Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 183
Filter
1.
Mol Genet Genomics ; 298(5): 1155-1172, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37338594

ABSTRACT

In plants, the ability to produce hydrophobic substances that would provide protection from dehydration was required for the transition to land. This genome-wide investigation outlines the evolution of GDSL-type esterase/lipase (GELP) proteins in the moss Physcomitrium patens and suggests possible functions of some genes. GELP proteins play roles in the formation of hydrophobic polymers such as cutin and suberin that protect against dehydration and pathogen attack. GELP proteins are also implicated in processes such as pollen development and seed metabolism and germination. The P. patens GELP gene family comprises 48 genes and 14 pseudogenes. Phylogenetic analysis of all P. patens GELP sequences along with vascular plant GELP proteins with reported functions revealed that the P. patens genes clustered within previously identified A, B and C clades. A duplication model predicting the expansion of the GELP gene family within the P. patens lineage was constructed. Expression analysis combined with phylogenetic analysis suggested candidate genes for functions such as defence against pathogens, cutin metabolism, spore development and spore germination. The presence of relatively fewer GELP genes in P. patens may reduce the occurrence of functional redundancy that complicates the characterization of vascular plant GELP genes. Knockout lines of GELP31, which is highly expressed in sporophytes, were constructed. Gelp31 spores contained amorphous oil bodies and germinated late, suggesting (a) role(s) of GELP31 in lipid metabolism in spore development or germination. Future knockout studies of other candidate GELP genes will further elucidate the relationship between expansion of the family and the ability to withstand the harsh land environment.


Subject(s)
Bryopsida , Lipase , Lipase/genetics , Lipase/metabolism , Phylogeny , Dehydration/genetics , Esterases/genetics , Esterases/metabolism , Bryopsida/genetics , Genes, Plant , Plant Proteins/metabolism , Spores
2.
Cell Res ; 18(6): 622-40, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18504460

ABSTRACT

The PML gene is involved in the t(15;17) translocation of acute promyelocytic leukaemia (APL), which generates the oncogenic fusion protein PML (promyelocytic leukaemia protein)-retinoic acid receptor alpha. The PML protein localises to a subnuclear structure called the PML nuclear domain (PML-ND), of which PML is the essential structural component. In APL, PML-NDs are disrupted, thus implicating these structures in the pathogenesis of this leukaemia. Unexpectedly, recent studies indicate that PML and the PML-ND play a tumour suppressive role in several different types of human neoplasms in addition to APL. Because of PML's extreme versatility and involvement in multiple cellular pathways, understanding the mechanisms underlying its function, and therefore role in tumour suppression, has been a challenging task. In this review, we attempt to critically appraise the more recent advances in this field and propose new avenues of investigation.


Subject(s)
Neoplasms/metabolism , Neoplasms/pathology , Tumor Suppressor Proteins/metabolism , Animals , Cell Nucleus/metabolism , Humans , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Protein Structure, Tertiary , Tumor Suppressor Proteins/chemistry
3.
J Pathol ; 211(4): 471-80, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17206596

ABSTRACT

Promyelocytic leukaemia nuclear domains (PML-NDs) comprise a shell of PML protein and many labile cargo proteins. The nature of their cargo, their juxtaposition to foci of damaged DNA following ionizing radiation (IR), and the altered DNA damage responses in PML null cells all implicate PML-NDs in the DNA damage response. In this work, the propensity of PML-NDs to increase in number and decrease in size following IR has been studied. Serial quantitative studies of endogenous PML-NDs prove that the PML-ND response to IR is not the result of the asymmetry in cell cycle distribution that can follow IR, but reflects more directly the process of DNA damage. The response is swift, sensitive (evident after 1 Gy), and potentially reversible in untransformed fibroblasts. In these cells and in HCT116 colon cancer cells, failure to restore PML-ND number within 24 h correlates with later loss of growth potential--in fibroblasts, through prolonged cell cycle arrest and in HCT116 cells, through apoptosis. Failure to express an intact ATM/CHK2 DNA damage signalling pathway in either cell type leads to a delay in the PML-ND response to IR. Conversely, cell cycle progression following IR in cells that detect damaged DNA accelerates PML-ND reorganization. Collectively, these data show that the increase in PML-ND number seen after irradiation is, in part, triggered by the receipt of the DNA damage stimulus. The senescent cell state is also associated with chronic DNA damage and Hayflick-limited fibroblasts were found to express nuclei with elevated numbers of PML-NDs before IR that remained unresponsive to IR. Though the underlying reasons for damage-induced PML alteration remain obscure, it is noteworthy that significant numbers of PML-NDs juxtapose with ionizing radiation-induced foci after IR. The co-regulation of these structures may necessitate the stereotyped increases in PML-ND number following damage.


