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S Bates

Publications and source records attributed to S Bates.

At least 73 records · Page 4Linked to original sources
PubMed1996

A high-resolution analysis of chromatin structure along p53 sequences.

A detailed investigation of how nucleosomes are formed and arranged on the DNA sequence is a prerequisite to understanding the molecular mechanisms of DNA-dependent processes such as transcription, replication, DNA repair, and mutagenesis. In this report we analyzed the chromatin structure of exons 5-8 of the p53 gene in human fibroblasts. We mapped at the nucleotide level the positions of DNase I and micrococcal nuclease cleavage sites in permeabilized cells. Areas of clear DNase I protection, which would be indicative of the binding of sequence-specific proteins, were not detected. Instead, the micrococcal nuclease and DNase digestion patterns suggested that this region was covered by nucleosomes and that two areas spanning exons 5 and 6 are occupied preferentially. These nucleosomes could influence DNA damage distribution, repair of certain lesions, and other aspects of the mutagenesis process in p53 sequences.

Base Sequence↗
PubMed1996

p53 in signaling checkpoint arrest or apoptosis.

The cell cycle arrest and apoptotic functions of p53 both contribute to the role of this tumour suppressor protein in preventing replication of cells suffering DNA damage. Although the ability of p53 to function as a sequence-specific transcription factor appears to be directly and causally linked to the implementation of an arrest at the G1 stage of the cell cycle, the contribution of transcriptional activation to the apoptotic response is less clear. It seems likely that several p53 activities, both transcriptionally dependent and transcriptionally independent, can play a role in mediating cell death. The requirement for each of these functions appears to depend on the cell type, the cell environment and other genetic alterations already sustained by the cell in which p53 function is activated.

Animals↗
PubMed1996

Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.

The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

Apoptosis↗
PubMed1996

Behavioral descriptors that differentiate between seizure and nonseizure events in a pediatric population.

The diagnosis and treatment of epilepsy relies heavily on descriptions of behavioral changes noted during seizure episodes. A pilot study was completed to determine the frequency of occurrence of behaviors commonly associated with seizures in a pediatric population (n = 153). Caretakers of the children (ages = 4 months to 19 years) were asked to respond to a checklist containing 40 behavioral descriptors. Thirteen descriptors were found to differentiate between seizure and nonseizure events. Twelve of these behaviors were endorsed significantly more frequently by caretakers of children with seizures including the following: does not remember what happened, moves mouth funny, drools, jerking/twitching, becomes stiff, changes in breathing, stares off, bites or chews tongue, eyes look glassy, will not respond, mumbles or slurs words, and eyes or head turn to one side. One behavior, fidgets in seat, was significantly more associated with nonseizure episodes. The behavioral descriptors may be presented in a checklist format or incorporated within a clinical interview in primary care settings for initial screening of children with possible seizure disorders.

Adolescent↗
PubMed1995

Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins.

A number of low molecular weight proteins have recently been identified that specifically inhibit the function of cyclin-dependent protein kinases in mammalian cells. These fall into two distinct families based on primary sequence comparisons and probable modes of action. Using a simple in vitro binding assay, we show that p21CDKN1 and the related p27KIP1 can efficiently interact with cyclins D1, D2, D3, E and A, and to a lesser extent with cyclin B. By generating a deleted form of cyclin D1 that binds to p21 and p27 but not to Cdks, we confirm that these interaction do not depend on stoichiometric amounts of the relevant kinase subunit. Moreover, p21 and p27 do not detectably associated with kinase subunits unless a cyclin is present. This is in sharp contrast to the properties of p16CDKN2 and p15MTS2/INK4b which bind to Cdk4 and Cdk6 in the absence of any cyclin. These data suggest that p21 and p27 act as broad spectrum regulators of cyclin dependent kinase function by participating in ternary complexes whereas the p16 family specifically interfere with the formation of cyclin D-dependent kinase complexes.

Carrier Proteins↗
PubMed1995

Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.

