St Bartholomew's Hospital

About: St Bartholomew's Hospital is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Cancer. The organization has 11054 authors who have published 13229 publications receiving 501102 citations. The organization is also known as: St. Bartholomew's Hospital & The Royal Hospital of St Bartholomew.

Anatomic and Disease Specificity of NADH CoQ1 Reductase (Complex I) Deficiency in Parkinson's Disease

Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is thought to produce parkinsonism in humans and other primates through its inhibition of complex I The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with Parkinson's disease has provided a remarkable link between the idiopathic disease and the action of the neurotoxin MPTP This article shows that complex I deficiency in Parkinson's disease is anatomically specific for the substantia nigra, and is not present in another neurodegenerative disorder involving the substantia nigra Evidence is also provided to show that there is no correlation between L-3,4-dihydroxyphenylalanine therapy and complex I deficiency These results suggest that complex I deficiency may be the underlying cause of dopaminergic cell death in Parkinson's disease

Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial

Abstract: Summary Background Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Methods PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m 2 on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. Findings 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81–13·47) in the panobinostat group and 5·59 months (2·14–11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33–12·94] vs 8·08 months [7·56–9·23]; hazard ratio [HR] 0·63, 95% CI 0·52–0·76; p vs 208 [54·6%, 49·4–59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2–32·4] vs 60 [15·7%, 12·2–19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76–14·92) in the panobinostat group and 10·87 months (9·23–11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41–1·64) in the panobinostat group and 2·00 months (1·61–2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3–4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). Interpretation Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. Funding Novartis Pharmaceuticals.

DNA damage is able to induce senescence in tumor cells in vitro and in vivo.

Abstract: Often the use of cytotoxic drugs in cancer therapy results in stabledisease rather than regression of the tumor, and this is typically seen as afailure of treatment. We now show that DNA damage is able to inducesenescence in tumor cells expressing wild-type p53. We also show thatcytotoxics are capable of inducing senescence in tumor tissue in vivo. Ourresults suggest that p53 and p21 play a central role in the onset ofsenescence, whereas p16 INK4a function may be involved in maintainingsenescence. Thus, like apoptosis, senescence appears to be a p53-inducedcellular response to DNA damage and an important factor in determiningtreatment outcome. INTRODUCTIONReplicative or cellular senescence, a process leading to irreversiblearrest of cell division, was first described in cultures of humanfibroblasts that lost the ability to divide upon continuous subculture(1). Since then, replicative senescence has been shown in variousmammalian tissues in culture and in vivo (2, 3). Contrary to normalsomatic cells, most tumors have extended or infinite life spans.Cellular and viral oncogenes, or the loss of tumor suppressors, areinvolved in the transformation and immortalization of primary cells.Inactivation of the p53 and p16

Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma

Abstract: Background The combination melphalan–prednisone–thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. Methods We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide–dexamethasone versus MPT. Results The median progression-free survival was 25.5 months with continuous lenalidomide–dexamethasone, 20.7 months with 18 cycles of lenalidomide–dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide–dexamethasone vs. MPT and 0.70 for continuous lenalidomide–dexamethasone vs. 18 cycles of len...