Subject(s)
Cell Nucleus/genetics , DNA Damage/genetics , Leukemia, Promyelocytic, Acute/genetics , Apoptosis/genetics , Cell Cycle/genetics , Cell Line , Cell Line, Tumor , Cellular Senescence/genetics , Checkpoint Kinase 2 , DNA Damage/radiation effects , Fibroblasts/physiology , Genes, Tumor Suppressor , Humans , Immunohistochemistry/methods , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Protein Serine-Threonine Kinases/genetics , Radiation, Ionizing , Signal Transduction/genetics
4.
Gut ; 53(2): 291-5, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14724166

ABSTRACT

BACKGROUND AND AIMS: Family history is used extensively to estimate the risk of colorectal cancer but there is considerable potential for recall bias and inaccuracy. Hence we systematically assessed the accuracy of family history reported at interview compared with actual cancer experience in relatives. METHODS: Using face to face interviews, we recorded family history from 199 colorectal cancer cases and 133 community controls, totalling 5637 first and second degree relatives (FDRs/SDRs). We linked computerised cancer registry data to interview information to determine the accuracy of family history reporting. RESULTS: Cases substantially underreported colorectal cancer arising both in FDRs (sensitivity 0.566 (95% confidence interval (CI) 0.433, 0.690); specificity 0.990 (95% CI 0.983, 0.994)) and SDRs (sensitivity 0.271 (95% CI 0.166, 0.410); specificity 0.996 (95% CI 0.992, 0.998)). There was no observable difference in accuracy of reporting family history between case and control interviewees. Control subjects similarly underreported colorectal cancer in FDRs (sensitivity 0.529 (95% CI 0.310, 0.738); specificity 0.995 (95% CI 0.989, 0.998)) and SDRs (sensitivity 0.333 (95% CI 0.192, 0.512); specificity 0.995 (95% CI 0.991, 0.995)). To determine practical implications of inaccurate family history, we applied family history criteria before and after record linkage. Only two of five families reported at interview to meet surveillance criteria did so after validation, whereas only two of six families that actually merited surveillance were identified by interview. CONCLUSIONS: This study has quantified the inaccuracy of interview in identifying people at risk of colorectal cancer due to a family history. Colorectal cancer was substantially underreported and so family history information should be interpreted with caution. These findings have considerable relevance to identifying patients who merit surveillance colonoscopy and to epidemiological studies.


Subject(s)
Colorectal Neoplasms/diagnosis , Family , Mental Recall , Aged , Case-Control Studies , Female , Humans , Interviews as Topic , Male , Medical Record Linkage , Middle Aged , Pedigree , Registries , Risk Assessment
5.
Brain Res ; 965(1-2): 57-66, 2003 Mar 07.
Article in English | MEDLINE | ID: mdl-12591120

ABSTRACT

Neurons are distinctive in that they are generally considered to be permanently post-mitotic cells. The oncoprotein p53 is a key regulator in neuronal development, notably in cell proliferation and neuronal death. We hypothesize that p53 maintains the post-mitotic characteristic of differentiated neurons. New lines of conditionally immortalized cortical cells were generated to test this hypothesis. Populations of cells were obtained from the neocortices of dual transgenic mice that were null for p53 and expressed a temperature-sensitive SV40 large T antigen. At a permissive temperature (32 degrees C), the cells continued to proliferate and most expressed nestin and proteins associated with glia. At a non-permissive temperature (39 degrees C), the cells expressed cytoskeletal proteins associated with differentiated neurons such as microtubule associated protein 2 and neurofilament 200. Under permissive conditions, both p53(+/-) and p53(-/-) cells exhibited similar cycling behaviors; the length of the cell cycle was 13-15 h and >85% of the cells were actively cycling. In non-permissive conditions, most p53(+/-) cells stopped dividing, whereas the p53(-/-) cells continued to proliferate. The survival of the cells also differed. In the non-permissive conditions, many p53(+/-) cells died following treatment with a neurotoxin (ethanol, 400 mg/dl), whereas the p53(-/-) cells did not. After re-introduction to the permissive conditions, both cell lines expressed neuron-like characteristics, but only the p53(-/-) cells retained their ability to cycle. Therefore, p53-mediated activities appear to be involved in the proliferation, survival, and post-mitotic nature of neuron-like cells.


