The efficacy of intravesicular sterile sodium chondroitin sulfate 0.2% in potassium tested positive patients with interstitial cystitis.
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Adolescent↗
Biomedical subjects
S Rowan
Publications and source records attributed to S Rowan.
The efficacy of chondroitin sulfate 0.2% in treating interstitial cystitis.
OBJECTIVE: An open label study of chondroitin sulfate was undertaken to determine the response of patients with interstitial cystitis and positive potassium test results to this agent. METHOD: Eighteen patients with classic features of interstitial cystitis were enrolled in the study. Patients received 40 mL chondroitin sulfate, 0.2% instilled intravesically once a week for four weeks and then once a month for 12 months. At the same times, Quality of Life Improvement scores, voiding diaries, and pain and voiding indices were reviewed. RESULTS: Thirteen of 18 patients were followed for the entire 13-month study. Twelve of these patients responded to treatment within 3 to 12 weeks, on average. A total of 6/13 (46.2%) showed a good response, 2/13 (15.4%) had a fair response, and 4/13 (30.8%) had a partial response and 1/13 (7.7%) showed no response. CONCLUSION: Intravesical chondroitin sulfate seems to demonstrate some beneficial effects in treatment of interstitial cystitis patients who have positive potassium stimulation test results.
Chondroitin Sulfates↗
Very high Q measurements on a fused silica monolithic pendulum for use in enhanced gravity wave detectors
We present for the first time the results of very high Q factor measurements for a 2.8 kg fused silica mass suspended by two fused quartz fibers attached by a novel technique for joining fused silica or quartz. The Q for the pendulum mode at 0.93 Hz was (2.3+/-0. 2)x10(7), the highest value demonstrated to date for a mass of this size. By employing such a new suspension system the sensitivity of the gravitational wave detectors currently under construction can be increased up to 1 order of magnitude.
Journal Article↗
A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer.
BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.
Adult↗
An improved tie-over dressing technique for skin grafts using a hydrocellular dressing.
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Adult↗
Oncogene-dependent regulation of caspase activation by p53 protein in a cell-free system.
The mechanism by which p53 modulates apoptosis in cancer therapy is incompletely understood. Here, cell-free extracts from irradiated tumor cells are described in which endogenous p53 protein is shown to participate in caspase activation. This apoptotic activity is also oncogene-dependent, but independent of transcription in general or the presence of Bax or cytochrome c. A general use for this system is as a cell-free screen for apoptosis modulators. In this way, profound effects of protein kinase A were identified and corroborated in vivo by the protection conferred by cAMP against diverse triggers of p53-dependent apoptosis. This system provides direct biochemical evidence that p53 protein can transduce apoptotic signals through protein-protein interactions and reveals a modulator kinase pathway capable of regulating p53-dependent caspase activation.
Adenylyl Imidodiphosphate↗
Provider and consumer perceptions of allied health service needs.
The study reported in this paper compared data from 20 separate focus groups, representing providers and consumers of health services in the Grampians region, Victoria, on their perceptions of the allied health service issues in that region. The results of the study indicated that providers and consumers raised many similar issues in regard to allied health services--access to allied health services, service delivery, social and rural issues--but discussed the issues from different perspectives. The provider discussion was concerned with service delivery issues and the consumer discussion was focused on broader social issues which affect health.
Allied Health Occupations↗
New chemotherapy combinations with docetaxel in the treatment of patients with non-small cell lung cancer.
The modest antitumor activity and clinical benefit of conventional platinum-containing multidrug regimens in locally advanced and metastatic non-small cell lung cancer have provided the impetus for the development of novel combinations. The promising single-agent activity of docetaxel makes it an obvious candidate for incorporation into active programs. The Irish Clinical Oncology Research Group is conducting a phase I-II evaluation of a three-drug combination of docetaxel, ifosfamide, and cisplatin with lenograstim support in patients with stages III-IV non-small cell lung cancer. Preliminary results indicate that the regimen is feasible and tolerable up to a maximum tolerated dose level of 3,000 mg/m2 ifosfamide, 75 mg/m2 cisplatin, and 75 mg/ m2 docetaxel. The regimen appears to be quite active, with nine of 12 evaluable patients responding in the phase I component of the trial. This dose level is currently being explored in a phase II trial.
Adult↗
Genetic interactions between atm and p53 influence cellular proliferation and irradiation-induced cell cycle checkpoints.
