ABSTRACT
The CBA/H mouse model of radiation-induced acute myeloid leukemia (AML) was re-examined using molecular approaches. In addition to the typical promyelocytic AMLs, 34% were reclassified as early pre-B lympho-myeloid leukemias (L-ML) based on leukemic blood cell morphology, immunoglobulin heavy-chain gene re-arrangements (IgH(R)), or expression of both lymphoid (Vpre-B1 and Rag1) and myeloid (myeloperoxidase and lysozyme M) genes. Allelic loss on chromosome 4 was frequently detected in AMLs (53%) and L-MLs (more than 95%), and the preferential loss of the maternally transmitted allele suggests the locus may be imprinted. A minimally deleted region (MDR) maps to a 3.4-cM interval, which is frequently deleted in radiation-induced thymic lymphomas (TLSR5) and contains a recessive, maternally transmitted genetic locus (Lyr2) that confers resistance to spontaneous and radiation-induced pre-B and T cell lymphomas, suggesting they are one and the same. Thus, the Lyr2/TLSR5 locus is frequently implicated in myeloid, lymphoid (B and T), and mixed-lineage mouse leukemias and lymphomas. Epigenetic inactivation of one Lyr2/TLSR5 allele during normal mouse development suggests that only a single hit is required for its inactivation during leukemogenesis, and this may be a significant contributing factor to the efficiency of the leukemogenic process in the mouse.
Subject(s)
Leukemia, Radiation-Induced/genetics , Loss of Heterozygosity , Mice/genetics , Acute Disease , Alleles , Animals , Burkitt Lymphoma/etiology , Burkitt Lymphoma/genetics , Burkitt Lymphoma/pathology , Cell Lineage , Cell Transformation, Neoplastic/genetics , Chromosome Mapping , DNA, Neoplasm/genetics , Gene Rearrangement, B-Lymphocyte , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Genes, Immunoglobulin , Genetic Markers , Genomic Imprinting , Immunity, Innate , Immunophenotyping , Leukemia, Myeloid/etiology , Leukemia, Myeloid/genetics , Leukemia, Myeloid/pathology , Leukemia, Radiation-Induced/classification , Leukemia, Radiation-Induced/pathology , Leukemia-Lymphoma, Adult T-Cell/etiology , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/pathology , Lymphoma/etiology , Lymphoma/genetics , Mice, Inbred C57BL , Mice, Inbred CBA , Neoplasms, Radiation-Induced/etiology , Neoplasms, Radiation-Induced/genetics , Receptors, Antigen, B-Cell/genetics , Spleen/pathology , Thymus Neoplasms/etiology , Thymus Neoplasms/geneticsABSTRACT
PURPOSE: To determine whether there is a relationship between the genetics underlying the susceptibility to radiation-induced leukaemia in CBA/H (acute myeloid leukaemia, AML) and C57BL/6 (thymic lymphoma, TL) mice, and the genetics underlying the sensitivity of CBA/H (sensitive) and C57BL/6 (resistant) mice to radiation-induced chromosomal instability. MATERIALS AND METHODS: CBA/H, (CBA/H x C57BL/6)F1, F1 x CBA/H, F1 x C57BL/6 and F1 x F1 mice were exposed to a single acute dose of 3.0 Gy X-rays. AML and TL were diagnosed over the subsequent 30 months. RESULTS: There was no statistically significant difference in the incidence of AML in F1, F1 x F1, F1 x CBA/H and F1 x C57BL/6 mice, which was approximately 50% that in CBA/H mice. AML susceptibility is therefore a dominant polygenic trait, and both susceptibility and resistance (variable penetrance) CBA/H and C57BL/6 loci are involved. The incidence of TL in the FM and F1 x CBA/H mice was negligible, indicating that TL susceptibility is a recessive trait. As the TL incidence in the F1 x C57BL/6 mice was about half that in C57BL/6 mice, one recessive locus is probably involved. CONCLUSIONS: AML susceptibility in CBA/H mice is a dominant trait in contrast to the recessive inheritance of CBA/H sensitivity to radiation-induced chromosomal instability. TL-susceptibility in C57BL/6 is a recessive trait in contrast to the dominant inheritance of C57BL/6 resistance to radiation-induced chromosomal instability.
