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Biomedical subjects

S Bates

Publications and source records attributed to S Bates.

At least 37 records · Page 2Linked to original sources
PubMed2000

Pretreatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs.

Cell-cycle checkpoint mechanisms, including the p53- and p21-dependent G(2) arrest that follows DNA damage, are often lost during tumorigenesis. We have exploited the ability of DNA-damaging drugs to elicit this checkpoint, and we show here that such treatment allows microtubule drugs, which cause cell death secondary to mitotic arrest, to kill checkpoint-deficient tumor cells while sparing checkpoint-competent cells. Low doses of the DNA-damaging drug doxorubicin cause predominantly G(2) arrest without killing HCT116 cells that harbor wt p53. Doxorubicin treatment prevented mitotic arrest, Bcl-2 phosphorylation, and cell death caused by paclitaxel, epothilones, and vinblastine. In contrast, doxorubicin enhanced cytotoxicity of FR901228, an agent that does not affect microtubules. Low doses of doxorubicin did not arrest p21-deficient clones of HCT116 cells and did not protect these cells from cytotoxicity caused by microtubule drugs, but cells in which p21 expression was restored enjoyed partial protection under these conditions. Moreover, in p53-deficient clones of HCT116 cells doxorubicin did not induce either p53 or p21 and provided no protection against paclitaxel-induced cytotoxicity. Therefore, (a) p53-dependent p21 induction caused by doxorubicin protects from microtubule drug-induced cytotoxicity, and (b) pretreatment with cytostatic doses of DNA-damaging drugs before treatment with microtubule drugs results in selective cytotoxicity to cancer cells with defective p53/p21-dependent checkpoint.

Antineoplastic Agents↗
PubMed2000

Amplification of 4q21-q22 and the MXR gene in independently derived mitoxantrone-resistant cell lines.

Molecular cytogenetic studies were conducted on three multidrug-resistant cancer sublines which are highly resistant to the chemotherapeutic agent mitoxantrone, an anthracenedione. The three independently selected sublines were derived by exposure to mitoxantrone or Adriamycin and do not overexpress MDR1 or MRP. Two sublines, MCF-7 AdVp3000 and MCF-7 MX, showed an amplification peak at 4q21-q22, as demonstrated by comparative genomic hybridization (CGH), while the third, S1-M1-80, did not. FISH using a whole chromosome 4 paint demonstrated multiple rearrangements involving chromosome 4 in MCF-7 AdVp3000 and MCF-7 MX, while S1-M1-80 contained only a simple reciprocal translocation. The parental cell lines had no chromosome 4 rearrangements and no copy number gain or amplification of chromosome 4. Spectral karyotyping (SKY) analysis revealed a balanced translocation, t(4;17)(q21-q22;p13) in S1-M1-80 and multiple clonal translocations involving chromosome 4 in MCF-7 AdVp3000 and MCF-7 MX. A novel cDNA, designated MXR, which encodes an ABC half-transporter and is highly overexpressed in the three sublines, was localized to chromosome 4 by somatic cell hybrid analysis. Southern blot analysis demonstrated amplification of the MXR gene in MCF-7 AdVp3000 and MCF-7 MX, but not in S1-M1-80. FISH studies with a BAC probe for MXR localized the gene to 4q21-22 in the normal chromosome 4 and revealed in both MCF-7 AdVp3000 and MCF-7 MX amplification of MXR at one translocation juncture, shown by SKY to be t(4;5)(4qter-->4cen-->4q21-22::5q13-->5qter++ +) in MCF-7 AdVp3000 and t(6;4;6;3)(6pter-->6q15::4q21-q22::hsr::6q?::3q?27-->+ ++3qter) in MCF MX; neither of the breakpoints in the partner chromosomes showed amplification by CGH. The data are consistent with the hypothesis of a transporter, presumably that encoded by the MXR gene, mediating mitoxantrone resistance. The MXR gene encodes a half-transporter and the absence of cytogenetic evidence of coamplification of other regions suggests that a partner may not be overexpressed, and instead the MXR half-transporter homodimerizes to mediate drug transport. Genes Chromosomes Cancer 27:110-116, 2000. Published 2000 Wiley-Liss, Inc.

Antineoplastic Agents↗
PubMed1999

Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times.

