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Biomedical subjects

R Strange

Publications and source records attributed to R Strange.

At least 19 recordsLinked to original sources
PubMed2003

Moderate exercise training slows mammary tumour growth in adolescent rats.

Adolescence and young adulthood may be critical windows in establishing risk for breast cancer development in humans. Epidemiological data suggest that exercise during this life stage is associated with decreased breast cancer risk yet few experimental studies to elucidate the mechanism have been performed. The purpose of these studies was to evaluate the effects of moderate exercise training on mammary tumour development in adolescent rats using the 1-methyl 1-nitrosourea (MNU) chemical carcinogen model. Exercise (EX) consisted of moderate-intensity treadmill running 30 min/day, 5 days a week. A total of 274 animals were used: 94 in study 1 and 180 in study 2. Animals were injected with MNU (50 and 25 mg/kg body weight in studies 1 and 2, respectively) at 21 days of age and began training at 28 days of age. Groups of animals (n=10-30 depending on the study and time point) were sacrificed every 2 weeks for 8 weeks to evaluate tumour development. No difference in median tumour-free survival time was observed in the EX versus sham-exercise (SHAM), nor were there any differences in multiplicity at either a high or moderate dose of MNU. Latency to first tumour palpated was increased in both studies by 3-4 days. Consistent across both studies, tumour weights were less and the growth rates of the tumours, defined as tumour weight divided by the number of days elapsed since the tumour was first palpated, were reduced in the EX group. The data suggest that latency is increased and tumour growth is retarded in response to moderate exercise training.

Animals↗
PubMed2002

Effect of exercise on the rat mammary gland: implications for carcinogenesis.

Physical activity has been associated with decreased risk for developing breast cancer yet to date, the mechanism remains unknown. The purpose of this investigation was to evaluate the effects of moderate exercise training on the normal mammary gland in an attempt to identify alterations or differences that might be associated with tumour inhibition. A total of 170 female Sprague-Dawley rats were randomized to baseline (n=10), exercise (EX; n=80), or sham-exercise groups (SHAM; n=80). Treadmill training (20-25 m min-1, 15% grade, 30 min day-1, 5 days week-1) was started at 28 days of age (DOA). Animals were killed at 28, 42, 56, 70 and 84 DOA. Mammary glands were evaluated by histology and immunohistochemistry. Terminal end buds (TEB), structures susceptible to carcinogenesis, were counted. Sexual maturation, estradiol and progesterone, and organ and muscle weights were also evaluated. No differences in growth, sexual maturation, or steroid hormones were observed in response to training. No difference in the number of TEBs was observed at any timepoint between EX and SHAM. Proliferation was significantly increased at 56 DOA and tended to be increased at 42 and 70 DOA in the EX animals whereas cell death was significantly increased at 70 DOA and tended to be increased at 84 DOA in the EX animals. These data suggest no difference in the number of carcinogen-susceptible structures as a result of moderate exercise. The changes in cell proliferation and apoptosis with exercise training suggest altered cell turnover that will necessitate future study particularly with relevance to carcinogenesis.

Animals↗
PubMed2002

Further support for the association of CCR5 allelic variants with asthma susceptibility.

English and German nuclear families containing multiple asthmatic children and asthmatic parents were analysed to retest a recently reported association between resistance to asthma and the delta32 allele of chemokine receptor 5 (CCR5). Analysis of the families by the transmission-disequilibrium test (TDT) revealed a non-significant trend in the English families that provided marginal confirmation of the association (P < 0.125), but no similar trend was observed in the German families. Case-control comparison of delta32 allele and genotype frequencies in asthmatic vs. non-asthmatic parents revealed a significantly lower frequency of delta32 in asthmatic English parents (P < 0.009) and a similar but non-significant trend in German parents (P < 0.265). Taken together, the pattern of results provides confirmation for the previously observed delta32-asthma association and indicates that susceptibility to asthma may be influenced by CCR5 or another gene in chromosomal region 3p21.

Alleles↗
PubMed2001

Apoptosis in normal and neoplastic mammary gland development.