D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, regulate events in the G1 phase of the cell cycle and may contribute to the phosphorylation of the retinoblastoma gene product (Rb). However, in cells in which the function of Rb has been compromised, either by naturally arising mutations or through binding to proteins encoded by DNA tumour viruses, Cdk4 and Cdk6 are not associated with D cyclins. Instead, both kinases form binary complexes with a stable 16 kDa protein (p16) encoded by the putative tumour suppressor gene INK4/MTS1 on human chromosome 9p21. Here we show an inverse correlation between Rb status and the expression of p16. Since Rb-negative cells express high levels of p16, we suggest that in these cells p16 competes with D cyclins for binding to Cdk4 and Cdk6 and prevents formation of active complexes. In line with these predictions, DNA tumour virus oncoproteins do not disrupt cyclin D1-Cdk4 complexes in cells lacking p16.

Carrier Proteins↗
PubMed1995

Cyclin D1 as a cellular proto-oncogene.

Deregulated expression of cyclin D1 occurs in several types of human cancer. Since it often results from a specific chromosomal abnormality, this over-expression is likely to be significant in the development of the disease. Cyclin D1 is also implicated in virally induced tumors in mice and transgenic models based on ectopic expression if cyclin D1 recapitulate features of the naturally occurring tumors. By these criteria, as well as its effects in transfected rodent cells, cyclin D1 has the hallmarks of a cellular proto-oncogene. Although the normal role of cyclin D1 is not well understood, its oncogenic properties appear to involve functional interactions with cyclin-dependent kinases, the retinoblastoma gene product and the MTS1/p16 tumor suppressor gene.

Amino Acid Sequence↗
PubMed1995

Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen.

Identifying new chemotherapeutic agents and characterizing mechanisms of resistance may improve cancer treatment. The Anticancer Drug Screen of the National Cancer Institute uses 60 cell lines to identify new agents. Expression of mdr-1/P-glycoprotein was measured by quantitative PCR. Expression was detected in 39 cell lines; the highest levels were in renal and colon carcinomas. Expression was also detected in all melanomas and central nervous system tumors, but in only one ovarian carcinoma and one leukemia cell line. Using a modified version of the COMPARE program, a high correlation was found between expression of mdr-1 and cellular resistance to a large number of compounds. Evidence that these compounds are P-glycoprotein substrates includes: (a) enhancement of cytotoxicity by verapamil; (b) demonstration of cross-resistance in a multidrug-resistant cell line, (c) ability to antagonize P-glycoprotein, increasing vinblastine accumulation by decreasing efflux; and (d) inhibition of photoaffinity labeling by azidopine. Identification of many heretofore unrecognized compounds as substrates indicates that P-glycoprotein has a broader substrate specificity than previously recognized. This study confirms the validity of this novel approach and provides the basis for similar studies examining a diverse group of gene products, including other resistance mechanisms, putative drug targets, and genes involved in the cell cycle and apoptosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Phase II study of paclitaxel in relapsed non-Hodgkin's lymphomas.

PURPOSE: To assess the efficacy and toxicity of paclitaxel administered as a 96-hour infusion to patients with relapsed non-Hodgkin's lymphomas (NHLs). PATIENTS AND METHODS: Eligible patients had relapsed NHL and measurable disease and were considered incurable. Paclitaxel was infused at a dose of 140 mg/m2 every 3 weeks. Premedications to prevent paclitaxel hypersensitivity reactions were not administered and no patients received corticosteroids. Expression of the multidrug resistance (mdr-1) gene was determined in tumor from 17 patients by mRNA quantitative polymerase chain reaction (PCR). RESULTS: Thirty-one patients received a total of 99 cycles of paclitaxel. Two patients were not assessable for response. The median age was 50 years, 71% had stage IV disease, and intermediate/high-grade histology was present in 65% of patients. Patients had received a median of three prior chemotherapy regimens, and 68% of patients had responded to the previous chemotherapy (chemotherapy-sensitive). Of 29 assessable patients, five (17%) achieved a partial response (PR). With a median potential follow-up time of 17 months, the median event-free and overall survival durations were 1.6 and 7.5 months, respectively. No correlation was found between response to paclitaxel and extent of prior treatment or response. The mdr-1 gene was easily detectable in 14 of 17 tumor biopsies, but was low in all but one sample. The most serious toxicity was grade 4 neutropenia, which occurred during 14% of cycles. CONCLUSION: Paclitaxel was well tolerated, but had a low response rate in patients with relapsed NHLs. There was no clear association between response to paclitaxel and extent of our response to prior treatment. Most patients had chemotherapy-sensitive disease, which suggests that the low response rate to paclitaxel was probably not due to general chemotherapy resistance. Paclitaxel provided good palliation in a minority of patients and is a reasonable agent to consider for use in patients who have failed to respond to standard chemotherapy.