BACKGROUND: The presence of an association between early subtherapeutic activated partial thromboplastin times (aPTTs) and recurrent venous thromboembolism (VTE) remains controversial. OBJECTIVE: To determine the relation between early subtherapeutic aPTTs and recurrent VTE in patients who were treated with intravenous (i.v.) unfractionated heparin (UFH). PATIENTS AND METHODS: We studied 961 patients with acute VTE who received i.v. UFH in 3 randomized trials that compared the use of i.v. UFH (loading dose: 5000 U i.v.; initial infusion, 1250-1280 U/h) with that of subcutaneous low-molecular-weight heparin. According to aPTT criteria, patients were classified as being in a subtherapeutic or a therapeutic state during the first 24 and 48 hours of treatment. All episodes of possible recurrent VTE were adjudicated by an independent committee that was unaware of the aPTTs. RESULTS: At 24 hours, in 886 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 6.7% (11/163) compared with 5.3% (38/723) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 24 hours was 1.30 (95% confidence interval: 0.64-2.63; P = .46). At 48 hours, in 917 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 7.8% (5/64) compared with 5.7% (49/853) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 48 hours was 1.32 (95% confidence interval: 0.51-3.44; P = .56). CONCLUSION: In patients with acute VTE who receive an i.v. bolus of 5000 U, followed by a starting dose of at least 1250 U/h of UFH, a subtherapeutic aPTT response during the first 48 hours of treatment is not associated with a large increase in the risk of recurrent VTE.

Aged↗
PubMed1999

Mdm2 binds p73 alpha without targeting degradation.

The function of the p53 tumor suppressor protein is regulated by interaction with Mdm2, which targets p53 for ubiquitin dependent degradation. We show here that like p53, p73 alpha forms an interaction with Mdm2, both in vitro and in cells, but this does not result in the degradation of the p73 alpha protein. The human papillomavirus E6 protein also fails to degrade p73 alpha, suggesting that the mechanisms governing p73 alpha stability are distinct from those known to regulate p53 stability. However, the interaction of Mdm2 with 73 alpha is sufficient to impede p73 alpha transcriptional function, despite the lack of degradation.

Amino Acid Sequence↗
PubMed1999

Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833.

The expression of high levels of P-glycoprotein (Pgp) in circulating mononuclear cells allowed us to use an ex vivo assay as a surrogate measure of Pgp antagonism. Efflux of rhodamine from CD56(+) cells was measured before the start of PSC 833 and at varying times thereafter. Patients receiving PSC 833 had decreased rhodamine efflux from their circulating CD56(+) cells. Time course studies showed that following a single oral dose of PSC 833, decreased rhodamine efflux was found in some patients within 15 minutes of treatment. Maximal inhibition was observed at times ranging from 45 minutes to 60 minutes. A dose-response relationship was shown between the concentration of PSC 833 in the blood and the inhibition of rhodamine efflux, with an apparent plateau of the inhibition of rhodamine efflux at approximately 1,000 ng/mL. The Ki, defined as the concentration required for half-maximal inhibition of Pgp-mediated rhodamine efflux, was determined to be in the range of 29 to 181 ng/mL; although results in two patients were distinctly different, with Ki values of 914 and 916 ng/mL. MRK-16 staining was similar among all patients. We conclude that measurement of rhodamine efflux from CD56(+) cells provides a surrogate assay with the potential for monitoring Pgp antagonism in clinical trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Reversal of p53-induced cell-cycle arrest.

Activation of the tumor suppressor protein p53 can lead to arrest in both G1 and G2 stages of the cell cycle and, in some cells, to apoptotic cell death. In this study, we showed that the p53 response to a chemotherapeutic drug, actinomycin D, was reversible in both normal and tumor cells, even when a substantial proportion of tumor cells were undergoing apoptosis. Despite the clear reversibility of the p53-induced cell-cycle arrest after removal of actinomycin D, a substantial proportion of the cells arrested in G2 failed to resume normal cell-cycle progression and underwent another round of DNA synthesis. This endoreduplication probably reflects a function of the cyclin-dependent kinase inhibitor p21Waf1Cip1, which is expressed in response to p53. Our observation that this abnormal re-replication of DNA occurred in both transformed and untransformed cells after reversal of a p53 response may have implications for the eventual outcome of tumor therapies in which p53 is transiently expressed in a substantial number of normal as well as tumor cells.

Apoptosis↗
PubMed1999

Mechanisms of p53-mediated apoptosis.

The loss of p53-mediated apoptosis (programmed cell death) has been implicated as an important event in tumour progression in a number of systems. p53 can induce or potentiate apoptosis through several mechanisms, both by regulating the expression of genes which can participate in the apoptotic response and through transcriptionally independent means. There appears to be cell type variability in both the response to p53 expression and in the requirement for p53 transcriptional transactivation for the induction of apoptosis. It seems clear, however, that the induction of p53 in untransformed cells is more likely to result in cell-cycle arrest, whereas the expression of p53 in their transformed counterparts is more likely to result in the induction of apoptosis, and this may, in part, reflect the deregulated expression of E2F-1 in tumour cells. The synergistic action of p53 and E2F-1 in the induction of apoptosis has raised the possibility that the reactivation of p53 in transformed cells can be an effective tumour therapy.

Apoptosis↗
PubMed1999

Regulating plant/insect interactions using CO2 enrichment in model ecosystems.