Subject(s)
Cell Cycle/physiology , Cell Line, Transformed/cytology , Neocortex/cytology , Neurons/cytology , Tumor Suppressor Protein p53/deficiency , Animals , Cell Death/physiology , Cell Survival/physiology , Crosses, Genetic , Female , Fetus , Mice , Mice, Transgenic , Neocortex/metabolism , Neurons/metabolism , Pregnancy , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/genetics
7.
Oncogene ; 20(35): 4871-6, 2001 Aug 09.
Article in English | MEDLINE | ID: mdl-11521198

ABSTRACT

Colorectal cancer has been described in terms of genetic instability selectively affecting either microsatellite sequences (MIN) or chromosome number and structure (CIN). A subgroup with apparently stable, near-diploid chromosomes and stable microsatellites (MACS) also exists. These distinctions are important, partly because of their value in highlighting different pathways of carcinogenesis, and partly because of their direct relevance to prognosis. Study of early-onset cancer has often proved a fruitful resource for the identification of the nature and function of cancer susceptibility genes. In a study of colorectal cancer with stable microsatellite DNA, we describe 22 early-onset tumours (mean age=33), compared with 16 late-onset tumours (mean age=68). Both groups contained carcinomas with the MACS phenotype, characterized by near diploid DNA content, as defined by flow cytometry, and minimal chromosome arm deletion or amplification (six or less events per genome), determined by comparative genomic hybridization (CGH). Minimal chromosome imbalance correlated strongly with diploid DNA content (P<0.001). The proportion of MACS cancers was significantly greater in early-onset as compared to late-onset tumours (64 vs 13%, P=0.005). Of the chromosome arm imbalances commonly observed in late-onset tumours, only 18q- was observed more than twice amongst the 14 early-onset MACS tumours. Seventy-nine per cent of these MACS tumours were located in the distal colon, and 69% were at advanced clinico-pathological stages (with lymph node or distant metastasis). A positive family history of colorectal or other cancers was elicited in seven patients in the MACS early-onset group, and one additional patient in this group had a metachronous ovarian cancer. The results suggest that MACS cancer may have a genetic basis different from either MIN or CIN, and further studies of these cancers may lead to discovery of new mechanisms of colorectal carcinogenesis and cancer susceptibility.


Subject(s)
Chromosome Aberrations , Colorectal Neoplasms/genetics , Diploidy , Microsatellite Repeats , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged
8.
Cell Death Differ ; 8(3): 210-8, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11319603

ABSTRACT

We have examined the effects of inhibition of the 26S proteasome in a murine mammary cell line, KIM-2 cells using the peptide aldehyde inhibitor MG132. These studies have demonstrated a clear requirement for proteasome function in cell viability. Induction of apoptosis was observed following MG132 treatment in KIM-2 cells and this death was shown to be dependent on the cell actively traversing the cell cycle. KIM-2 cells were generated using a temperature sensitive T-antigen (Tag) and studies at the permissive temperature (33 degrees C) have shown that a Tag binding protein was essential for this apoptotic response. Studies in two additional cell lines, HC11, which is a mammary epithelial cell line carrying mutant p53 alleles and p53 null ES cells suggest that p53 is actively required for the apoptosis induced as a consequence of proteasome inhibition. These results suggest a pivotal role for the 26S proteasome degradation pathway in progression through the cell cycle in proliferating cells.


Subject(s)
Apoptosis/physiology , Leupeptins/pharmacology , Mammary Glands, Animal/cytology , Protease Inhibitors/pharmacology , Proteasome Inhibitors , Tumor Suppressor Protein p53/physiology , Animals , Annexin A5/analysis , Antigens, Viral, Tumor/biosynthesis , Antigens, Viral, Tumor/physiology , Apoptosis/drug effects , Blotting, Western , Cell Cycle/drug effects , Cell Cycle/physiology , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/enzymology , Mice , Proteasome Endopeptidase Complex , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics
9.
Proc Natl Acad Sci U S A ; 98(5): 2538-43, 2001 Feb 27.
Article in English | MEDLINE | ID: mdl-11226274