Subject(s)
Genetic Predisposition to Disease , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/genetics , Lymphoma/etiology , Lymphoma/genetics , Neoplasms, Radiation-Induced/genetics , Radiation Tolerance , Thymus Neoplasms/etiology , Thymus Neoplasms/genetics , Animals , Blotting, Northern , Chromosomes/radiation effects , Crosses, Genetic , Genes, Recessive , Leukemia , Leukemia, Myeloid, Acute/mortality , Lymphoma/mortality , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , RNA, Messenger/metabolism , Thymus Neoplasms/mortality , Time Factors , X-Rays/adverse effectsABSTRACT
As part of its participation in the international network of health promoting hospitals (HPH), South Tyneside Health Care NHS Trust has initiated a series of sub-projects that are informed by the contemporary evidence-base and the principles of the HPH programme. This paper concerns the first of these sub-projects, whose aim is to establish an equitable and effective Trust-wide system to address smoking in South Tyneside. The ambition is to build a framework for, and foster a culture within which, individuals will be treated considerately, whilst managing "unhealthy" behaviour in such a way as to have a long-term positive impact within the organisation and the surrounding community. This paper will briefly outline the key activities underway, and the manner in which it is hoped this approach to undertaking a HPH sub-project will contribute to sustainable local health improvement, while also supporting the Trust's broader transformation into a truly health promoting organisation.
Subject(s)
Community Health Planning , Community-Institutional Relations , Health Promotion/organization & administration , Hospitals, Public/organization & administration , Smoking Prevention , State Medicine/organization & administration , England , Health Policy , Humans , Organizational Culture , Organizational Innovation , Organizational Objectives , Organizational Policy , Patient Care Team/organization & administration , Referral and Consultation/organization & administration , Smoking Cessation , Social SupportABSTRACT
Mouse radiation-induced acute myeloid leukaemias (AMLs) which arose in a (CBA/H x C57BL/6) genetic background have a 45% incidence of loss of heterozygosity (LOH) on chromosome 4. Frequent chromosome 4 LOH in mouse radiation-induced (C57BL/6 x RF/J) thymic lymphomas (TLs) is associated with promoter/exon 1 region hypermethylation of the remaining p15INK4b and p16INK4a alleles, so this may be common to mouse radiation myeloid and lymphoid leukaemogenesis. We addressed the question of p15INK4b/p16INK4a/p19ARF gene promoter hypermethylation in radiation-induced AMLs by comparison to TLs which arose in a similar (C57BL/6 x CBA/H) genetic background as a consequence of the same initiating dose of 3 Gy X-rays. Only one homozygous deletion was detected in the approximately 100 leukaemias analysed. p15INK4b gene promoter/exon 1 hypermethylation was readily detected (21%) in the lymphoid but not myeloid (3.1%) leukaemias, and p16INK4a and p19ARF gene promoter/exon 1 methylation was rare (<3%) in both. Thus, allelic loss and promoter hypermethylation of the p15INK4b gene is particular to radiation-induced lymphoid leukaemias and is independent of p16INK4a and p19ARF gene promoter/exon 1 hypermethylation.
Subject(s)
Cell Cycle Proteins , Chromosome Deletion , DNA Methylation , Leukemia, Lymphoid/genetics , Leukemia, Myeloid/genetics , Leukemia, Radiation-Induced/genetics , Microtubule Proteins , Promoter Regions, Genetic , Transcription Factors/genetics , Tumor Suppressor Proteins , Alleles , Animals , Cyclin-Dependent Kinase Inhibitor p15 , Genes, p16 , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Phosphoproteins/genetics , StathminABSTRACT
PURPOSE: To determine whether loss of heterozygosity (LOH) at specific chromosomal loci in radiation-induced leukaemias, arising in a similar genetic background, is leukaemia-type specific (myeloid versus lymphoid) or common to both. MATERIALS AND METHODS: Leukaemias that arose in 3 Gy X-irradiated (CBA/H x C57BL/6)F1 intercross and backcross mice were diagnosed as acute myeloid leukaemia (AML) or thymic lymphoma (TL). LOH was determined using 28 polymorphic microsatellite markers distributed over seven chromosomes using control and leukaemic DNA from individual mice. RESULTS: LOH incidences of 0-20% were observed at most loci in both leukaemia types. Specific LOH incidences of 38-76% were observed for myeloid (chromosome 2) and lymphoid (chromosomes 11 and 14) leukaemias. Chromosome 4 LOH was frequently (38-50%) observed in both types, although the commonly deleted regions differed. LOH was detected at either chromosome 2 or 4 in AML and either chromosome 4 or 11 in TL. CONCLUSIONS: LOH incidences of 38-76% suggest a causal role of particular loci which is mainly, but not exclusively, dependent on leukaemia type. LOH incidences of 0-20% at other loci in both leukaemias suggest that many genetic deletions are non-causal and incidental in radiation-leukaemogenesis.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Leukemia, Radiation-Induced/genetics , Leukemia, T-Cell/genetics , Loss of Heterozygosity , Animals , Chromosomes/genetics , Female , Gene Deletion , Leukemia, Myeloid, Acute/etiology , Leukemia, Radiation-Induced/etiology , Leukemia, T-Cell/etiology , Lymphoma, T-Cell/etiology , Lymphoma, T-Cell/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Microsatellite RepeatsABSTRACT
