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Biomedical subjects

R Wiseman

Publications and source records attributed to R Wiseman.

At least 19 recordsLinked to original sources
PubMed2001

A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage.

A mouse model with a targeted mutation in the 3' end of the endogenous Brca1 gene, Brca1(1700T), was generated to compare the phenotypic consequences of truncated Brca1 proteins with other mutant Brca1 models reported in the literature to date. Mice heterozygous for the Brca1(1700T) mutation do not show any predisposition to tumorigenesis. Treatment of these mice with ionizing radiation or breeding with Apc, Msh-2 or Tp53 mutant mouse models did not show any change in the tumor phenotype. Like other Brca1 mouse models, the Brca1(1700T) mutation is embryonic lethal in homozygous state. However, homozygous Brca1(1700T) embryos reach the headfold stage but are delayed in their development and fail to turn. Thus, in contrast to Brca1(null) models, the mutant embryos do not undergo growth arrest leading to a developmental block at 6.5 dpc, but continue to proliferate and differentiate until 9.5 dpc. Homozygous embryos die between 9.5-10.5 dpc due to massive apoptosis throughout the embryo. These results indicate that a C-terminal truncating Brca1 mutation removing the last BRCT repeat has a different effect on normal cell function than does the complete absence of Brca1.

Animals↗
PubMed2001

Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice.

Cre-loxP based gene deletion approaches hold great promise to enhance our understanding of molecular pathways controlling mammary development and breast cancer. We reported earlier the generation of transgenic mice that express the Cre recombinase under the control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). These mice have become a valuable research tool to delete genes specifically in the mammary gland, other secretory organs, and the female germline. We have now characterized in depth the expression of the MMTV-Cre transgene using the ROSA26-lox-Stop-lox-LacZ reporter strain to determine the temporal and spatial activation of Cre on the level of single cells. Our results show that MMTV-mediated Cre-activation is restricted to specific cell types of various secretory tissues and the hematopoietic system. Secondly, the timing of Cre expression varies between tissues and cell types. Some tissues express Cre during embryonic development, while other selected cell types highly activate Cre around puberty, suggesting a strong influence of steroid hormones on the transcriptional activation of the MMTV-LTR. Thirdly, Cre expression in the female germline is restricted to individual mouse lines and is therefore dependent on the site of integration of the transgene. Information provided by this study will guide the researcher to those cell types and developmental stages at which a phenotype can be expected upon deletion of relevant genes.

Animals↗
PubMed2001

Collaborating to manage polypharmacy.

DiNCQUMGP (Divisions National Consortium for the Quality Use of Medicines in General Practice) reports on a collaboration between doctors, pharmaceutical companies, government agencies, and medicine users to manage polypharmacy (prescribing multiple medicines to a patient) amongst older people. We have reported the outcomes of our collaboration (improving the Quality Use of Medicines) elsewhere. Here we discuss how we worked together, opened up new opportunities, and learned from one another. The first part of this article outlines a constructive new way of thinking about collaborating, that we argue is fundamentally different from current approaches. The second part describes what we did in the words of those involved.

Cooperative Behavior↗
PubMed1999

Does Psi exist? Lack of replication of an anomalous process of information transfer.

D. J. Bem and C. Honorton (1994) recently presented in this journal a set of ganzfeld extrasensory perception (ESP) experiments conducted by C. Honorton that appeared to support the existence of a communication anomaly. In this article, the authors present a meta-analysis of 30 ganzfeld ESP studies from 7 independent laboratories adhering to the same stringent methodological guidelines that C. Honorton followed. The studies failed to confirm his main effect of participants scoring above chance on the ESP task, Stouffer z = 0.70, p = .24, one-tailed; M effect size (z/N1/2) = 0.013, SD = 0.23. The new studies included replication attempts of 3 out of 5 internal effects reported as statistically significant by D. J. Bem and C. Honorton. Only 1 was confirmed, and the authors found that D. J. Bem and C. Honorton were mistaken in describing the original effect as being statistically significant. The authors conclude that the ganzfeld technique does not at present offer a replicable method for producing ESP in the laboratory.

