John Radcliffe Hospital

About: John Radcliffe Hospital is a healthcare organization based out in Oxford, Oxfordshire, United Kingdom. It is known for research contribution in the topics: Population & Antigen. The organization has 14491 authors who have published 23670 publications receiving 1459015 citations.

The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages

Abstract: The cellular response to hypoxia includes the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in diverse processes such as glycolysis and angiogenesis. Induction of the HIF-regulated genes, as a consequence of the microenvironment or genetic changes, is known to have an important role in the growth of experimental tumors. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) are known to dimerize with the aryl hydrocarbon receptor nuclear translocator in mediating this response. Because regulation of the α chain protein level is a primary determinant of HIF activity, our aim was to investigate the distribution of HIF-1α and HIF-2α by immunohistochemistry in normal and pathological tissues using monoclonal antibodies (mAb). We raised a new mAb to detect HIF-1α, designated 122, and used our previously validated mAb 190b to HIF-2α. In the majority of solid tumors examined, including bladder, brain, breast, colon, ovarian, pancreatic, prostate, and renal carcinomas, nuclear expression of HIF-1α and -2α was observed in varying subsets of the tumor cells. HIF-2α was also strongly expressed by subsets of tumor-associated macrophages, sometimes in the absence of any tumor cell expression. Less frequently staining was observed in other stromal cells within the tumors and in normal tissue adjacent to tumor margins. In contrast, in normal tissue neither molecule was detectable except within subsets of bone marrow macrophages, where HIF-2α was strongly expressed.

Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport.

Abstract: THE ATP-binding cassette (ABC) superfamily of transport systems now includes over thirty proteins that share extensive sequence similarity and domain organization (reviewed in refs 1–3). This superfamily includes the well characterized periplasmic binding protein-dependent uptake systems of prokaryotes, bacterial exporters, and eukaryotic proteins including the P-glycoprotein associated with multidrug resistance in tumours (MDR), the STE6 gene product that mediates export of yeast a-factor mating pheromone, pfMDR that is implicated in chloroquine resistance of the malarial parasite, and the product of the cystic fibrosis gene (CFTR). Here we present a tertiary structure model of the ATP-binding cassettes characteristic of this class of transport system, based on similarities between the predicted secondary structures of members of this family and the previously determined structure of adenylate kinase. This model has implications for both the molecular basis of transport and cystic fibrosis and provides a framework for further experimentation.

Validation and Clinical Utility of a 70-Gene Prognostic Signature for Women With Node-Negative Breast Cancer

Abstract: Background: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. Methods: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from fi ve European centers were divided into high- and low-risk groups based on the gene signature classifi cation and on clinical risk classifi cations. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis – free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER] – positive patients) or 92% (for ERnegative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. Results: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confi dence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low – and high – clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. Conclusions: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cancer. [J Natl Cancer Inst 2006;98: 1183 – 92 ]

Evidence based medicine: an approach to clinical problem-solving

Abstract: Doctors within the NHS are confronting major changes at work. While we endeavour to improve the quality of health care, junior doctors' hours have been reduced and the emphasis on continuing medical education has increased. We are confronted by a growing body of information, much of it invalid or irrelevant to clinical practice. This article discusses evidence based medicine, a process of turning clinical problems into questions and then systematically locating, appraising, and using contemporaneous research findings as the basis for clinical decisions. The computerisation of bibliographies and the development of software that permits the rapid location of relevant evidence have made it easier for busy clinicians to make best use of the published literature. Critical appraisal can be used to determine the validity and applicability of the evidence, which is then used to inform clinical decisions. Evidence based medicine can be taught to, and practised by, clinicians at all levels of seniority and can be used to close the gulf between good clinical research and clinical practice. In addition it can help to promote self directed learning and teamwork and produce faster and better doctors.

Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria.

Abstract: Tumour-necrosis factor-alpha (TNF-alpha) is believed to have an important role in the pathogenesis of severe infectious disease and fatal cerebral malaria is associated with high circulating levels of this cytokine. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighbouring HLA alleles, we show that this disease association is independent of HLA class I and class II variation. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biological advantage.