Biomedical subjects

R Parsons

Publications and source records attributed to R Parsons.

At least 19 recordsLinked to original sources

PubMed2001

Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression.

The PTEN gene encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase pathway and is inactivated in a wide variety of malignant neoplasms. High rates of loss of heterozygosity are observed at the 10q23.3 region containing the human PTEN gene in prostate cancer and other human malignancies, but the demonstrated rate of biallelic inactivation of the PTEN gene by mutation or homozygous deletion is significantly lower than the rate of loss of heterozygosity. The transgenic adenocarcinoma of mouse prostate model is a well characterized animal model of prostate cancer. Analysis of prostate cancer progression in transgenic adenocarcinoma of mouse prostate mice bred to Pten(+/-) heterozygous mice, coupled with analysis of the Pten gene and protein in the resulting tumors, reveals that haploinsufficiency of the Pten gene promotes the progression of prostate cancer in this model system. This observation provides a potential explanation for the discordance in rates of loss of heterozygosity at 10q23 and biallelic PTEN inactivation observed in prostate cancer and many human malignancies.

Animals↗

PubMed2001

An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice.

PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN(+/-) mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR/RAFT/FRAP reduced neoplastic proliferation, tumor size, and p70/S6 kinase activity, but did not affect the status of Akt. These data suggest that p70/S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.

Alleles↗

PubMed2001

PTEN: life as a tumor suppressor.

PTEN, a tumor suppressor located at chromosome 10q23, is mutated in a variety of sporadic cancers and in two autosomal dominant hamartoma syndromes. PTEN is a phosphatase which dephosphorylates phosphatidylinositol (3,4,5)-triphosphate (PtdIns-3,4,5-P3), an important intracellular second messenger, lowering its level within the cell. By dephosphorylating PtdIns-3,4,5-P3, PTEN acts in opposition to phosphatidylinositol 3-kinase (PI3K), which has a pivotal role in the creation of PtdIns-3,4,5-P3. PtdIns-3,4,5-P3 is necessary for the activation of Akt, a serine/threonine kinase involved in cell growth and survival. By blocking the activation of Akt, PTEN regulates cellular processes such as cell cycling, translation, and apoptosis. In this review, we will discuss the identification of PTEN, its mutational status in cancer, its role as a regulator of PI3K, and its domain structure.

Animals↗

PubMed2001

A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.

Adolescent↗

PubMed2001

Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice.

BACKGROUND: Germline mutations in the tumor suppressor PTEN predispose human beings to breast cancer, and genetic and epigenetic alterations of PTEN are also detected in sporadic human breast cancer. Germline Pten mutations in mice lead to the development of a variety of tumors, but mammary carcinomas are infrequently found, especially in mice under the age of six months. RESULTS: To better understand the role of PTEN in breast tumor development, we have crossed Pten heterozygous mice to MMTV-Wnt-1 transgenic mice that routinely develop ductal carcinomas in the mammary gland. Female Wnt-1 transgenics heterozygous for Pten developed mammary tumors earlier than Wnt-1 transgenics that were wild type for Pten. In most tumors arising in Pten heterozygotes, the Pten wild-type allele was lost, suggesting that cells lacking Pten function have a growth advantage over cells retaining a wild type allele. Tumors with LOH contained high levels of activated AKT/PKB, a downstream target of the PTEN/PI3K pathway. CONCLUSIONS: An animal model has been developed in which the absence of Pten collaborates with Wnt-1 to induce ductal carcinoma in the mammary gland. This animal model may be useful for testing therapies specific for tumors deregulated in the PTEN/PI3K/AKT pathway.

Journal Article↗

PubMed2001

Nitrogen nutrition and the role of root-shoot nitrogen signalling particularly in symbiotic systems.