Bias↗
PubMed1998

BRCA1 and BRCA2 in breast cancer families from Wales: moderate mutation frequency and two recurrent mutations in BRCA1.

Mutations in the BRCA1/BRCA2 genes account for varying proportions of breast cancer families studied, and demonstrate considerable variation in mutational spectra coincident with ethnic and geographical diversity. We have screened for mutations in 17 families from Wales with two or more cases of breast cancer under age 50 and/or ovarian cancer. Eight out of 17 (47%) families had demonstrable mutations. Six out of 17 (35%) carried BRCA1 mutations and 2 out of 17 (12%) carried BRCA2 mutations. Two recurrent mutations in BRCA1 were identified, which appear to represent founder mutations in this population. These data support the existence of additional breast and ovarian cancer susceptibility genes.

Adult↗
PubMed1998

Can animals detect when their owners are returning home? An experimental test of the 'psychic pet' phenomenon.

In his book, Seven Experiments That Could Change The World, Rupert Sheldrake suggested that the public carry out experiments to test whether pets can psychically detect when their owners are returning home. The first of these tests was undertaken by an Austrian television company and involved an owner in the north-west of England, Pam Smart (PS) and her dog (Jaytee). The test appeared remarkably successful and seemed to show Jaytee responding when PS set off to return home from a remote location. Rupert Sheldrake and PS asked the authors if they would like to carry out their own investigation into Jaytee's abilities. This paper outlines various 'normal' explanations that might account for the phenomenon and presents an experimental design that minimizes these possibilities. The paper then details the procedure and results of four experiments. Analysis of the data did not support the hypothesis that Jaytee could psychically detect when his owner was returning home. Finally, the paper discusses a possible reason for the difference in results of these studies and those carried out by the Austrian television company.

Animals↗
PubMed1997

Similar incidence of K-ras mutations in lung carcinomas of FVB/N mice and FVB/N mice carrying a mutant p53 transgene.

Mutated p53 genes are capable of complementing activated ras genes in the transformation of primary rat embryo fibroblasts in vitro. Mutations in both genes have also been found in several human cancers, including lung carcinomas. We generated transgenic mice containing a p53 construct with a missense mutation in exon 5 (ala135val) to study the role of p53 mutations in lung tumorigenesis, and to facilitate identification of other genetic events that might complement p53 mutations in mouse lung carcinogenesis. The p53 transgenic lines exhibited a higher frequency of lethal lung tumors than the parental FVB/N strain. We examined the spontaneously-arising lung carcinomas from mice expressing the mutated p53 transgene for K-ras mutations using single-stranded conformation polymorphism (SSCP) and/or direct sequencing approaches. Fifteen of 29 (52%) carcinomas contained mutations in the K-ras oncogene. Six of 15 of the K-ras mutations were in codon 61 and 9/15 were in codon 12. Subsequent analysis of spontaneous lung carcinomas from mice of the FVB/N parental strain showed that 9/12 (75%) carcinomas examined contained K-ras mutations. Two of these were in codon 12, one in codon 13, and 6 were in codon 61. These results demonstrate that the frequency of ras mutations does not differ between the p53 FVB/N transgenic mice and their parental FVB/N strain but suggest that a high frequency of mutations K-ras can be correlated with lung tumorigenesis in both groups of mice.

Animals↗
PubMed1996

Molecular modeling of the amino-terminal zinc ring domain of BRCA1.