Adult↗
PubMed1995

Socialization to the culture of a rehabilitation hospital: an ethnographic study.

OBJECTIVES: Most previous research on rehabilitation of patients after spinal cord injuries has dealt with the attainment of outcomes valued by staff members or with the prediction of successful outcomes based on sociodemographic characteristics of patients. This study examined the rehabilitation process from the insider's perspective of an individual patient to determine his view of important adaptive problems and to examine how these problems were addressed. METHODS: Ethnographic methods were used for fine-grained documentation of the experiences of one 30-year-old man with spinal cord injury. Daily interview were conducted with this patient during his 116 days of inpatient rehabilitation. An interdisciplinary research team analyzed the data with the constant comparative method to identify a number of recurring themes. RESULTS: Findings indicate that in addition to learning how to function in the local world of the rehabilitation hospital, the patient also learned a new identify as a person with a long-term disability. DISCUSSION: A central theme was the patient's ongoing attempt to figure out how his future was related to his life before the injury and how he could use previous competencies in adapting to disability. Staff members seemed so intent on teaching the patient new skills that they often discounted the significance of his past experience and failed to engage in helping the patient connect his future life story to his past.

Activities of Daily Living↗
PubMed1994

Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.

PURPOSE: A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. PATIENTS AND METHODS: In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. RESULTS: Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. CONCLUSION: The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.

Adult↗
PubMed1994

Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein.

Cyclins D1, D2 and D3 are thought to function in the G1 phase of the cell division cycle by regulating the activity of cyclin-dependent protein kinases. All three D-type cyclins can be shown to associate with two specific kinases, cdk4 and cdk6, providing at least six possible combinations. To establish whether different cell types require different subsets of these complexes and whether they are altered in tumours where D-cyclin expression is perturbed, we surveyed a series of tumour cell lines and compared them where possible to non-tumorigenic counterparts. Although complexes involving cdk4 or cdk6 were readily observed in many of the cell lines, no complexes were detectable in human cells harbouring DNA tumour virus oncoproteins or in which the retinblastoma gene product (pRb) is mutated or missing. These data suggest that as well as being a potential substrate for D-cyclin-kinases, functional pRb contributes to the formation or stability of the complexes, at least in human cells.

Breast Neoplasms↗
PubMed1994

CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1.

Deregulated expression of cyclin D1 is a feature of several neoplastic and proliferative disorders, but its normal role in the cell cycle remains unclear. Here we show that in a squamous carcinoma cell line with 11-fold amplification of the CCND1 gene, cyclin D1 associates specifically with p33cdk4 (PSK-J3) and p38cdk6 (PLSTIRE), two closely related members of the cyclin-dependent kinase (CDK) family. In these tumour cells, there is little evidence for an association between cyclin D1 and other CDKs, but in diploid human fibroblasts both CDK2 and CDK5 can be co-precipitated with cyclin D1, as well as CDK4. The data suggest that D-type cyclins participate in multiple interactions with CDKs but that the nature or stoichiometry of these associations may differ in different types of cell.

Amino Acid Sequence↗
PubMed1993

EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma.