Apoptosis plays important roles in mammary development from early embryonic formation of the mammary gland to the regression that follows cessation of cycling. The most dramatic occurrence of apoptosis is found during mammary involution. Most of the secretory epithelium in the lactating breast undergoes apoptosis as the mammary gland regresses and is reorganized for another cycle of lactation. We used the morphology, biochemical changes, and gene expression detected in apoptotic mammary epithelium during involution as a model for studying cell death during other stages of mammary development and for approaching the failure of apoptosis found in mammary hyperplasia. Morphological studies and gene expression have suggested that apoptosis during involution is comprised of two phases: an early limited apoptosis in response to hormone ablation and later protease promoted widespread apoptosis in response to altered cell-matrix interactions and loss of anchorage. We examined protein expression during involution for changes associated with loss of hormone stimulation and altered cell-matrix interactions. One of the proteins whose expression is able to inhibit apoptosis, and is altered during mammary epithelial cell was the serine-threonine protein kinase, Akt 1. Akt 1 activation is common to hormone, growth factor, and anchorage-mediated survival of epithelial cells. We found regulated expression of activated Akt 1 in the mammary gland during involution. Akt 1 activation peaked in pregnancy and lactation, and decreased significantly during apoptosis in mammary involution. Mechanisms of Akt 1 action include modulation of the ratio bcl-2 family members implicated in control of apoptosis. Bcl-2 family proteins were also expressed in pattern consistent with Akt 1 regulation. These observations led us to examine expression of activated Akt 1 and bcl-2 family proteins in premalignant hyperplasias. Akt 1 activation was increased; expression of anti-apoptotic proteins bcl-2 and bcl-x was strongly increased while pro-apoptotic bax was greatly diminished in three different lines of transplantable premalignant mammary hyperplasia. This data suggest that activation of Akt 1 by hormone- or anchorage-mediated pathways regulates survival of mammary epithelium and can contribute to initiation of neoplasia. These data suggest that perturbation of normal cell turnover can contribute to initiation of neoplasia.

Animals↗
PubMed2001

Early stages of p53-induced apoptosis are reversible.

Apoptosis is a type of physiological cell death that occurs during development, normal tissue homeostasis, or as a result of different cellular insults. The phenotype of an apoptotic cell is relatively consistent in most cases of apoptosis and involves at least changes in the cell membrane, proteolysis of cytoplasmic and nuclear proteins, and eventual destruction of nuclear DNA. Our laboratory is interested in the reversibility of apoptosis. We have initial evidence that DNA repair is activated early in p53-induced apoptosis and may be involved in its reversibility. The present work further strengthens our proposition that p53-induced apoptosis is reversible. We show that p53 activation induces phosphatidylserine (PS) externalization early in apoptosis, and that these early apoptotic cells with externalized PS can be rescued and proliferate if the apoptotic stimulus is removed. In addition, we show that unscheduled DNA synthesis occurs in early apoptotic cells, and that if DNA repair is inhibited by aphidicolin, apoptosis is accelerated. These results confirm that early p53-induced apoptotic cells can be rescued from the apoptotic program, and that DNA repair can modulate that cell death process.

Animals↗
PubMed2001

Glutamine metabolism in sepsis and infection.

Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism. Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis. Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis. Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver. Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds. Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level. The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis. Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased. Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production.

Animals↗
PubMed2000

DNA repair is activated in early stages of p53-induced apoptosis.

p53 is a complex molecule involved in apoptosis, cell cycle arrest, and DNA repair. Since apoptosis may play an important role in deletion of neoplastic cells, an understanding of the mechanism of p53-induced apoptosis may be critical for possible future therapeutic interventions. Recent evidence suggests that p53-induced apoptosis may involve members of the nucleotide excision repair (NER) family, linking these two cellular events. Our work using a temperature-sensitive p53 construct further analyzes p53-induced apoptosis in cultured murine mammary epithelial cells and also suggests that DNA repair plays a role in that process. Although p21 is induced in our system, apoptosis occurs without a detectable preceding G1 cell cycle arrest and independent of cellular alterations brought on by the temperature shift. In addition, clonogenic assays suggest that early stages of p53-induced apoptosis may be reversible upon removal of the apoptosis stimulus. As a possible explanation for this reversibility, our results show that general DNA repair activity increases early in p53-induced apoptosis. We also show that caspase-3 is activated at a timepoint when colony formation begins to drop, suggesting a possible mechanism for the point of no return in p53-induced apoptosis.

Amino Acid Substitution↗
PubMed2000

Fibronectin fragments induce MMP activity in mouse mammary epithelial cells: evidence for a role in mammary tissue remodeling.