The equine herpes virus zinc ring domain nuclear magnetic resonance structure was used for homology-based modeling of the amino-terminal zinc ring domain of the BRCA1 breast and ovarian cancer susceptibility gene. The zinc ring domain of BRCA1 is of particular interest because it is the location of significant and frequently occurring missense (Cys(61)Gly, Cys(64)Gly, and Cys(64)Tyr) and frameshift (185delAG) mutations observed in several high-risk kindreds. The BRCA1 zinc ring domain possesses 54% sequence similarity with the equine herpes virus zinc ring domain. The model structure undergoes little conformational variance after 140 ps of solvated molecular dynamics. This model proposes BRCA1 zinc ring domain residues that may play a role in DNA binding and/or protein-protein interactions. These predictions provide a point of departure for the design of mutants to probe BRCA1 zinc ring domain functionality.

Amino Acid Sequence↗
PubMed1995

Hepatic and pulmonary carcinogenicity of methylene chloride in mice: a search for mechanisms.

An inhalation study utilizing over 1400 female B6C3F1 mice was undertaken to study mechanistic factors associated with liver and lung tumor induction following exposure to 2000 ppm of methylene chloride. Mice were exposed to methylene chloride (treated) or chamber air (controls) 6 h per day, for varying durations up to 104 weeks. Several interim sacrifices and 'stop exposures' were included. Exposure to 2000 ppm methylene chloride caused an increase in liver and lung neoplasia in the absence of overt cytotoxicity. Measurement of replicative DNA synthesis done after 13, 26, 52 and 78 weeks of exposure showed a significant decrease in the hepatocyte labeling index at 13 weeks. Replicative DNA synthesis in pulmonary airways after 1, 2, 3, 4, 13 and 26 weeks of exposure to methylene chloride was significantly lower than in air-exposed controls. Likewise, the increase in tumor induction in treated mice was not associated with increased replicative DNA synthesis in liver foci or in alveolar parenchyma. The frequency and pattern of H-ras gene activation were similar in control and methylene chloride-induced liver neoplasms. Similarly, the frequency and pattern of K-ras activation in lung neoplasms were not altered by exposure to methylene chloride. Early exposure to methylene chloride for only 26 weeks was sufficient to cause an increase in lung tumors by 2 years, suggesting that methylene chloride may cause early and persistent loss of growth control in lung cells. This implies that risk management strategies should be aimed at minimizing or eliminating exposure to methylene chloride. Liver neoplasms continued to increase in incidence and multiplicity as exposure continued, suggesting that methylene chloride-induced hepatocarcinogenesis is facilitated by continuing exposure to methylene chloride. Since methylene chloride is a more potent inducer of lung than liver neoplasia, it is recommended that health risk assessment be based on the lung data. While no novel molecular lesions have been found to explain the induction of lung and liver neoplasia in mice, ongoing studies may identify other molecular changes that are important in the genesis of these neoplasms. Hence, it may be necessary to revise risk assessment and management strategies in light of future research findings.

Administration, Inhalation↗
PubMed1994

The p53 tumor suppressor gene frequently is altered in gynecologic cancers.

Mutation of the p53 tumor suppressor gene, often accompanied by overexpression of mutant p53 protein, is the most frequent molecular genetic event described thus far in human cancers. In adenocarcinomas of the ovary and endometrium, p53 overexpression is seen in approximately 10% to 15% of early and 40% to 50% of advanced cancers. Similar to many other types of human cancers, ovarian and endometrial cancers that overexpress p53 protein contain mutations in conserved regions of the p53 gene. These mutations are predominantly transitions, which suggests that they arise spontaneously rather than being caused by carcinogen exposure. Alteration of the p53 gene does not appear to be a feature of endometrial hyperplasias or benign or borderline ovarian tumors. Although mutation and overexpression of p53 rarely occur in cancers of the cervix, vulva, and vagina, it has been shown that human papillomavirus E6 oncoproteins bind to and inactivate p53 protein. Studies of the p53 gene have begun to provide insight into the molecular pathogenesis of gynecologic cancers.

Adenocarcinoma↗
PubMed1994

Loss of heterozygosity in spontaneous and chemically induced tumors of the B6C3F1 mouse.

