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1. Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants

Author

Angelo Agathanggelou, Victoria J. Weston, Tracey Perry, Nicholas J. Davies, Anna Skowronska, Daniel T. Payne, John S. Fossey, Ceri E. Oldreive, Wenbin Wei, Guy Pratt, Helen Parry, David Oscier, Steve J. Coles, Paul S. Hole, Richard L. Darley, Michael McMahon, John D. Hayes, Paul Moss, Grant S. Stewart, A. Malcolm R. Taylor, and Tatjana Stankovic

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumors with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia.

Published
2015
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2. Outcomes of undernutrition in patients in the community with cancer or cardiovascular disease

Author

Jackie Edington, Christopher Martyn, P D Winter, Steve J. Coles, and Catharine R. Gale

Subjects
Adult, Male, medicine.medical_specialty, Population, Medicine (miscellaneous), Disease, Drug Prescriptions, Body Mass Index, Ambulatory care, Neoplasms, Ambulatory Care, Medicine, Humans, education, Aged, Aged, 80 and over, education.field_of_study, Nutrition and Dietetics, business.industry, Mortality rate, Public health, Smoking, Middle Aged, medicine.disease, Obesity, Nutrition Disorders, Hospitalization, Malnutrition, Cardiovascular Diseases, Physical therapy, Female, business, Body mass index, Demography
Abstract

Public health concern has tended to focus on the dangers of obesity, but there is evidence that undernutrition may also pose a risk to physical and mental well-being, particularly in those who are already ill. Using the General Practice Research Database (see office for Population Censuses and Surveys, 1995), we followed up 10 128 men and women aged 18 years and over who had been diagnosed with cancer or cardiovascular disease to examine whether nutritional status, as indicated by BMI, affected rates of use of health care resources and mortality. In both diagnostic groups, patients with a BMI below 20 kg/m 2 had higher rates of consultation with GP, higher rates of prescription and higher death rates during the follow-up period compared with those with a BMI of 20 – < 25 kg/m 2. In men and women with cardiovascular disease, poor nutritional status was associated with a sharply increased risk of hospital admission. Patients whose BMI was 30 – 2 also tended to have increased rates of GP consultation and prescription, and if they were under the age of 65 years, they had an increased risk of death. The results of the present study suggest that in men and women with cancer or cardiovascular disease, even minor degrees of undernutrition are associated with a marked increase in morbidity and mortality.

Published
1999

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