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.

Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion

Abstract: Carbonic anhydrase IX (CAIX) is a membrane-associated carbonic anhydrase (CA), strongly induced by hypoxia. CAIX is overexpressed in a variety of tumor types and associated with increased metastasis and poor prognosis. An inhibitor of CAs, acetazolamide has been reported to inhibit invasion. We used RNA interference (RNAi) to examine the function of CAIX in MDA468 and MDA231 breast carcinoma cells, which express high levels of CAIX under hypoxia. Hypoxia-induced CA activity was completely blocked by specific RNAi (P < 0.01). RNAi-treated cells showed growth delay in dense monolayer culture and a 50% reduction in clonogenic survival under hypoxia. In the MDA468 cells, there was no effect of RNAi treatment on invasion. In a cell line that did not induce CAIX under hypoxia, RT112, we found no effect on the ability of cells transfected with CAIX to invade or migrate. Thus, CAIX plays an important role in the growth and survival of tumor cells under normoxia and hypoxia, making it a potential target for cancer therapy, but is not involved in invasion.

Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria.

Abstract: Sequestration of malaria-infected erythrocytes in the peripheral circulation has been associated with the virulence of Plasmodium falciparum. Defining the adhesive phenotypes of infected erythrocytes may therefore help us to understand how severe disease is caused and how to prevent or treat it. We have previously shown that malaria-infected erythrocytes may form apparent autoagglutinates of infected erythrocytes. Here we show that such autoagglutination of a laboratory line of P. falciparum is mediated by platelets and that the formation of clumps of infected erythrocytes and platelets requires expression of the platelet surface glycoprotein CD36. Platelet-dependent clumping is a distinct adhesive phenotype, expressed by some but not all CD36-binding parasite lines, and is common in field isolates of P. falciparum. Finally, we have established that platelet-mediated clumping is strongly associated with severe malaria. Precise definition of the molecular basis of this intriguing adhesive phenotype may help to elucidate the complex pathophysiology of malaria.

Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis

Abstract: Human immunodeficiency virus (HIV) and Mycobacterium tuberculosis annually cause 3 million and 2 million deaths, respectively. Last year, 600,000 individuals, doubly infected with HIV and M. tuberculosis, died. Since World War I, approximately 150 million people have succumbed to these two infections—more total deaths than in all wars in the last 2,000 years. Although the perceived threats of new infections such as SARS, new variant Creutzfeldt-Jakob disease and anthrax are real, these outbreaks have caused less than 1,000 deaths globally, a death toll AIDS and tuberculosis exact every 2 h. In 2003, 40 million people were infected with HIV, 2 billion with M. tuberculosis, and 15 million with both. Last year, 5 million and 50 million were newly infected with HIV or M. tuberculosis, respectively, with 2 million new double infections. Better control measures are urgently needed.

Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease.

Abstract: Graft-versus-host disease (GvHD) is a chief complication of allogeneic bone marrow transplantation1. In HLA-identical bone marrow transplantation, GvHD may be induced by disparities in minor histocompatibility antigens (mHags) between the donor and the recipient, with the antigen being present in the recipient and not in the donor2. Cytotoxic T lymphocytes (CTLs) specific for mHags of the recipients can be isolated from the blood of recipients with severe GvHD (ref. 3). A retrospective study demonstrated an association between mismatch for mHags HA-1, -2, -4 and -5 and the occurrence of GvHD in adult recipients of bone marrow from HLA genotypically identical donors4. Tetrameric HLA-peptide complexes have been used to visualize and quantitate antigen-specific CTLs in HIV-infected individuals and during Epstein-Barr virus and lymphocytic choriomeningitis virus infections5,6,7,8. Here we show the direct ex vivo visualization of mHag-specific CTLs during GvHD using tetrameric HLA-class and I-mHag HA-1 and HY peptide complexes. In the peripheral blood of 17 HA-1 or HY mismatched marrow recipients, HA-1- and HY-specific CTLs were detected as early as 14 days after bone marrow transplantation. The tetrameric complexes demonstrated a significant increase in HA-1- and HY-specific CTLs during acute and chronic GvHD, which decreased after successful GvHD treatment. HLA class I–mHag peptide tetramers may serve as clinical tools for the diagnosis and monitoring of GvHD patients.