Leicester Royal Infirmary

About: Leicester Royal Infirmary is a healthcare organization based out in Leicester, United Kingdom. It is known for research contribution in the topics: Population & Carotid endarterectomy. The organization has 5300 authors who have published 6204 publications receiving 208464 citations.

Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an ∼700 kDa Apaf-1 containing apoptosome complex

Abstract: Proteasome inhibitors, including lactacystin and MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal), potently induce apoptosis in leukaemic B cells from patients with B cell chronic lymphocytic leukaemia (B-CLL). This pro-apoptotic effect occurs in cells from patients at all stages of the disease, including those resistant to conventional chemotherapy, suggesting that proteasome inhibitors may be useful for treatment of B-CLL. Following initial inhibition of proteasomal activity, these agents induce mitochondrial cytochrome c release and caspase-dependent apoptosis, involving cleavage/activation of caspases -2, -3, -7, -8 and -9. Pre-treatment with the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe)fluoromethyl ketone (Z-VAD.fmk), did not prevent the release of cytochrome c or partial processing of caspase-9 but prevented activation of effector caspases and the induction of apoptosis. These results suggest that the release of cytochrome c is caspase independent and that caspase-9 is the initiator caspase in proteasome inhibitor-induced apoptosis of B-CLL cells. Activation of B-CLL lysates with dATP results in the formation of an 700 kDa caspase-activating apoptosome complex containing Apaf-1. We describe for the first time the formation of a similar 700 kDa caspase-activating apoptosome complex in B-CLL cells induced to undergo apoptosis by proteasome inhibitors.

Screening for cancer-related distress: Summary of evidence from tools to programmes

Abstract: Introduction. A number of studies have addressed the development and testing of tools for measuring cancer-related distress. Except for studies of diagnostic validity, knowledge on the effect of screening for psychological distress on psychological well-being is limited. We aimed to describe and critically discuss the findings of randomized trials of the effect of screening and to identify components necessary for future studies of the effectiveness of screening programmes. Methods. A search was made of the Embase/Medline and Web of Knowledge abstract databases from inception to September 2010. Our inclusion criterion was randomized controlled trials concerning the effect of screening for psychological distress on psychological outcomes. We compared the randomized trials on the following aspects: design and methods, setting and sample, screening and intervention, effects on psychological distress, staff utilization of screening results, possible confounding factors and other methodological limitat...

Alteration of stromal protein and integrin expression in breast--a marker of premalignant change?

Abstract: Interactions between epithelia and the extracellular matrix are important in the modulation of cellular growth, differentiation, and motility. To investigate the possible roles of these interactions in the neoplastic process, this study examines the expression of the integrin subunits a2, a6, beta 1, and beta 4 and the stromal protein tenascin in 53 breast carcinomas, non-involved breast tissue from 21 of these cases, and 32 normal/benign cases. Frozen tissue and an indirect immunoperoxidase technique were used throughout. Linear staining in relation to the basement membrane was seen for all integrins in the normal/benign cases. The carcinomas showed complete loss of reactivity in 65 per cent of cases for a2, 80 per cent for a6 and beta 4, and 90 per cent for beta 1. Those showing reactivity displayed a diffuse cytoplasmic type of staining. The non-involved breast tissue showed linear basement membrane type staining with a2 and beta 1, but for a6 and beta 4 66 per cent of cases displayed reactivity identical to that of the corresponding tumour. For tenascin, band-like staining around ducts was seen in normal/benign cases, with a diffuse coarse reactivity in all carcinomas. Most non-involved cases stained as for normal breast. The altered a6 beta 4 integrin staining in non-involved tissue in cancerous breast may be an early event in the neoplastic process, and as such, may be of use as a marker of pre-malignant change.

Rapid analysis of curcumin and curcumin metabolites in rat biomatrices using a novel ultraperformance liquid chromatography (UPLC) method.

Abstract: The bioavailability of the putative cancer chemopreventive agent curcumin is limited, making measurement either in target tissues or in biofluids difficult and variable between studies. The purposes of these investigations were to develop validated methods of extraction of curcumin from biomatrices and of detection of curcumin and its conjugated metabolites using ultraperformance liquid chromatography (UPLC) and to identify metabolites of curcumin using online tandem mass spectrometry (MS/MS). The limit of detection for curcumin after solid-phase extraction from plasma or urine was 2.5 ng/mL. Extraction efficiencies were 62 and 64% for urine and plasma. Intra- and interday variabilities (RSD) for extraction of curcumin from biofluids were less than 10 and 15%, respectively, and accuracies were 92 +/- 10% for plasma and 95 +/- 6% for urine. Curcumin was extracted from tissues using protein precipitation with quercetin as internal standard. Curcumin extraction from intestinal mucosa spiked with 0.2, 1, and 5 mug/g curcumin was validated. Extraction efficiency was 65-84%, accuracy was 94-106%, limit of detection was 12.5 ng/g, and intra- and interday variabilitiies (RSD) were 0.7-4.9 and 4.9-5.5%, respectively. The methods were applied to measure curcumin in tissues from rats that had received oral curcumin (340 mg/kg). Curcumin was found in plasma (16.1 ng/mL), urine (2.0 ng/mL), intestinal mucosa (1.4 mg/g), liver (3671.8 ng/g), and, for the first time, kidney (206.8 ng/g) and heart (807.6 ng/g). Curcumin metabolites identified by UPLC-MS/MS in plasma and urine were phenolic glucuronides and, probably, alcoholic glucuronides. Products of reduction of curcumin and their metabolites were found in the liver. The methods described here represent improvements on existing analytical methods for curcuminoids and metabolites in terms of sensitivity, speed, and separation.