The B6C3F1 mouse is used worldwide to gauge the carcinogenic hazard posed by chemicals to humans. An assessment of the ability of this rodent model to predict human neoplasia requires an evaluation of similarities and differences in the genetics of tumor formation between these two species. We examined 142 spontaneous and chemically-induced liver tumors isolated from the B6C3F1 mouse for losses of heterozygosity (LOH) at 78 polymorphic loci and compared these results to genetic changes known to occur in human hepatocellular carcinoma. Approximately a third of the 142 mouse tumors exhibited LOH, suggesting that tumor suppressor gene inactivation may be involved in the formation of mouse liver tumors. Most of the LOH observed was restricted to seven chromosome sites and most of the tumors that underwent LOH lost alleles from only one of those seven sites. The relatively few losses seen in these mouse tumors distinguished them from clinical stage human tumors in that, in the mouse tumors, interstitial deletions appeared more frequently than losses of whole chromosomes. Only four mouse tumors lost a whole chromosome. LOH occurred at loci of the mouse genome syntenic to areas of the human genome known to harbor the Wilms', retinoblastoma, APC, MCC and DCC tumor suppressor genes; these genes have never been associated with hepatocellular carcinomas. Losses observed on chromosomes 5 and 8 (syntenic to human chromosomes 4 and 16) suggest tumor suppressor genes that are common to hepatocellular carcinomas from both species, while losses on chromosome 9 suggest involvement of a previously unidentified tumor suppressor gene.

Animals↗
PubMed1993

Coordinate regulation of collagen II(alpha 1) and H19 expression in immortalized hamster cells.

Loss of tumor suppressor gene function is essential in the multistep progression of cells to neoplasia. Immortalized cells were established by carcinogen treatment of Syrian hamster embryo cells. At early passages, these nontumorigenic cells retained the ability to suppress tumorigenicity in cell hybrids with malignant cells. Upon passage and subcloning of these suppressor-positive (supB+) cells, variant clones that had lost tumor suppressor activity were isolated. These suppressor-negative (supB-) clones remained nontumorigenic. The mRNAs encoding collagen II(alpha 1a), a chondrocyte differentiation marker, and H19, a developmentally controlled gene, were more abundant in supB+ cells than in supB- cells. Nuclear run-on analysis indicated that the transcription of these genes is differentially regulated. Transient transfection experiments revealed that a cis-acting element in the rat collagen II 5' flanking sequences directs differentially regulated transcription. Gel retention analysis demonstrated the presence of a nuclear DNA-binding factor(s) that specifically recognizes a DNA sequence common to both the rat collagen II sequences and the mouse H19 enhancer. In one set of clones, transcriptional regulation could account for differential collagen II and H19 expression in supB+ and supB- cells. In another set of clones, posttranscriptional controls are responsible for the decreased expression of these genes in supB- cells. The emergence of two independent mechanisms that cause differential expression of collagen II and H19 related to tumor suppressor loss suggests that coordinate regulation of these genes, or others regulated by common mechanisms, may be important in tumor suppression.

Animals↗
PubMed1993

Linkage analysis in German breast cancer families with early onset of the disease, using highly polymorphic markers from the chromosome 17q11-q24 region.

Linkage analysis in German breast cancer families with early onset of the disease by using six markers on chromosome 17q11-q24 has been carried out. In the region between markers D17S250 and GH, three markers showed positive LOD scores at an estimated distance of zero. Evidence for linkage is greatest for D17S250, with a LOD score of 2.42.

Adult↗
PubMed1990

Bacterial colonization of the skin after chemical depilation.

A study of the effects of preoperative skin depilation on skin microflora has been performed. Areas of skin were prepared with a chemical depilatory agent and compared with areas of unprepared skin. Preparation of skin with a chemical depilatory agent causes no increase in skin microflora, in contrast to the effects of shaving as demonstrated by earlier studies.

Bacteria↗