Ataxia-telangiectasia and Li-Fraumeni syndrome, pleiotropic disorders caused by mutations in the genes atm and p53, share a marked increase in cancer rates. A number of studies have argued for an interaction between these two genes (for comprehensive reviews, see M. S. Meyn, Cancer Res., 55: 5991-6001, 1995, and M. F. Lavin and Y. Shiloh, Annu. Rev., Immunol., 15: 177-202, 1996). Specifically, atm is placed upstream of p53 in mediating G1-S cell cycle checkpoint control, and both atm and p53 are believed to influence cellular proliferation. To analyze the genetic interactions of atm and p53, mouse embryonic fibroblasts (MEFs) homozygously deficient for both atm and p53 were used to assess cell cycle and growth control. These double-null fibroblasts proliferate rapidly and fail to exhibit the premature growth arrest seen with atm-null MEFs. MEFs null for both atm and p53 do not express any p21(cipl/wafl), showing that p53 is required for p21(cipl/wafl) expression in an atm-null background. By contrast, homozygous loss of either atm, p53, or both results in similar abnormalities of the irradiation-induced G1-S cell cycle checkpoint. Our results suggest two separate pathways of interaction between atm and p53, one linear, involving G1-S cell cycle control, and another more complex, involving aspects of growth regulation.
Animals↗
atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity.
Mutations in atm and p53 cause the human cancer-associated diseases ataxia-telangiectasia and Li-Fraumeni syndrome, respectively. The two genes are believed to interact in a number of pathways, including regulation of DNA damage-induced cell-cycle checkpoints, apoptosis and radiation sensitivity, and cellular proliferation. Atm-null mice, as well as those null for p53, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. To study the interactions of these two genes on an organismal level, we bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumour formation relative to singly null mice, indicating that both genes collaborate in a significant manner to prevent tumorigenesis. With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. This implies that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. Finally-and in contrast to prior predictions-atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumours.
Acute Disease↗
Mechanisms of apoptotic cell death.
Apoptosis is the mechanism by which cells are programmed to die under a wide range of physiological and developmental stimuli. Several mediators of programmed cell death have been identified and signals of apoptosis have been found to utilize common pathways, some of which have been elucidated. This review focuses on a number of apoptotic systems that have been widely studied and discuss recent progress and opinion in these areas. These include studies on Fas signaling, tumor suppressor genes, cell cycle interfaces, stress responses, genetic systems, and the Bcl-2 family. Understanding apoptosis from these perspectives sheds substantial light on processes of biological homeostasis. Furthermore, the ability to manipulate the apoptotic response may lead to novel therapeutic interventions in cancer and other diseases.
Animals↗
p53 mediated apoptosis in HeLa cells: transcription dependent and independent mechanisms.
The most frequent target for genetic alterations in human cancers is the p53 tumor suppressor gene. Mutations in p53 abrogate its ability to inhibit cell growth and to suppress tumor progression. The anti-proliferative activity of p53 can be mediated by the induction of growth arrest and/or programmed cell death (apoptosis). Recent in vivo studies support the involvement of apoptosis in tumor suppression by p53. To gain further insight into the mechanisms by which p53 induces apoptosis, the activity of p53 was studied in HeLa cells using a transient transfection assay. To define the functional domains of p53 required for apoptosis a C-terminal deletion mutant of p53 was used. This mutant, p53d1214, lacks the oligomerization domain, the nuclear localization signal and a large part of the core DNA binding domain. This mutant was shown to be deficient in sequence specific transactivation activity. Overexpression of wt p53 induced an efficient apoptosis in transiently transfected HeLa cells. Surprisingly p53d1214, containing only the first 214 N-terminal residues induced extensive apoptosis. The induction of apoptosis by p53d1214 is slower than that induced by wt p53. Furthermore, p53d1214 suppressed the transformation of rat embryo fibroblasts by several oncogene combinations, such as myc plus ras. In view of the fact that p53d1214 lacks measurable transactivation potential, our findings suggest the existence of two p53 dependent-apoptotic pathways--one involves activation of specific target genes, and the other is independent of it. Transactivation independent apoptosis may play a central role in tumor suppression by p53.
Animals↗
Managing the overweight and obese. A low fat approach.
Conventional weight loss methods usually fail in the long term. An approach that focuses on a low fat diet together with moderate increases in physical activity shows promise. Its most attractive feature is that patients do not have to starve themselves. This approach can be used in general practice.
Body Weight↗
Characterisation of human cyclin G1 and G2: DNA damage inducible genes.
Several genes have been identified as targets for transcriptional activation by the p53 tumour suppressor protein. Rodent cyclin G was previously identified as a p53 responsive gene and in order to assess the role played by cyclin G as a mediator of p53 function in humans cells we have isolated full length human cyclin G1 and identified a related gene designated cyclin G2. Both human G-cyclins are induced by the DNA damaging agent actinomycin-D and although the induction of cyclin G1 is clearly p53 dependent, activation of cyclin G2 expression was observed in the absence of p53. Based on sequence similarity, the G-cyclins and the recently identified cyclin I form a distinct sub-group within the larger cyclin family, possibly reflecting some degree of functional similarity.