Mammary gland form and function are regulated by interactions between epithelium and extracellular matrix. Major glycoprotein components of extracellular matrix have been identified that give survival, proliferation and differentiation signals to mammary epithelial cells. We provide evidence that proteolytic fragments of the extracellular matrix glycoprotein, fibronectin, suppress growth and can promote apoptosis of mouse mammary epithelial cells. During mammary gland involution, total fibronectin and fibronectin fragment levels are increased. The peak levels of fibronectin protein and fragments are observed 4-6 days post-weaning, coincident with the peak in epithelial cell death. Using a model for hormone withdrawal-induced death of mammary epithelium, elevated levels of fibronectin proteolytic fragments were associated with apoptosis in TM-6 cells, a tumorigenic mouse mammary epithelial cell line. Treatment of TM-6 cells with exogenous fibronectin fragments (FN120) reduced cell number, and induced apoptosis and matrix degrading protease activity. Inhibition of matrix protease activity rescued TM-6 cell viability, indicating that FN120-induced cell loss is mediated through matrix protease activity. In a three-dimensional model for mammary gland development, FN120 reduced alveolar-like and promoted ductal-like development by a matrix protease-dependent mechanism. These data suggest that during post-lactational involution, fibronectin fragments may contribute to epithelial cell loss and dissolution of mammary alveoli by inducing matrix degrading proteinases.

Animals↗
PubMed1999

Apoptosis in the estrous and menstrual cycles.

In the absence of pregnancy, the adult mammary gland is subjected to cyclic fluctuations of hormonal stimulation that constitute the estrous and menstrual cycles. The mammary epithelium responds to these systemic hormonal changes by regional proliferation, differentiation and cell death by apoptosis. The fact that the mammary epithelial response involves only a minor subset of the epithelial cells implies a delicate local control of epithelial cell fate resulting in either cell death or survival. Evidence gleaned from descriptive data suggests that the apoptosis-related genes of the Bcl-2 gene family, tissue remodeling genes, protein tyrosine kinases and master genes of the homeotic gene cluster may be involved in determining epithelial cell fate during the estrous cycle.

Animals↗
PubMed1998

Influence of tumour necrosis factor microsatellite polymorphisms on susceptibility to head and neck cancer.

While cigarette smoking and alcohol consumption are recognized covariates for head and neck squamous cell carcinoma (SCC), the role of genetic factors in determining individual susceptibility is unknown. The human tumour necrosis factor (TNF) region on chromosome 6p21 within the major histocompatibility complex (MHC) includes a number of immunologically important genes. Recently, five microsatellite markers have been described in the TNF locus. TNF levels vary with different TNF microsatellite alleles, and associations of these microsatellite markers with autoimmune diseases and different types of cancer have been shown. Therefore, the TNF locus represents candidate susceptibility genes for head and neck cancer. This study describes the influence of TNF a-d microsatellite polymorphisms on susceptibility to head and neck cancer by comparing the allele frequencies of 269 patients suffering from laryngeal cancer and 123 patients suffering from oral cavity pharyngeal cancer and 113 German controls. DNA was extracted from peripheral blood samples, amplified by polymerase chain reaction with fluorescently labelled primers for TNF microsatellite (a-d) and electrophoresed on polyacrylamide gels using an automated DNA sequencer. The data showed no differences in allele frequencies between controls and pharyngeal cancer patients. By contrast, the TNF b3 allele was associated with altered risk for laryngeal cancer (p = 0.0006, odds ratio 2.2). Homozygosity for TNF b3/b3 resulted in an increased risk of developing laryngeal cancer (p = 0.004, odds ratio 5.3). Susceptibility to supraglottic SCC and multiple primary tumours was mediated by the absence of the a11 allele. The data provide the first evidence that allelism at the TNF microsatellite markers alter the risk of developing SCC of the larynx.

Alleles↗
PubMed1997

Differential induction of growth arrest inducible genes by selenium compounds.

The effects of two types of selenium compounds on the expression levels of growth arrest and DNA damage-inducible (gadd) genes and on selected cell death genes were examined in mouse mammary MOD cells to test the hypothesis that the diversity of selenium-induced cellular responses to these compounds could be distinguished by unique gene expression patterns. Whereas the expression patterns of known cell death-related genes (bcl-2 and bax) were not informative with respect to the cellular response patterns upon exposure to selenium compounds, time-dependent and selenium species-specific induction patterns were observed for gadd34, gadd45 and gadd153 genes. It was also observed that the MOD cells expressed a truncated p53 transcript but no detectable immunoreactive P53 protein, indicating a null p53 phenotype. The fact that selenium compounds induced growth arrest and death of these cells and that these compounds induced specific patterns of expression of gadd genes indicates that these genes may mediate some selenium-induced cellular responses. The findings further imply that selenium compounds may be effective chemopreventive agents for human breast carcinogenesis, in which p53 mutations are frequent.

