Swi/Snf chromatin remodeling/tumor suppressor complex establishes nucleosome occupancy at target promoters.

Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these patterns are established, are dynamically maintained, and subsequently contribute to transcriptional control are poorly understood. The switch/sucrose non-fermentable chromatin remodeling complex, also known as the Brg1 associated factors complex, is a master developmental regulator and tumor suppressor capable of mobilizing nucleosomes in biochemical assays. However, its role in establishing the nucleosome landscape in vivo is unclear. Here we have inactivated Snf5 and Brg1, core subunits of the mammalian Swi/Snf complex, to evaluate their effects on chromatin structure and transcription levels genomewide. We find that inactivation of either subunit leads to disruptions of specific nucleosome patterning combined with a loss of overall nucleosome occupancy at a large number of promoters, regardless of their association with CpG islands. These rearrangements are accompanied by gene expression changes that promote cell proliferation. Collectively, these findings define a direct relationship between chromatin-remodeling complexes, chromatin structure, and transcriptional regulation.

TCR-dependent transformation of mature memory phenotype T cells in mice.

A fundamental goal in cancer research is the identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth, as this has the potential to reveal therapeutic targets. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies. However, the identity of the cells in which mature lymphoid neoplasms are initiated remains unclear. Here, we investigate the origin of peripheral T cell lymphomas using mice in which Snf5, a chromatin remodelling-complex subunit with tumor suppressor activity, could be conditionally inactivated in developing T cells. In this model of mature peripheral T cell lymphomas, the cell of origin was a mature CD44hiCD122loCD8⁺ T cell that resembled a subset of memory cells that has capacity for self-renewal and robust expansion, features shared with stem cells. Further analysis showed that Snf5 loss led to activation of a Myc-driven signaling network and stem cell transcriptional program. Finally, lymphomagenesis and lymphoma proliferation depended upon TCR signaling, establishing what we believe to be a new paradigm for lymphoid malignancy growth. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells are associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.

Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex.

Alterations in chromatin play an important role in oncogenic transformation, although the underlying mechanisms are often poorly understood. The SWI/SNF complex contributes to epigenetic regulation by using the energy of ATP hydrolysis to remodel chromatin and thus regulate transcription of target genes. SNF5, a core subunit of the SWI/SNF complex, is a potent tumor suppressor that is specifically inactivated in several types of human cancer. However, the mechanism by which SNF5 mutation leads to cancer and the role of SNF5 within the SWI/SNF complex remain largely unknown. It has been hypothesized that oncogenesis in the absence of SNF5 occurs due to a loss of function of the SWI/SNF complex. Here, we show, however, distinct effects for inactivation of Snf5 and the ATPase subunit Brg1 in primary cells. Further, using both human cell lines and mouse models, we show that cancer formation in the absence of SNF5 does not result from SWI/SNF inactivation but rather that oncogenesis is dependent on continued presence of BRG1. Collectively, our results show that cancer formation in the absence of SNF5 is dependent on the activity of the residual BRG1-containing SWI/SNF complex. These findings suggest that, much like the concept of oncogene addiction, targeted inhibition of SWI/SNF ATPase activity may be an effective therapeutic approach for aggressive SNF5-deficient human tumors.

Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability.

There is a growing appreciation of the role that epigenetic alterations can play in oncogenesis. However, given the large number of genetic anomalies present in most cancers, it has been difficult to evaluate the extent to which epigenetic changes contribute to cancer. SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the epigenome as a core member of the SWI/SNF chromatin remodeling complex. While the SWI/SNF complex displays potent tumor suppressor activity, it is unknown whether this activity is exerted genetically via maintenance of genome integrity or epigenetically via transcriptional regulation. Here we show that Snf5-deficient primary cells do not show altered sensitivity to DNA damaging agents, defects in gamma-H2AX induction, or an abrogated DNA damage checkpoint. Further, the aggressive malignancies that arise following SNF5 loss are diploid and genomically stable. Remarkably, we demonstrate that most human SNF5-deficient cancers lack genomic amplifications/deletions and, aside from SNF5 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays. Finally, we show that epigenetically based changes in transcription that occur following SNF5 loss correlate with the tumor phenotype. Collectively, our results provide novel insight into the mechanisms of oncogenesis by demonstrating that disruption of a chromatin remodeling complex can largely, if not completely, substitute for genomic instability in the genesis of aggressive cancer.

The rise and fall of cardiac rehabilitation in the United Kingdom since 1998.

BACKGROUND: Provision of cardiac rehabilitation is inadequate in all countries in which it has been measured. This study assesses the provision in the United Kingdom and the changes between 1998 and 2004. METHODS: All UK cardiac rehabilitation programmes were surveyed annually. Figures for each year were up-rated to account for missing data and compared with national data for acute myocardial infarction, coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). The total numbers and percentage of eligible patients included were charted for 7 years. RESULTS: For centres giving figures, the total number treated rose from 29,890 in 1998 to 37,129 in 2004. The up-rated figures show that the percentage of eligible patients enrolled rose from 25.0% in 1998 to 31.5% in 1999 and has changed little since, falling from 31.3% in 2002 to 28.5% in 2004. About 25% of myocardial infarction patients, 75% of CABG patients and 20% of PCI patients joined cardiac rehabilitation programmes. CONCLUSIONS: The National Service Framework for Coronary Heart Disease set a target for 85% of myocardial infarct and coronary revascularization patients to be enrolled in rehabilitation programmes. Only one-third of this number is currently being enrolled and the percentage is falling.