ABSTRACT

The abundant chromosome abnormalities in most carcinomas are probably a reflection of genomic instability present in the tumor, so the pattern and variability of chromosome abnormalities will reflect the mechanism of instability combined with the effects of selection. Chromosome rearrangement was investigated in 17 colorectal carcinoma-derived cell lines. Comparative genomic hybridization showed that the chromosome changes were representative of those found in primary tumors. Spectral karyotyping (SKY) showed that translocations were very varied and mostly unbalanced, with no translocation occurring in more than three lines. At least three karyotype patterns could be distinguished. Some lines had few chromosome abnormalities: they all showed microsatellite instability, the replication error (RER)+ phenotype. Most lines had many chromosome abnormalities: at least seven showed a surprisingly consistent pattern, characterized by multiple unbalanced translocations and intermetaphase variation, with chromosome numbers around triploid, 6-16 structural aberrations, and similarities in gains and losses. Almost all of these were RER-, but one, LS411, was RER+. The line HCA7 showed a novel pattern, suggesting a third kind of genomic instability: multiple reciprocal translocations, with little numerical change or variability. This line was also RER+. The coexistence in one tumor of two kinds of genomic instability is to be expected if the underlying defects are selected for in tumor evolution.


Subject(s)
Colorectal Neoplasms/genetics , Translocation, Genetic , Colorectal Neoplasms/pathology , Humans , Karyotyping , Tumor Cells, Cultured
11.
J Pathol ; 192(4): 440-5, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11113860

ABSTRACT

Current opinion of the genetic events driving colorectal tumourigenesis focuses on genomic instability. At least two apparently independent mechanisms are recognized, microsatellite instability and chromosomal instability. The genetic defects underlying each type of instability are only partially understood and controversy remains as to the role of p53 in the generation of chromosomal defects in colorectal cancer. This study sought to clarify the relationships between chromosomal abnormalities and defects of both p53 and mismatch repair. Extensive chromosomal analysis was undertaken, using flow cytometry and comparative genomic hybridization, of a series of sporadic colorectal cancers which had been grown to early passage as subcutaneous xenografts in SCID mice. Overall levels of chromosomal defects were observed to be low in RER+ cancers compared with RER- and distinctive patterns of chromosomal anomalies were found to be associated with both the RER+ and RER- phenotype. No particular level or pattern of chromosomal anomalies appeared to be associated with p53 status, supporting recent observations that abnormal p53 function is not sufficient to cause chromosomal anomalies in colorectal tumours.


Subject(s)
Chromosome Aberrations , Colorectal Neoplasms/genetics , Microsatellite Repeats , Adult , Aged , Aged, 80 and over , Animals , Colorectal Neoplasms/metabolism , Genes, p53 , Humans , Mice , Mice, SCID , Middle Aged , Neoplasm Proteins/metabolism , Neoplasm Transplantation , Nucleic Acid Hybridization , Ploidies , Transplantation, Heterologous , Tumor Suppressor Protein p53/metabolism
12.
Nature ; 407(6805): 777-83, 2000 Oct 12.
Article in English | MEDLINE | ID: mdl-11048728

ABSTRACT

DNA damage frequently triggers death by apoptosis. The irreversible decision to die can be facilitated or forestalled through integration of a wide variety of stimuli from within and around the cell. Here we address some fundamental questions that arise from this model. Why should DNA damage initiate apoptosis in the first place? In damaged cells, what are the alternatives to death and why should they be selected in some circumstances but not others? What signals register DNA damage and how do they impinge on the effector pathways of apoptosis? Is there a suborganellar apoptosome complex effecting the integration of death signals within the nucleus, just as there is in the cytoplasm? And what are the consequences of failure to initiate apoptosis in response to DNA damage?


Subject(s)
Apoptosis , Carrier Proteins , Cell Cycle Proteins , DNA Damage , DNA-Binding Proteins , Animals , Ataxia Telangiectasia Mutated Proteins , E2F Transcription Factors , Forecasting , Humans , Protein Serine-Threonine Kinases/physiology , Proto-Oncogene Proteins c-abl/physiology , Retinoblastoma-Binding Protein 1 , Transcription Factor DP1 , Transcription Factors/physiology , Tumor Suppressor Protein p53/physiology , Tumor Suppressor Proteins
13.
Mol Pathol ; 53(4): 173-6, 2000 Aug.
Article in English | MEDLINE | ID: mdl-11040938

ABSTRACT

Traditionally, the retrovirus is regarded as an enemy to be overcome. However, for the past two decades retroviruses have been harnessed as vehicles for transferring genes into eukaryotic cells, a process known as transduction. During this time, the technology has moved from being a scientific laboratory tool to a potential clinical molecular medicine to be used in gene therapy. This review explains the strategy for harnessing the retrovirus life cycle, the scientific research and clinical applications of this methodology, and its limitations, as well as possible future developments.


