHS Blood and Transplant | Ghevaert C.,University of Cambridge | Herbert N.,National Health Service NHS Blood and Transplant | Hawkins L.,National Health Service NHS Blood and Transplant | And 13 more authors.
Blood | Year: 2013

Fetomaternal alloimmune thrombocytopenia, caused by the maternal generation of antibodies against fetal human platelet antigen-1a (HPA-1a), can result in intracranial hemorrhage and intrauterine death. We have developed a therapeutic human recombinant high-affinity HPA-1a antibody (B2G1Δnab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fcγ receptors. In vitro studies with a range of clinical anti-HPA-1a sera have shown that B2G1Δnab blocks monocyte chemiluminescence by >75%. In this firstin- man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1Δnab have the same intravascular survival as unsensitized platelets (190 hours), while platelets sensitized with a destructive immunoglobulin G1 version of the antibody (B2G1) are cleared from the circulation in 2 hours. Mimicking the situation in fetuses receiving B2G1Δnab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1Δnab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1Δnab. The efficient clearance of platelets sensitized with B2G1 also opens up the opportunity to carry out studies of prophylaxis to prevent alloimmunization in HPA-1a-negative mothers. © 2013 by The American Society of Hematology.

Albers C.A.,University of Cambridge | Albers C.A.,National Health Service NHS Blood and Transplant | Albers C.A.,Wellcome Trust Sanger Institute | Paul D.S.,Wellcome Trust Sanger Institute | And 43 more authors.
Nature Genetics | Year: 2012

The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 x 10 -228) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome. © 2012 Nature America, Inc. All rights reserved.

PubMed | Anglia, National Health Service NHS Blood and Transplant, University of Bristol, Cancer Research UK Research Institute and 15 more.
Type: Journal Article | Journal: Science (New York, N.Y.) | Year: 2014

Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.

Dor F.J.M.F.,Erasmus University Rotterdam | Massey E.K.,Erasmus University Rotterdam | Frunza M.,Babes - Bolyai University | Frunza M.,Academic Society for the Research of Religions and Ideologies SACRI | And 11 more authors.
Transplantation | Year: 2011

In the literature, varying terminology for living organ donation can be found. However, there seems to be a need for a new classification to avoid confusion. Therefore, we assessed existing terminology in the light of current living organ donation practices and suggest a more straightforward classification. We propose to concentrate on the degree of specificity with which donors identify intended recipients and to subsequently verify whether the donation to these recipients occurs directly or indirectly. According to this approach, one could distinguish between "specified" and "unspecified" donation. Within specified donation, a distinction can be made between "direct" and "indirect" donation. © 2011 by Lippincott Williams & Wilkins.

Ilicic T.,European Bioinformatics Institute | Ilicic T.,Wellcome Trust Sanger Institute | Kim J.K.,European Bioinformatics Institute | Kolodziejczyk A.A.,European Bioinformatics Institute | And 12 more authors.
Genome Biology | Year: 2016

Single-cell RNA sequencing (scRNA-seq) has broad applications across biomedical research. One of the key challenges is to ensure that only single, live cells are included in downstream analysis, as the inclusion of compromised cells inevitably affects data interpretation. Here, we present a generic approach for processing scRNA-seq data and detecting low quality cells, using a curated set of over 20 biological and technical features. Our approach improves classification accuracy by over 30 % compared to traditional methods when tested on over 5,000 cells, including CD4+ T cells, bone marrow dendritic cells, and mouse embryonic stem cells. © 2016 Ilicic et al.

Frunza M.,Babes - Bolyai University | Van Assche K.,Ghent University | Lennerling A.,Sahlgrenska University Hospital | Lennerling A.,Gothenburg University | And 8 more authors.
Transplantation | Year: 2015

Although transplant professionals have initially been reluctant to perform transplants after public solicitation of organs from living donors, nowadays these transplants are increasingly being performed and reported. After clarifying the existing terminology, we elaborate an operational definition of public solicitation that is consistent with the Ethical, Legal, and Psychosocial Aspects of Transplantation classification for living organ donation. Our aimis to critically assess this phenomenon, froma legal,moral, and practical perspective, and to offer some recommendations. From a legal point of view, we analyze the current situation in the Europe and the United States. From a moral perspective, we evaluate the various arguments used in the literature, both in favor and against. Finally, we offer a set of recommendations aimed atmaximizing the organ donor pool while safeguarding the interests of potential living donors. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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