NSF for CHD: 3 years of 12-month follow-up audit after cardiac rehabilitation.

BACKGROUND: The coronary heart disease (CHD) National Service Framework (NSF) sets standards and milestones. For acute myocardial infarction (AMI) or coronary revascularization, 'Milestone 3, of Standard 12 requires that, by April 2002, every hospital should have clinical audit data no more than 12 months old showing 'total number and % of those recruited to cardiac rehabilitation who, one year after discharge, report: regular physical activity of at least 30 minutes duration on average five times a week, not smoking and a Body Mass Index (BMI) of <30 kg/m2'. This study looked at cost, method and practicalities of retrieving this data. METHODS: A postal questionnaire was used to follow-up coronary patients who started our cardiac rehabilitation programme between 1 April 2001 and 31 March 2004. The project was costed. RESULTS: Three hundred and seventy-five (33 per cent) AMI patients, 412 (36 per cent) coronary artery bypass grafting (CABG) patients and 343 (30 per cent) percutaneous coronary intervention (PCI) patients entered the cardiac rehabilitation programme over 3 years. Completed questionnaires were received from 903 (80 per cent). Post-AMI patients or those stratified as high risk for further cardiac events were least likely to respond. Of responders, 74 per cent were exercising regularly, 95 per cent were not smoking and 79 per cent had a BMI <30 kg/m2. CONCLUSION: Targets for smoking and BMI set by the NSF are too low and were achieved by most patients before the start of cardiac rehabilitation. Patients who are post-AMI or are stratified as high risk need to be targeted if a high level of follow-up is to be achieved.

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation.

Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.

Psychological assessments for cardiac rehabilitation patients.

Psychological and quality of life measures are important in the assessment of cardiac rehabilitation (CR) patients and the outcome of treatment. This study aimed to assess the utility and sensitivity to change of three simple questionnaires in a CR setting. A total of 1403 patients who entered CR over 51 months were studied. Patients completed questionnaires before and after their phase 3 CR program-Hospital Anxiety and Depression (HAD) scale, WONCA/COOP charts and an analogue score of wellbeing. The three instruments took about 5.5 min in total to complete and 30 s to interpret. There were highly significant reductions in mean anxiety score-from 6.04 to 4.67 (P<0.001, 95% CI -1.52 to -1.16) and depression from 4.00 to 2.52 (P<0.001, 95% CI -1.62 to -1.29) The mean analogue of wellbeing score improved from 7.09 to 8.19 (P<0.001, 95% CI 0.97-1.22 ) There were highly significant improvements in five of the six WONCA domains. There were significant correlations between improvements in scores from all instruments. The sensitivity indices were in the 'good' range for changes in WONCA physical fitness domain and subjective well-being score and in the (moderate) range for changes in depression, well-being and WONCA overall health. Initial physical fitness was significantly correlated with the initial levels of all psychometric scores except anxiety and WONCA feelings, but improvements in fitness were not correlated with any changes in psychometric scores. The instruments described were quick to administer and to interpret and showed sensitivities to change superior to those which have been reported for other questionnaires. We believe them to be practical tools for use in CR units.

Patient characteristics and outcomes of cardiac rehabilitation.

PURPOSE: To investigate changes in physical fitness and psychological characteristics of patients after cardiac rehabilitation, and to assess predictors of defaulting from the program. METHODS: A prospective study of 1902 consecutive patients admitted to a community-based, hospital-linked cardiac rehabilitation program was conducted over a period of 6 years and 7 months. The cardiac rehabilitation program centered on a 2-to 6-month circuit training course with education, stress management, relaxation, and risk factor monitoring. Before and after the program, measures of physical fitness and of hospital anxiety and depression were performed. RESULTS: The course was completed by 1443 patients (76%), with 240 patients (13%) defaulting. For those who completed the course, peak oxygen consumption per minute increased by 3.2 mL/min/kg (95% confidence interval [CI], 3.1-3.4) or 19% (95% CI, 17.7%-20.3%). According to the hospital anxiety and depression scores, anxiety fell by 1.1 (95% CI, -1.3 to -0.98) and depression by 1.3 (95% CI, -1.4 to -1.2). The main predictors of defaulting were depression (patients with depression were twice as likely to default as nondepressed patients) and diagnosis (patients who had experienced angina or percutaneous transluminal coronary angioplasty were twice as likely to default as those who had experienced infarct or coronary artery bypass graft). CONCLUSIONS: The identification of depressed coronary patients known to be at increased risk should be a priority for cardiac rehabilitation coordinators. Every effort should be made to keep them in the cardiac rehabilitation program.