Clonogenic murine B cell precursors are normally ultrasensitive to apoptosis following genotoxic exposure in vitro but can be protected by expression of an E mu-BCL-2 transgene. Such exposures are likely to be mutagenic. This in turn suggests that a level of in vivo genotoxic exposure that usually has minimal pathological consequences might become leukaemogenic when damaged cells fail to abort by apoptosis. If this were to be the case, then the cell type that becomes leukaemic and the chromosomal/molecular changes that occur would also be of considerable interest. We tested this possibility by exposing E mu-BCL-2 and wild-type mice of differing ages to a single dose of X-irradiation of 1-4 Gy. Young (approximately 4-6 weeks) transgenic mice developed leukaemia at a high rate following exposure to 2 Gy but adult mice (4-6 months) did not. Exposure to 4 Gy produced leukaemia in both young and adult transgenic mice but at a higher frequency in the former. Leukaemic cell populations showed clonal rearrangements of the IGH gene but in most cases analysed had immunophenotypic features of an early B lympho-myeloid progenitor population which has not previously been recorded in radiation leukaemogenesis. Molecular cytogenetic analysis of leukaemic cells by banded karyotype and FISH revealed a consistent double abnormality: trisomy 15 plus an interstitial deletion of chromosome 4 that was confirmed by LOH analysis.
Subject(s)
Genes, bcl-2 , Leukemia, Radiation-Induced/genetics , Transgenes , Animals , Apoptosis/radiation effects , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , DNA Repair , Genes, Immunoglobulin , Humans , Immunoglobulin Heavy Chains/genetics , In Situ Hybridization, Fluorescence , Karyotyping , Mice , Mice, Transgenic , Recombinant Fusion Proteins/physiologyABSTRACT
PURPOSE: Genetic instability plays a major role in multi-stage carcinogenesis. Ionizing radiation induces delayed genetic instability which can be transmitted to the clonal offspring of the irradiated cell, so it is of considerable importance to determine whether radiation-induced genetic instability contributes to radiation-leukaemogenesis. RESULTS: The experimental data obtained using radiation-induced leukaemias in mouse models were reviewed, and an attempt was made to distinguish between the instability detectable in de novo cancers and that which is associated with ionising radiation. Genetic lesions identified in mouse leukaemias include non-clonal chromosomal aberrations, loss of heterozygosity, and minisatellite/microsatellite mutations. CONCLUSIONS: Studies of mouse radiation-induced leukaemias have detected evidence of genetic instability. However, with few exceptions, most of this instability was also observed during de novo multi-stage carcinogenesis. This raises the possibility that radiation induces ongoing genetic instability that is functionally indistinguishable to that implicated in de novo tumour progression.
Subject(s)
Disease Models, Animal , Genes/radiation effects , Leukemia, Radiation-Induced/genetics , Animals , Chromosome Aberrations/genetics , Chromosomes/radiation effects , DNA Damage/radiation effects , Loss of Heterozygosity/genetics , Loss of Heterozygosity/radiation effects , Mice , Radiation, Ionizing , Tandem Repeat Sequences/geneticsABSTRACT
As health education has become a major strategy for addressing current health problems, the need for expertise in health education has increased. Today health education specialists work not only in health agencies and educational institutions but also in hospitals and other health and medical facilities, in businesses and industries, and in consulting firms. To promote quality assurance in the delivery of health education services to the public, the profession has launched a voluntary credentialing system for health education specialists. Seven areas of responsibilities and the competencies that they require have been delineated as generic to the practice of entry level health education specialists, regardless of the setting (for example, school, health agency, work site) where they work. The purposes and rationale for new National Commission for Health Education Credentialing, Inc., are described as well as the benefits of certification for the profession. The events and accomplishments of the past decade that have provided the foundation for the newly established credentialing program for the health education profession are chronicled.
Subject(s)
Allied Health Personnel/standards , Certification , Health Education/standards , Clinical Competence , Credentialing , Education, Continuing , Humans , Quality Assurance, Health Care , United StatesSubject(s)
Family Practice , Health Education , Medicine , Physician's Role , Role , Specialization , HumansABSTRACT
The failure to plan the health education component of a health service program together with the total planning effort has severely limited the contribution education could make to program goals. This case study illustrates the use of the systematic observation of behavior to identify factors which facilitated or hindered the development of a hypertension control program in ambulatory facilities and boards of health. The relationship of these factors to the planning process is discussed. Although this project deals with hypertension, the factors identified as facilitating or hindering change are applicable to any public health program.