ABSTRACT
The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.
Subject(s)
Antineoplastic Agents/therapeutic use , Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Phthalazines/therapeutic use , Piperazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/genetics , Animals , Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , DNA Damage/drug effects , Gene Knockdown Techniques , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Lymphoma, Mantle-Cell/genetics , Mice , Mice, SCID , Mutation , Phthalazines/pharmacology , Piperazines/pharmacologyABSTRACT
BACKGROUND: Human Papilloma Virus (HPV) vaccine has undergone successful trials and has recently been approved for use for the primary prevention of cervical cancer. The aim of this study was to determine knowledge and attitudes towards HPV vaccination. METHODS: Semi-structured interview and questionnaire delivered in a street survey. Standardised HPV-related statements used to measure HPV knowledge and attitudes to vaccination. The setting was three different areas of Birmingham, to target a mix of social class and ethnicity. The sample population was composed of 16-54 year olds. RESULTS: A total of 420 participants were recruited. Poor knowledge of HPV and its links with cervical cancer were observed. 81% had a knowledge score of zero. Knowledge about HPV was associated with different ethnic group and socio-economic group. The majority (88%) of participants were in favour of vaccination, with 83.6% indicating that they would allow a child under their care to be vaccinated. CONCLUSION: Initial responses to the proposed HPV vaccination within the UK public are favourable. However, knowledge levels are poor and media and health professional promotion are required to raise awareness.
Subject(s)
Health Knowledge, Attitudes, Practice , Papillomavirus Vaccines , Public Opinion , Adolescent , Adult , Cross-Sectional Studies , England , Ethnicity , Female , Humans , Interviews as Topic , Male , Middle Aged , Social Class , Surveys and Questionnaires , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/prevention & control , Young AdultABSTRACT
Neuroblastoma is a heterogeneous tumour with a variety of clinical phenotypes, ranging from a localised tumour with excellent outcome (stage 1) to a metastatic, usually fatal malignancy (stage 4). In order to investigate the genetic relationship between these tumour subtypes, a loss of heterozygosity (LOH) analysis was carried out. Composite LOH allelotypes incorporating data from 96 loci on 5 chromosomes (1p, 3p, 4p, 11q, 14q), were constructed for 62 neuroblastomas. Neuroblastomas with similar allelotypes were clustered into groups and allelotype patterns correlated with clinical features. Three distinct genetic subgroups of neuroblastoma were observed. The largest group (50% of tumours) was characterised by specific allelotype patterns indicative of a stepwise accumulation of genetic alterations (11q LOH-->1p, 4p, and/or 14q LOH-->3p LOH), associated with progression from low to high stage disease. These tumours are distinct from MYCN amplified neuroblastomas which have a more rapid and aggressive disease course, and also a proportion of low stage tumours, often ganglioneuromas or ganglioneuroblastomas, with restricted growth potential.