Whittington Hospital

About: Whittington Hospital is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Diabetes mellitus. The organization has 1771 authors who have published 1734 publications receiving 45284 citations.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Abstract: The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

The autoxidation of human red cell lipids induced by hydrogen peroxide.

Abstract: Summary. Malonyldialdehyde (MDA) formation, a measure of polyunsaturated fat autoxidation, was estimated in normal human red cells incubated in vitro. Exposure to oxygen under a variety of conditions did not induce autoxidation. Exposure to hydrogen peroxide was either by the addition of a hydrogen peroxide solution or by incubation in an atmosphere saturated with hydrogen peroxide vapour. A pattern of MDA formation was established with both methods. Lack of reproducibility, a feature of previous methods of measuring the susceptibility of red cells to exogenous peroxide, could be overcome by (i) catalase inhibition, (ii) attention to the non-linear relation between packed-cell volume and MDA formation, and (iii) elimination of potentially misleading coloured complexes on spectroscopy. A number of recognized antioxidants inhibited peroxide-induced MDA formation. Inhibition was proportional to the logarithm of the antioxidant concentration. Under certain conditions pre-incubation with nucleosides and with lecithin protected the cells against autoxidation on subsequent exposure to peroxide. Peroxide-induced cell autoxidation was also influenced by plasma, bovine albumin, and ascorbic acid. Haemolysis was an invariable consequence of autoxidation. Similarities and dissimilarities between autoxidation and antioxidation in free lipid emulsions and in organized biological structures were examined and discussed in the light of the experimental findings.

Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness

Abstract: H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis. Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac. Our data, together with the known requirement for active proton secretion to maintain proper endolymph pH, implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function. ATP6B1 is the first member of the H+-ATPase gene family in which mutations are shown to cause human disease.

Ki67 protein: the immaculate deception?

Abstract: This article updates our previous review of Ki67 published in Histopathology 10 years ago. In this period the numbers of papers published featuring this antibody has increased 10-fold from 338 to 3489 indicating the considerable enthusiasm with which this antibody has been studied. This review attempts to provide an update on the characterization of the Ki67 protein, its function and its use as a prognostic or diagnostic tool.