To obtain and concentrate reduced N from the environment, plants have evolved a diverse array of adaptations to utilize soil, biotic and atmospheric N. In symbiotic N(2)-fixing systems the potential for oversupply exists and regulation of activity to match demand is crucial. N status in plants is likely to be most strongly sensed in the shoot and signals translocated to the roots may involve phloem transported amino compounds or very low concentrations of specific signal molecules. The mechanism for sensing N status in plant cells is not understood at the molecular level although it may be expected to be similar in all plants. Mechanisms for the regulation of symbiotic N(2) fixation may be very different in the different symbiotic types. Rhizobia, Frankia and cyanobacteria are all symbiotic with different species of plants and the provision of O(2), carbohydrate or other nutrients may control symbiotic activity to varying extents in the different symbioses.

Adaptation, Physiological↗

PubMed2001

PTEN expression causes feedback upregulation of insulin receptor substrate 2.

PTEN is a tumor suppressor that antagonizes phosphatidylinositol-3 kinase (PI3K) by dephosphorylating the D3 position of phosphatidylinositol (3,4,5)-triphosphate (PtdIns-3,4,5-P3). Given the importance of PTEN in regulating PtdIns-3,4,5-P3 levels, we used Affymetrix GeneChip arrays to identify genes regulated by PTEN. PTEN expression rapidly reduced the activity of Akt, which was followed by a G(1) arrest and eventually apoptosis. The gene encoding insulin receptor substrate 2 (IRS-2), a mediator of insulin signaling, was found to be the most induced gene at all time points. A PI3K-specific inhibitor, LY294002, also upregulated IRS-2, providing evidence that it was the suppression of the PI3K pathway that was responsible for the message upregulation. In addition, PTEN, LY294002, and rapamycin, an inhibitor of mammalian target of rapamycin, caused a reduction in the molecular weight of IRS-2 and an increase in the association of IRS-2 with PI3K. Apparently, PTEN inhibits a negative regulator of IRS-2 to upregulate the IRS-2-PI3K interaction. These studies suggest that PtdIns-3,4,5-P3 levels regulate the specific activity and amount of IRS-2 available for insulin signaling.

Apoptosis↗

PubMed2000

Endovascular grafts in the treatment of thoracic aortic aneurysms and pseudoaneurysms.

The purpose of this study was to describe our experience with balloon and self-expanding endovascular grafts for the management of thoracic aortic lesions. Between February 1997 and June 1998, 20 endovascular grafts were implanted in 14 patients for the treatment of thoracic aortic aneurysms and pseudoaneurysms. Endovascular procedures were performed using one of four different devices: (1) Dacron-covered balloon-expandable Palmaztrade mark stent, (2) balloon-expandable Palmaz stent-PTFE graft prosthesis (BE-PS), (3) self-expanding internally supported Nitinol Dacron prosthesis (Vanguardtrade mark SE-V), and (4) self-expanding externally supported Nitinol PTFE prosthesis (Excludertrade mark SE-E). The results show that endovascular grafting represents a potentially important alternative therapy to open repair of the thoracic aorta. Self-expanding devices were, in our experience, easier to use and more accurately deployed.

Adult↗

PubMed2000

Identification of alanine dehydrogenase and its role in mixed secretion of ammonium and alanine by pea bacteroids.

N2-fixation by Rhizobium-legume symbionts is of major ecological and agricultural importance, responsible for producing a substantial fraction of the biosphere's nitrogen. On the basis of 15N-labelling studies, it had been generally accepted that ammonium is the sole secretion product of N2-fixation by the bacteroid and that the plant is responsible for assimilating it into amino acids. However, this paradigm has been challenged in a recent 15N-labelling study showing that soybean bacteroids only secrete alanine. Hitherto, nitrogen secretion has only been assessed from in vitro 15N-labelling studies of isolated bacteroids. We show that both ammonium and alanine are secreted by pea bacteroids. The in vitro partitioning between them will depend on whether the system is open or closed, as well as the ammonium concentration and bacteroid density. To overcome these limitations we identified and mutated the gene for alanine dehydrogenase (aldA) and demonstrate that AldA is the primary route for alanine synthesis in isolated bacteroids. Bacteroids of the aldA mutant fix nitrogen but only secrete ammonium at a significant rate, resulting in lower total nitrogen secretion. Peas inoculated with the aldA mutant are green and healthy, demonstrating that ammonium secretion by bacteroids can provide sufficient nitrogen for plant growth. However, plants inoculated with the mutant are reduced in biomass compared with those inoculated with the wild type. The labelling and plant growth studies suggest that alanine synthesis and secretion contributes to the efficiency of N2-fixation and therefore biomass accumulation.