Animals↗
PubMed1997

Glutathione S-transferase and cytochrome P450 genotypes as risk factors for laryngeal carcinoma.

While cigarette smoking and alcohol consumption have been linked to laryngeal squamous cell carcinoma (SCC), the role of genetic factors in determining individual susceptibility is unknown. We describe the role of allelism at the glutathione S-transferase GSTM1, GSTM3, GSTT1 and cytochrome P450 CYP1A1, CYP2E1, CYP2D6 loci in determining individual susceptibility to laryngeal SCC. Enzyme genotypes were determined using polymerase chain reaction and restriction enzyme digestion of leukocyte DNA collected from 269 patients with T1-T4 laryngeal carcinomas and 216 controls. While the frequencies of the heterozygote GSTM1 A/B genotype and the homozygote GSTM3 B/B genotype were statistically significantly lower in the patients with tumors than in controls, the frequency of the GSTT1 null genotype was higher in the patients than in controls. The data suggest that allelism at GST loci mediates susceptibility to SCC of the larynx. GSTM1 A/B and GSTM3 B/B appear to be associated with reduced risk, while GSTT1 null may confer increased risk. These findings are compatible with the view that genetic predisposition is important in determining risk for this cancer.

Alcohol Drinking↗
PubMed1997

Tumor necrosis factor microsatellite haplotypes are different in male and female patients with RA.

We investigated whether tumor necrosis factor (TNF) microsatellite polymorphisms are associated with sex and age at disease onset in rheumatoid arthritis (RA). A case-control study was used to compare the frequencies of TNF microsatellite alleles in 181 Caucasian RA cases and 251 controls. TNF microsatellite genotyping was performed using fluorescent based polymerase chain reaction (PCR) techniques and HLA-DR typing using PCR based sequence specific oligonucleotide probing. The association of TNF microsatellite alleles a6, b5, and d4 with RA was confirmed. These polymorphisms were more frequent in female patients. Male patients with RA with young age at onset had a different TNF microsatellite profile, TNFa2, b1, and c2 being the most frequent. TNF microsatellite polymorphisms are different in male and female patients with RA. This difference was more obvious in patients stratified according to age at onset. Sex and age at onset should be considered in studies of genetic factors in RA.

Adult↗
PubMed1997

Immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues.

Prostate apoptosis response 4 (par-4) is a recently identified gene that encodes a transcription factor, Par-4, with a leucine zipper domain. Par-4 protein is constitutively expressed in various cell lines and is functionally required but not sufficient for apoptosis. Induction of Par-4 in cultured cells is found exclusively during apoptosis, and ectopic overexpression of Par-4 enhances the potency of apoptotic stimuli. Western or Northern blot analysis on mRNA or protein extracts, respectively, from rat organs revealed that the expression of Par-4 was ubiquitous and was not restricted to any specific organ(s). To further identify specific cell types that expressed Par-4, we performed an immunohistochemical analysis of the protein in paraffin-embedded sections of various organs from rats. Our findings indicated that consistent with its proapoptotic role, Par-4 is expressed in apoptotic granulosa cells of atretic ovarian follicles and in terminally differentiated cells, such as the cardiomyocytes, cerebellar Purkinje cells, and pyramidal cells of the hypothalamus. Moreover, testosterone ablation by castration of rats caused an early and transient induction of Par-4 in the ductal cells of the prostate that undergo apoptosis. By contrast, in tissues in which the cells could be visually differentiated from their mature counterparts, Par-4 expression was lowest in the mature cells. This was the case for epithelia of the mammary and the prostate gland in which the basal cells maintained higher protein levels of Par-4 than did the terminally differentiated ductal cells. Similarly, cells of the stratum corneum of the skin and cells on top of the duodenal villi stained less intensely for Par-4 as compared to the stem cells in the stratum basale and at the bottom of the crypts of Lieberkühn, respectively. It is possible that Par-4 has to be down-regulated for successful differentiation in these tissues. Taken together, the widespread expression of Par-4 in various adult cell types underscores the physiological importance of the protein. The observation of constitutive Par-4 expression in the stem cell compartments is inconsistent with the probability of apoptosis per se and can be extended to determine whether Par-4 plays a role in other cellular processes.

Animals↗