Subject(s)
Genetic Vectors , Retroviridae/genetics , Gene Transfer Techniques , Genetic Therapy/methods , Humans , Neoplasms/therapy
14.
S Afr Med J ; 90(7): 715-9, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10985135

ABSTRACT

OBJECTIVE: To determine the molecular basis and establish a routine molecular diagnostic service for familial adenomatous polyposis coli (FAP) families in South Africa. DESIGN: The coding region of the adenomatous polyposis coli (APC) gene in affected FAP kindreds was screened using heteroduplex analysis, single-strand conformation polymorphism analysis and the protein truncation test. SETTING: Department of Human Genetics, University of Stellenbosch, and the Cancer Research Campaign Laboratories, Department of Pathology, University of Edinburgh and Molecular Medicine Centre, Western General Hospital, Edinburgh, Scotland (academic visit of 6 months). SUBJECTS: FAP-affected individuals and at-risk family members in 28 apparently unrelated South African families. RESULTS: A total of nine different APC mutations was identified, allowing DNA-based diagnosis in 20 families. Three of these mutations have not been described previously in other populations. CONCLUSION: Pre-symptomatic diagnosis using direct mutation detection is cost-effective and surgical intervention has the potential to prevent cancer in at-risk individuals from FAP families.


Subject(s)
Adenomatous Polyposis Coli/genetics , Genetic Testing/methods , Mutation/genetics , Adenomatous Polyposis Coli/diagnosis , Codon , DNA, Neoplasm/analysis , Electrophoresis, Polyacrylamide Gel , Female , Humans , Male , Pedigree , Polymerase Chain Reaction , Sequence Analysis, DNA , South Africa/epidemiology
15.
Oncogene ; 19(35): 4079-83, 2000 Aug 17.
Article in English | MEDLINE | ID: mdl-10962567

ABSTRACT

We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbetaRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 - 4083.


Subject(s)
Adenocarcinoma/genetics , Base Pair Mismatch/genetics , Brain Neoplasms/genetics , Cell Transformation, Neoplastic/genetics , Colorectal Neoplasms/genetics , DNA Repair/genetics , Genes, p53 , Glioblastoma/genetics , Microsatellite Repeats , Neoplastic Syndromes, Hereditary/genetics , Adenocarcinoma/pathology , Adult , Brain Neoplasms/pathology , Chromosome Aberrations , Chromosome Deletion , Chromosomes, Human, Pair 9/genetics , Codon/genetics , Colorectal Neoplasms/pathology , DNA, Neoplasm/genetics , ErbB Receptors/genetics , Flow Cytometry , Gene Amplification , Gene Expression Regulation, Neoplastic , Glioblastoma/pathology , Humans , Neoplasm Proteins/biosynthesis , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/pathology , Neoplastic Syndromes, Hereditary/pathology , Nucleic Acid Hybridization , Organ Specificity , Ploidies , Syndrome , Tumor Suppressor Protein p53/biosynthesis
16.
J Biol Chem ; 275(17): 12737-42, 2000 Apr 28.
Article in English | MEDLINE | ID: mdl-10777569

ABSTRACT

The transcription factor NF-kappaB is a key modulator of apoptosis in a variety of cell types, but to date this specific function of NF-kappaB has not been demonstrated in epithelia. Here, we describe the activation of NF-kappaB during post-lactational involution of the mouse mammary gland, a period of extensive apoptosis of luminal epithelial cells. Significantly, active NF-kappaB localized exclusively to nonapoptotic epithelial cells both in vivo and in the mammary epithelial cell line, KIM-2, transduced with an NF-kappaB-dependent green fluorescent protein reporter. Activation of NF-kappaB in vitro coincided with a decrease in the cytosolic repressor, IkappaBalpha. Furthermore, induction of NF-kappaB either by extracellular ligands or, more specifically, by inhibition of the IkappaB repressor with adenoviral constructs expressing antisense mRNA, resulted in enhanced survival of KIM-2 cells. Therefore, although coincident with induction of apoptosis both in vivo and in vitro, NF-kappaB appeared to exert a selective survival function in epithelial cells. This study highlights for the first time a role for NF-kappaB in modulating apoptosis in epithelium.