Alanine↗

PubMed2000

10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2-3,N+) versus lymph node-negative (pT2-3,N0) prostate cancer.

Loss of heterozygosity (LOH) in the region of 10q23.3 has been associated with multiple tumors, including glioblastoma multiforme, melanoma, endometrial carcinoma, and prostate carcinoma. The tumor suppressor gene, PTEN/MMAC1, is also located in this region, and, in addition to other tumor types (eg, glioblastoma multiforme, endometrial, and melanoma), PTEN/MMAC1 mutations have been found in prostate cancer cell lines, xenografts, and hormone refractory prostate cancer tissue specimens. The aim of this study was to evaluate LOH at 10q23.3 as a marker of cancer progression in node-positive prostate cancer. Genetic alterations in the region of 10q23.3 were assessed in 23 node-positive (pT2-3, N+) and 44 node-negative prostate (pT2-3, N0) cancers with D10S532, D10S1687, D10S541, and D10S583 flanking polymorphic genetic markers; PTENCA, a genetic marker within PTEN/MMAC1, was also tested. Using DNA from paired normal and microdissected tumor samples, LOH at microsatellite loci was determined after polymerase chain reaction amplification. LOH in at least 1 marker was identified in 14% (6 of 44) of lymph node-negative and 43% (10 of 23) of lymph node-positive prostate cancers (chi-square test, P = .007). This increase in genetic alterations in node-positive prostate cancer suggests that 10q23.3 is a marker for metastatic progression.

Adenocarcinoma↗

PubMed2000

Integration of nurse executives into executive level administration in Utah hospitals.

Nurse executives (NEs) in Utah acute care hospitals perceive that they are integrated into executive level administration. This perception is shared by NEs' career supporters and hinderers. To integrate NEs, influential colleagues used active methods, especially involvement. NEs add value to the administrative team by combining clinical and managerial expertise. NE integration is manifest in decision making, participation and interaction. Continued integration depends upon commitment from the chief executive officer (CEO), leadership in organizational change, addressing "glass ceiling" issues, and NEs' continuous demonstration of competence.

Career Mobility↗

PubMed2000

The design and applications of a recursive molecular modeling framework.

In this paper, we present a recursive molecular model suitable for multiresolution analysis in a variety of application areas. Our approach allows ease of use by computer scientists and biologists by proposing a software interface for molecular analysis that hides programming details. We demonstrate that our design is flexible enough for use in desktop analytical applications, in large-scale parallel simulations, and as a server for remote molecular analysis across wide-area networks.

Algorithms↗

PubMed2000

Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers.

Germline mutations in PTEN can predispose people to Cowden syndrome (CS) and Bannayan-Ruvalcaba-Riley (BRR) syndrome, rare, autosomal dominantly inherited neoplastic disorders. To determine whether germline mutations in PTEN contribute to genetic predisposition to multiple primary tumours within the general population, we conducted a nested case-control study, among 32 826 members of the prospective Nurses' Health Study cohort; cases were women with more than one primary tumour at different anatomical sites. We screened all nine exons of PTEN and flanking intronic splice sites for all 103 eligible cases using SSCP and sequencing. We observed two novel germline heterozygous missense mutations in exon 5 in five of the cases; three were V119L and two were V158L. Neither mutation was observed in 115 controls free of diagnosed cancer (p = 0.02). Both mutants showed partial tumour suppressor activity when compared to wild type PTEN when transfected into a PTEN null breast cancer cell line. The phenotype was cell line specific suggesting that genetic background affects growth suppression activity of the mutants. These data provide evidence that germline mutations in PTEN may be a more frequent predisposing factor for cancers in women than previously suggested.