The greenhouse environment is a challenging artificial ecosystem in which it is possible to study selected plant/insect interaction in a controlled environment. Due to a combination of "direct" and "indirect" effects of CO2 enrichment on plant photosynthesis and plant development, canopy productivity is generally increased. In this paper, we discuss the effects of daytime and nighttime CO2 enrichment protocols on gas exchange of pepper plants (Capsicum annuum L, cv Cubico) grown in controlled environments. In addition, we present the effects of thrips, a common Insect pest, on the photosynthetic and respiratory activity of these plant canopies. Carbon dioxide has diverse effects on the physiology and mortality of insects. However, our data indicate that thrips and whiteflies, at least, are not killed "directly" by CO2 levels used to enhance photosynthesis and plant growth. Together the data suggest that the insect population is affected "indirectly" by CO2 and that the primary effect of CO2 is via its effects on plant metabolism.

Animals↗
PubMed1999

E2F-1 potentiates cell death by blocking antiapoptotic signaling pathways.

The E2F family of transcription factors plays an essential role in promoting cell cycle progression, and one member of the family, E2F-1, is also capable of inducing apoptosis. We show here that E2F-1 can induce apoptosis by a death receptor-dependent mechanism, by downregulating TRAF2 protein levels and inhibiting activation of antiapoptotic signals including NF-kappa B. In this way, E2F-1 expression can lead to the sensitization of cells to apoptosis by a number of agents independently of p53. Deregulation of E2F-1 activity occurs in the majority of human tumors, and the ability of E2F-1 to inhibit antiapoptotic signaling may contribute to the enhanced sensitivity of transformed cells to chemotherapeutic agents.

Animals↗
PubMed1999

Expression of leading region genes on IncI1 plasmid ColIb-P9: genetic evidence for single-stranded DNA transcription.

The leading region of a plasmid is the first sector to enter the recipient cell in bacterial conjugation. This sector of IncI1 plasmid ColIb-P9 includes genes that are transcribed in a transient pulse early in the conjugatively infected cell to promote establishment of the immigrant plasmid. Evidence is presented that the burst of gene expression is regulated by a process which is independent of a repressor but dependent on the orientation of the genes on the unique plasmid strand transferred in conjugation. The nucleotide sequence of 11.7 kb of the leading region was determined and found to contain 10 ORFs; all are orientated such that the template strand for transcription corresponds to the transferred strand. The leading region contains three dispersed repeats of a sequence homologous to a novel promoter in ssDNA described by H. Masai & K. Arai (1997, Cell 89, 897-907). It is proposed that the repeats are promoters that form in the transferring strand of ColIb to support transient transcription of genes transferred early in conjugation.

Bacterial Proteins↗
PubMed1998

Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression.

p21Waf1/Cip1 is a major transcriptional target of p53 and has been shown to be one of the principal mediators of the p53 induced G1 cell cycle arrest. We show that in addition to the G1 block, p21Waf1/Cip1 can also contribute to a delay in G2 and expression of p21Waf1/Cip1 gives rise to cell cycle profiles essentially indistinguishable from those obtained following p53 expression. Arrest of cells in G2 likely reflects an inability to induce cyclin B1/cdc2 kinase activity in the presence of p21Waf1/Cip1, although the inefficient association of p21Waf1/Cip1 and cyclin B1 suggests that the mechanism of inhibition is indirect. Cells released from an S-phase block were not retarded in their ability to progress through S-phase by the presence of p21Waf1/Cip1, despite efficient inhibition of cyclin E, A and B1 dependent kinase activity, suggesting that p21Waf1/Cip1 is inefficient at inhibiting replicative DNA synthesis in vivo. Interestingly, significant numbers of cells released from the p21Waf1/Cip1 activated G2 block undergo endoreduplication, passing through another S-phase before undergoing mitosis. This supports a function of the mitotic kinases in both entry into mitosis, and also in preventing re-replication of DNA following S-phase and suggests a role for p21Waf1/Cip1 in coupling DNA synthesis and mitosis. Unlike p53, which induces apoptosis in these cells, extended expression of p21Waf1/Cip1 resulted in the expression of a senescent-like phenotype in these p53 null, pRB null tumor cells.

Cell Cycle↗
PubMed1998

The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2.

The two distinct proteins encoded by the CDKN2A locus are specified by translating the common second exon in alternative reading frames. The product of the alpha transcript, p16(INK4a), is a recognized tumour suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta transcript, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G1 and G2/M. As a consequence, p14(ARF)-induced cell cycle arrest is p53 dependent and can be abrogated by the co-expression of human papilloma virus E6 protein. p14(ARF) acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14(ARF) expression and there is an inverse correlation between p14(ARF) expression and p53 function in human tumour cell lines. However, p14(ARF) expression is not involved in the response to DNA damage. These results place p14(ARF) in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.