PURPOSE: Based on in vitro evidence that tumor cells are less resistant to prolonged exposure to low concentrations of the natural product class, compared with brief higher concentration exposure, we developed a chemotherapy regimen (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]) in which the natural products are administered as a continuous infusion. PATIENTS AND METHODS: This is a phase II study of etoposide, vincristine, and doxorubicin, administered as a 96-hour continuous infusion, with intravenous (IV) bolus cyclophosphamide and oral prednisone (EPOCH) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule. Patients with aggressive lymphomas who achieved a good response after EPOCH were eligible to undergo bone marrow transplantation. RESULTS: Patients with intermediate- or high-grade lymphoma comprised 76% of this series and 77% had stage IV disease. Seventy-one percent had previously received all of the drugs contained in the EPOCH regimen and 92% had received at least four of the drugs. Seventy patients were assessable for response, of whom 19 (27%) achieved a complete remission (CR) and 42 (60%) a partial remission (PR). Among 21 patients who had no response to prior chemotherapy, 15 (71%) responded, but only one achieved a CR. Patients who relapsed from an initial CR had a 100% response rate, with 76% CRs. With a median potential follow-up duration of 19 months, there was a 28% probability of being event-free at 1 year. Toxicity was primarily hematologic with neutropenia during 51% of cycles, but only a 17% incidence of febrile neutropenia. Gastrointestinal, neurologic, and cardiac toxicity were minimal. CONCLUSION: EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the natural drug component of this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity (DI) was > or = that achieved in primary treatment regimens for aggressive lymphomas.

Adult↗
PubMed1993

Blood loss following tonsillectomy in children. A blind comparison of diclofenac and papaveretum.

One hundred and ninety-eight children, aged 3 to 12 years, who were scheduled for tonsillectomy were randomly allocated to receive either diclofenac 1.0 mg.kg-1 or papaveretum 0.2 mg.kg-1 by intramuscular injection after induction of anaesthesia. There were no significant differences between the treatment groups in operating theatre blood loss, the frequency of bleeding on the ward, or the need for operative haemostasis. However, the incidence of above average bleeding in the recovery room was significantly higher in the diclofenac group (p < 0.05). Similarly, marked restlessness in the recovery room was more frequent in the diclofenac group (p < 0.01). In both treatment groups there was an association between bleeding and restlessness during recovery so the increased bleeding in the diclofenac group may not be a direct effect.

Akathisia, Drug-Induced↗
PubMed1991

Does intensive glycemic control in diabetic pregnancies result in normalization of other metabolic fuels?

Intensive treatment of insulin-dependent diabetes mellitus during pregnancy often normalizes plasma glucose levels. However, it is unclear whether this adversely affects other metabolic fuels that are essential to normal fetal growth and development. Metabolic studies were conducted after the subjects ingested a standardized mixed meal during each trimester in 7 normal and 15 insulin-dependent diabetic pregnant women. The latter were treated with continuous subcutaneous insulin infusion or multiple injections, which were adjusted to achieve strict glucose control throughout pregnancy. Insulin, alanine, branched-chain amino acids, triglycerides, free fatty acids, and ketones were measured every 15 to 30 minutes before a standardized breakfast and for 150 minutes after the breakfast. Patients with insulin-dependent diabetes mellitus were studied while they received their unusual insulin dosages. Fasting glucose levels (87 +/- 7 mg/dl) and glucose levels 150 minutes after the meal (112 +/- 11 mg/dl) were near normal. However, normoglycemia was achieved at the expense of increased plasma insulin levels (area under insulin response curves, p less than 0.01, vs nondiabetic curves). Nevertheless, fasting and post-prandial plasma branched-chain amino acids, alanine, and free fatty acids were similar in both groups. Fasting cholesterol, triglyceride, and ketone levels were also normalized. We conclude that normalization of circulating amino acids and lipids in conjunction with correction of hyperglycemia may contribute to favorable outcomes in infants of intensively treated diabetic mothers.

Adult↗