Breast Neoplasms↗

PubMed2000

Safety and efficacy of high-dose adenosine-induced asystole during endovascular AAA repair.

PURPOSE: To assess the safety and efficacy of high-dose adenosine administration to increase the precision of endovascular abdominal aortic aneurysm (AAA) repair using a balloon deployed stent-graft. METHODS: From January 1997 to March 1999, 98 AAA patients (79 men; mean age 71 years, range 62-91) were treated with balloon-expandable stent-grafts under an approved protocol. After placing a temporary transvenous ventricular lead or an external transthoracic pacing electrode, adenosine (24 mg initially) was administered in an escalating dose fashion to induce at least 10 seconds of asystole, during which the proximal stent was expanded. RESULTS: Adenosine dosages ranged from 24 to 90 mg (median 24 mg). Nine (9.2%) self-limiting cardiac events were observed: 2 (2.0%) episodes of transient myocardial ischemia, 2 (2.0%) cases of atrial fibrillation requiring cardioversion, 1 (1.0%) transient left bundle branch block lasting <10 seconds, and 4 (4.1%) prolonged periods of asystole requiring temporary pacemaker activation. There were no cases of bronchospasm or worsening obstructive pulmonary disease, and no patients required inotropic support after adenosine-induced asystole. CONCLUSIONS: Cardiac events following adenosine-induced asystole are infrequent, mild, and easily treated. The perioperative use of high-dose adenosine to ensure precise stent-graft placement appears to be a safe method of inducing temporary asystole during endovascular aortic repair.

Adenosine↗

PubMed2000

APC truncation and increased beta-catenin levels in a human breast cancer cell line.

Mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gene or the beta-catenin gene are present in most colon cancers and less frequently in other tumor types. In this study, we screened 24 human breast cancer cell lines and three immortalized human breast epithelial cell lines for alterations in beta- and gamma-catenin and APC by western blotting, protein truncation assay and DNA sequence analysis. In one cell line (DU 4475), an APC mutation was identified (E1577stop) that resulted in expression of truncated APC. This mutation was associated with elevated cytosolic beta-catenin levels, probably due to loss of APC function, as in colon cancers. No mutations were found in exon 3 of the beta- or gamma-catenin genes. We conclude that APC mutations and beta-catenin upregulation may occur with low frequency in human breast cancer cells.

Adenomatous Polyposis Coli Protein↗

PubMed1999

Differential subtraction chain, a method for identifying differences in genomic DNA and mRNA.

Identifying the genetic differences between two organisms or cell types has been a major goal in modern biomedical research. Recently, we developed a novel methodology that can rapidly identify the differences between two populations of DNA. This method, termed 'differential subtraction chain' (DSC), is based on a novel 'negative amplification' strategy that converts (amplifiable) tester sequences to counterpart (unamplifiable) driver sequences. The result is a double exponential elimination of amplifiable sequences in the testers, while preserving the sequences in the testers that have no counterpart in the drivers. We applied this methodology to the genome of a glioblastoma cell line. A homozygous deletion was rapidly identified. We extended this technique to identifying the unique sequences in mRNA. Two CDC25 transgene fragments were quickly identified in a cdc25B transgenic mouse. We also applied this methodology to systems with profound differences in mRNA expression. In a 'prostate epithelia subtracting blood cells' DSC reaction, a sample of unique gene fragments which are absent in the prostate but present in the blood were identified. Lastly, we detected rare (1 virus/100 cells) Herpes simplex virus type 2 (HSV-2) sequences in a tissue culture, indicating good sensitivity of this methodology. Overall, DSC represents a fast, efficient and sensitive method for identifying differences in genomic DNA and mRNA and can be easily applied in a variety of biological systems.