Alternative Splicing↗
PubMed1998

The transcription-repair coupling factor CSA is required for efficient repair only during the elongation stages of RNA polymerase II transcription.

The known nucleotide excision repair (NER) defects of xeroderma pigmentosum (XP) and Cockayne syndrome (CS) cells can be exploited to analyze mechanisms of repair of UV-induced cyclobutane pyrimidine dimers (CPDs) at nucleotide (nt.) resolution. The two gene products of the CS complementation groups (CSA and CSB) have been implicated in the preferential repair of the transcribed strand of human genes. We had previously described very efficient repair of CPDs at sequences near the transcription initiation site of the human JUN gene in normal fibroblasts. Here, we have analyzed repair in a CSA fibroblast strain. CSA cells exhibited rapid repair near the transcription initiation site (positions -45 to +15) but were deficient in repair of sequences on the transcribed strand beginning around nt. +20. There was also no strand-selective repair of sequences further downstream of the start site (+260 to +450). The results suggest that the transcription-repair coupling factor (TRCF) CSA is required for efficient repair only during the elongation stages of RNA polymerase II transcription. We also discuss possible mechanisms of differential repair observed near the transcription initiation site in XP and CS cells and conclude that these in vivo repair data support some recent models obtained from nucleotide excision repair experiments in vitro.

Cell Line↗
PubMed1998

Risk of fatal pulmonary embolism in patients with treated venous thromboembolism.

CONTEXT: The most serious complication of deep vein thrombosis (DVT) or nonfatal pulmonary embolism (PE) is fatal PE. However, reliable estimates as to the risk of fatal PE in patients with treated DVT or PE are lacking. OBJECTIVE: To provide reliable estimates of the risk of fatal PE and the case-fatality rate of recurrent DVT or PE among patients presenting with symptomatic DVT or PE, during and following 3 months of anticoagulant therapy. DATA SOURCES: A MEDLINE literature search was performed to identify prospective studies in which patients with symptomatic DVT or PE were treated with 5 to 10 days of heparin and 3 months of oral anticoagulants. We searched the years 1966 to September 1997 using the search terms thrombophlebitis, diagnosis, drug therapy, and prognosis. Current Contents and bibliographies were also scanned. DATA EXTRACTION: Of 137 retrieved studies, 25 studies satisfied predetermined methodologic criteria and were included in the analysis. DATA SYNTHESIS: Among patients presenting with DVT, the rate of fatal PE during anticoagulant therapy was 0.4% (95% confidence interval [CI], 0.2%-0.6%); following anticoagulant therapy it was 0.3 per 100 patient-years (95% CI, 0.1-0.8). The case-fatality rate of recurrent DVT or PE during anticoagulant therapy was 8.8% (95% CI, 5.0%-14.1%); following anticoagulant therapy it was 5.1% (95% CI, 1.4%-12.5%). Among patients presenting with PE, the rate of fatal PE during anticoagulant therapy was 1.5% (95% CI, 0.9%-2.2%); following anticoagulant therapy it was 0 per 265 patient-years (95% CI, 0-3.6). The case-fatality rate of recurrent DVT or PE among patients presenting with PE was 26.4% (95% CI, 16.7%-38.1%). CONCLUSION: Among patients with symptomatic PE or DVT who are treated with anticoagulants for 3 months, fatal PE is rare during and following anticoagulant therapy. Patients presenting with PE are more likely to die of recurrent PE or DVT than are patients presenting with DVT.

Anticoagulants↗
PubMed1998

The efficacy of local anaesthesia for percutaneous epididymal sperm aspiration and testicular sperm aspiration.

A total of 37 percutaneous epididymal sperm aspiration (PESA) and/or testicular sperm aspiration (TESA) procedures were performed under local anaesthesia (LA) on 34 men between June and November 1996. Local anaesthesia was achieved by injecting 10 ml of 1% lignocaine solution along the sides of the vas deferens near the external inguinal ring (spermatic cord block). Sperm retrieval was successful in 92% of the procedures. Of the 37 procedures, in 29 the patients felt either no pain or mild discomfort while in six they experienced moderate but tolerable pain. Analgesia was incomplete in two procedures and was supplemented with i.v. sedation. Vasovagal reflex in two procedures was reversed by i.v. atropine. In 24 procedures patients felt relaxed, whilst in 13 they felt anxious. In 32 procedures the patients expressed overall satisfaction. If the procedure was to be repeated, after 29 procedures the patients requested LA again, while after four procedures they preferred i.v. sedation and after four were undecided. LA is adequate for PESA and TESA in a large proportion of patients. Prior discussion of LA technique with the patient is necessary. Back-up facilities for i.v. sedation and atropine should be available.

Adult↗