Subject(s)
Apoptosis , Mammary Glands, Animal/pathology , NF-kappa B/physiology , Adenoviridae/metabolism , Animals , Annexin A5/metabolism , Cell Line , DNA, Antisense/metabolism , Dose-Response Relationship, Drug , Epithelium/metabolism , Epithelium/pathology , Female , Genes, Reporter , I-kappa B Proteins/metabolism , Immunohistochemistry , Ligands , Mammary Glands, Animal/metabolism , Mice , NF-kappa B/biosynthesis , Pregnancy , Time Factors , Transcription Factor RelA
18.
Addiction ; 95(12): 1821-32, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11177497

ABSTRACT

AIMS: To examine the dose-response relationship between self-reported alcohol consumption and levels of self-reported negative consequences of drinking. DESIGN: Data from 10 general population random sample surveys over the years 1990-1997 were combined and responses were plotted and subjected to regression analysis. SETTING: Auckland, a city of approximately 1 million people in the North Island of New Zealand. Participants were interviewed in their homes using a computer-assisted telephone interviewing system. PARTICIPANTS: General population sample of 11,817 aged 14-65 years, representative of the Auckland population. MEASUREMENTS: Frequency of experience of 14 negative consequences; annual volume of alcohol consumed; frequency of drinking larger quantities of alcohol. RESULTS: Three different patterns of relationship between consequences and consumption were found for different consequences. These differed between the prevalence and the frequency of consequences but were similar for two different measures of consumption, annual volume and larger quantity drinking. Analysis of the frequency of experienced consequences found that the risk curves for the most common consequences approximated a straight line and the effects at low volume intake were due to those drinking larger quantities. Three less common consequences clearly showed a concave curve suggesting a threshold effect, with effects beginning at about 20 litres per annum of absolute alcohol. CONCLUSION: The different relationships between consumption and consequences imply that some consequences occur only once a very heavy volume of drinking is reached, while others show a direct relationship with consumption, reflecting that volume of alcohol consumed is closely related to the quantities consumed.


Subject(s)
Alcohol Drinking/adverse effects , Adolescent , Adult , Aged , Alcohol Drinking/epidemiology , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , New Zealand/epidemiology , Prevalence , Regression Analysis , Risk Factors
19.
Br J Cancer ; 82(7): 1247-8, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10755395

ABSTRACT

The CYP19 gene codes for the aromatase enzyme that is involved in the synthesis of oestrogens. This case-control study examines the relationship between a tetranucleotide repeat sequence in the CYP19 gene and the development of male breast cancer. No significant differences were found between male breast cancer cases and controls.


Subject(s)
Aromatase/genetics , Breast Neoplasms, Male/genetics , Microsatellite Repeats/genetics , Case-Control Studies , Genetic Predisposition to Disease , Humans , Male , Polymerase Chain Reaction
20.
Oncogene ; 18(51): 7219-25, 1999 Dec 02.
Article in English | MEDLINE | ID: mdl-10602475

ABSTRACT

We have analysed the pattern of beta-catenin expression by immunohistochemistry in mice singly or multiply mutant for Apc, p53 and Msh2. We observed increased expression of beta-catenin in all intestinal lesions arising on an ApcMin+/- background. In all categories of lesion studied mosaic patterns of beta-catenin expression were observed, with the proportion of cells showing enhanced expression decreasing with increasing lesion size. p53 status did not alter these patterns. We also show that beta-catenin dysregulation marks pancreatic abnormalities occurring in ApcMin+/- and (ApcMin+/-, p53-/-) mice. In these mice both adenomas and adenocarcinomas of the pancreas arose and were characterized by increased expression of beta-catenin. We have extended these analyses to intestinal lesions arising in mice mutant for the mismatch repair gene Msh2. In these mice, increased expression of beta-catenin was again observed. However, in contrast with ApcMin+/- mice, a subset of lesions retained normal expression. Taken together, these findings show that increased expression of beta-catenin is an efficient marker of early neoplastic change in both murine intestine and pancreas in Apc mutant mice. However, we also show that dysregulation of beta-catenin is not an obligate step in the development of intestinal lesions, and therefore that genetic events other than the loss of Apc function may initiate the transition from normal to neoplastic epithelium.


Subject(s)
Cell Transformation, Neoplastic/genetics , Cytoskeletal Proteins/genetics , DNA-Binding Proteins , Gene Expression Regulation, Neoplastic , Genes, APC , Intestines/pathology , Proto-Oncogene Proteins/genetics , Trans-Activators , Adenomatous Polyposis Coli Protein , Animals , Cadherins/genetics , Intestines/physiology , Mice , MutS Homolog 2 Protein , Mutation , Proto-Oncogene Proteins/deficiency , Tumor Suppressor Protein p53/genetics , beta Catenin
SELECTION OF CITATIONS
SEARCH DETAIL
...