Animals↗

PubMed1999

Suicide within 12 months of contact with mental health services: national clinical survey.

OBJECTIVE: To describe the clinical circumstances in which psychiatric patients commit suicide. DESIGN: National clinical survey. SETTING: England and Wales. SUBJECTS: A two year sample of people who had committed suicide, in particular those who had been in contact with mental health services in the 12 months before death. MAIN OUTCOME MEASURES: Proportion of suicides in people who had had recent contact with mental health services; proportion of suicides in inpatients; proportion of people committing suicide and timing of suicide within three months of hospital discharge; proportion receiving high priority under the care programme approach; proportion who were recently non-compliant and not attending. RESULTS: 10 040 suicides were notified to the study between April 1996 and March 1998, of whom 2370 (24%; 95% confidence interval 23% to 24%) had had contact with mental health services in the year before death. Data were obtained on 2177, a response rate of 92%. In general these subjects had broad social and clinical needs. Alcohol and drug misuse were common. 358 (16%; 15% to 18%) were psychiatric inpatients at the time of death, 21% (17% to 25%) of whom were under special observation. Difficulties in observing patients because of ward design and nursing shortages were both reported in around a quarter of inpatient suicides. 519 (24%; 22% to 26%) suicides occurred within three months of hospital discharge, the highest number occurring in the first week after discharge. 914 (43%; 40% to 44%) were in the highest priority category for community care. 488 (26% excluding people whose compliance was unknown; 24% to 28%) were non-compliant with drug treatment while 486 (28%; 26% to 30%) community patients had lost contact with services. Most people who committed suicide were thought to have been at no or low immediate risk at the final service contact. Mental health teams believed suicide could have been prevented in 423 (22%; 20% to 24%) cases. CONCLUSIONS: Several suicide prevention measures in mental health services are implied by these findings, including measures to improve compliance and prevent loss of contact with services. Inpatient facilities should remove structural difficulties in observing patients and fixtures that can be used in hanging. Prevention of suicide after discharge may require earlier follow up in the community. Better suicide prevention in psychiatric patients is likely to need measures to improve the safety of mental health services as a whole, rather than specific measures for people known to be at high risk.

Adolescent↗

PubMed1999

Mental disorder and clinical care in people convicted of homicide: national clinical survey.

OBJECTIVES: To estimate the rate of mental disorder in those convicted of homicide and to examine the social and clinical characteristics of those with a history of contact with psychiatric services. DESIGN: National clinical survey. SETTING: England and Wales. SUBJECTS: Eighteen month sample of people convicted of homicide. MAIN OUTCOME MEASURES: Offence related and clinical information collected from psychiatric court reports on people convicted of homicide. Detailed clinical data collected on those with a history of contact with psychiatric services. RESULTS: 718 homicides were reported to the inquiry between April 1996 and November 1997. Of the 500 cases for whom psychiatric reports were retrieved, 220 (44%; 95% confidence interval 40% to 48%) had a lifetime history of mental disorder, while 71 (14%; 11% to 17%) had symptoms of mental illness at the time of the homicide. Of the total sample, 102 (14%; 12% to 17%) were confirmed to have been in contact with mental health services at some time, 58 (8%; 6% to 10%) in the year before the homicide. The commonest diagnosis was personality disorder (20 cases, 22%; 13% to 30%). Alcohol and drug misuse were also common. Only 15 subjects (18%; 10% to 26%) were receiving intensive community care, and 60 (63%; 53% to 73%) were out of contact at the time of the homicide. CONCLUSIONS: There are substantial rates of mental disorder in people convicted of homicide. Most do not have severe mental illness or a history of contact with mental health services. Inquiry findings suggest that preventing loss of contact with services and improving the clinical management of patients with both mental illness and substance misuse may reduce risk, but clinical trials are needed to examine the effectiveness of such interventions.

Adult↗