Actins↗
Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant.
The p53 tumor-suppressor gene product is frequently inactivated in malignancies by point mutation. Although most tumor-derived p53 mutants show loss of sequence specific transcriptional activation, some mutants have been identified which retain this activity. One such mutant, p53175P, is defective for the suppression of transformation in rodent cells, despite retaining the ability to suppress the growth of p53-null human cells. We now demonstrate that p53175P can induce a cell-cycle arrest in appropriate cell types but shows loss of apoptotic function. Our results therefore support a direct role of p53 transcriptional activation in mediating a cell-cycle arrest and demonstrate that such activity is not sufficient for the full apoptotic response. These data suggest that either p53 can induce apoptosis through a transcriptionally independent mechanism, a function lost by p53175P, or that this mutant has specifically lost the ability to activate genes which contribute to cell death, despite activation of genes responsible for the G1 arrest. This dissociation of the cell-cycle arrest and apoptotic activities of p53 indicates that inactivation of p53 apoptotic function without concomitant loss of growth inhibition can suffice to relieve p53-dependent tumor-suppression in vivo and thereby contribute to tumor development.
Animals↗
Induction of apoptosis in HeLa cells by trans-activation-deficient p53.
The p53 tumor suppressor protein is a transcriptional activator, which can mediate apoptotic cell death in a variety of cell types. To determine whether sequence-specific trans-activation is a prerequisite for the induction of apoptosis by p53, the apoptotic effects of various p53 deletion mutants were monitored in an assay based on the transient transfection of HeLa cells. A truncated protein (p53dl214), containing only the first 214 amino-terminal residues of murine p53, induced extensive apoptosis, albeit at a slower rate than trans-activation-competent wild-type p53. p53dl214 also suppressed the transformation of rat fibroblasts by several oncogene combinations and particularly by myc plus ras and HPV E7 plus ras. p53dl214 lacks a major portion of the DNA-binding domain and cannot activate p53-responsive promoters. Moreover, a human p53 protein carrying mutations in residues 22 and 23 also triggered HeLa cell apoptosis, despite failing to induce significant activation of relevant p53 target promoters. These data suggest the existence of two p53-dependent apoptotic pathways--one requiring activation of specific target genes, and the other independent of sequence-specific trans-activation. The latter pathway may actually be totally uncoupled from the binding of p53 to its consensus DNA sites. The relative contribution of trans-activation-independent apoptosis to tumor suppression by p53 may be dictated by the specific genetic lesions present in the particular tumor.
Animals↗
p53-mediated apoptosis in HeLa cells can be overcome by excess pRB.
Studies on DNA tumor viruses have suggested a link between p53 and pRB in the control of cell growth and apoptosis. We examined the role of pRB in the control of p53-mediated apoptosis in HeLa cells, in which the activities of p53 and members of the pRB family are very low. Transient overexpression of wild type (wt) p53 in HeLa cells induced apoptotic cell death. Importantly, coexpression of functional pRB resulted in significant protection of HeLa cells from p53-mediated apoptosis, without interfering with the transcriptional activity of wt p53. These results suggest that pRB, and possibly other pRB-related proteins, play a major role in the decision of whether cells respond to activated p53 by undergoing growth arrest or apoptosis. Our findings demonstrate a direct link between these two tumor suppressors in the control of cell growth and cell death.
Apoptosis↗
Retroviral integration within the Fli-2 locus results in inactivation of the erythroid transcription factor NF-E2 in Friend erythroleukemias: evidence that NF-E2 is essential for globin expression.
Activation of either Fli-1 or Spi-1 members of the ets family of transcription factors as a result of retroviral insertion and mutational inactivation of the p53 tumor suppressor gene play essential roles in the multistage erythroleukemias induced in mice by various strains of Friend virus. We have previously identified another common site for provirus integration, designated Fli-2 (Friend leukemia integration 2), in some erythroleukemia clones induced either by Friend murine leukemia virus (F-MuLV) or by the polycythemia-inducing strain of Friend virus complex (FV-P). Here we show that genomic sequences adjacent to Fli-2 correspond to the coding region of the erythroid-specific DNA binding protein NF-E2 p45. In one erythroleukemia cell line the expression of NF-E2 p45 is undetectable due to proviral integration in one allele and loss of the other allele. The complete loss of NF-E2 p45 in this cell line is associated with a drastic reduction in expression of the alpha- and beta-globin genes that were partially restored by reintroduction of the NF-E2 p45 gene. Taken together, these results provide direct evidence that NF-E2 gene is essential for globin transcription and suggest that perturbation in expression of this transcription factor may contribute to erythroleukemia progression.
Animals↗