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Biomedical subjects

S Taylor

Publications and source records attributed to S Taylor.

At least 235 records · Page 13Linked to original sources
PubMed1996

Continued malignant cell proliferation in head and neck tumors during cytotoxic therapy.

The effect of cytotoxic therapy on the proliferation of squamous cell carcinoma of the head and neck in vivo in patients was evaluated before and 15-35 days after the start of therapy. To accomplish this, iododeoxyuridine was administered at t = 0, and bromodeoxyuridine was administered 15-35 days later during treatment with a tumor biopsy obtained for study immediately after each pyrimidine infusion. Monoclonal antibodies specific for the halogenated pyrimidines were used to identify cells that were in the S-phase at the time of the infusions. Eleven patients were studied prior to treatment. Of those, the intratreatment biopsy of eight patients contained tumor tissue. In the other three patients, tumor tissue was not present in the second biopsy. Continued precursor incorporation into DNA-synthesizing cells during treatment was detected in six of eight tumor specimens. In two tumor specimens, an increase in the percentage of S-phase cells was noted, in two specimens tumor cells synthesizing DNA were not detected, and in four specimens the percentage of S-phase tumor cells was lower than that in the pretherapy specimen. Patients in whom there were no S-phase cells detected during treatment or in whom no tumor was detected in the second biopsy had a favorable treatment outcome in comparison to those patients in whom continued tumor proliferation during treatment was detected. The number of cells in S-phase prior to the initiation of treatment was not predictive of whether or not proliferation would continue during cytotoxic therapy. Evidence for reentry of kinetically quiescent cells into the cycle during treatment was noted. Additionally, cytotoxic therapy altered the proliferation pattern of normal-appearing mucosa as well. The results of this study demonstrate that tumor cell proliferation does continue in some squamous cell carcinoma of the head and neck during intensive cytotoxic therapy.

Adult↗
PubMed1995

Bound to activate: conformational consequences of cyclin binding to CDK2.

The cyclin-dependent kinases (CDKs) are among the most highly regulated enzymes in the protein-kinase family. The crystal structures of cyclin A and the CDK2-cyclin A complex spectacularly reveal the atomic basis for regulation of these enzymes and provide a template for understanding the function and regulation of other members of the CDK family.

CDC2-CDC28 Kinases↗
PubMed1995

Mutagenesis of the human apolipoprotein B gene in a yeast artificial chromosome reveals the site of attachment for apolipoprotein(a).

Lipoprotein(a) [Lp(a)] is a lipoprotein formed by the disulfide linkage of apolipoprotein (apo) B100 of a low density lipoprotein particle to apolipoprotein(a). Prior studies have suggested that one of the C-terminal Cys residues of apo-B100 is involved in the disulfide linkage of apo-B100 to apo(a). To identify the apo-B100 Cys residue involved in the formation of Lp(a), we constructed a yeast artificial chromosome (YAC) spanning the human apo-B gene and used gene-targeting techniques to change Cys-4326 to Gly. The mutated YAC DNA was used to generate transgenic mice expressing the mutant human apo-B100 (Cys4326Gly). Unlike the wild-type human apo-B100, the mutant human apo-B100 completely lacked the ability to bind to apo(a) and form Lp(a). This study demonstrates that apo-B100 Cys-4326 is required for the assembly of Lp(a) and shows that gene targeting in YACs, followed by the generation of transgenic mice, is a useful approach for analyzing the structure of large proteins coded for by large genes.

Animals↗
PubMed1995

Structure of the hepatic control region of the human apolipoprotein E/C-I gene locus.

The specificity of expression in the liver of the human apolipoprotein (apo) E/C-I gene locus is determined by a hepatic control region (HCR) that is located 15 kilobases downstream of the apoE gene. DNase I footprint studies of this sequence using nuclear extracts identified a region of the HCR that is enriched in nuclear protein-binding sites. Nuclease analysis of chromatin revealed liver-specific DNase I-hypersensitive sites that were associated with this region, and additional liver-specific nuclease-sensitive sites associated with the apoE gene were identified. The HCR domain has a limited binding affinity for the nuclear scaffold. The specific domain required for liver expression was tested by ligating subfragments of the HCR to the apoE gene and examining their activity in transgenic mice. A segment of 319 nucleotides that contained several potential regulatory sequences was required for full activity of liver-specific transcription with shorter segments yielding much lower levels of expression in the liver. All constructs that contained a fully active HCR were expressed in approximately a copy-dependent manner, suggesting that transgene expression was independent of integration position. Taken together, the properties of the HCR are consistent with its function as a locus control region for the liver-specific expression of the apoE gene.

Animals↗
PubMed1995

Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals.

Apolipoprotein (apo-) B mRNA editing is the deamination of cytidine that creates a new termination codon and produces a truncated version of apo-B (apo-B48). The cytidine deaminase catalytic subunit [apo-B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1)] of the multiprotein editing complex has been identified. We generated transgenic rabbits and mice expressing rabbit APOBEC-1 in their livers to determine whether hepatic expression would lower low density lipoprotein cholesterol concentrations. The apo-B mRNA from the livers of the transgenic mice and rabbit was extensively edited, and the transgenic animals had reduced concentrations of apo-B100 and low density lipoproteins compared with control animals. Unexpectedly, all of the transgenic mice and a transgenic rabbit had liver dysplasia, and many transgenic mice developed hepatocellular carcinomas. Many of the mouse livers were hyperplastic and filled with lipid. Other hepatic mRNAs with sequence motifs similar to apo-B mRNA were examined for this type of editing (i.e., cytidine deamination). One of these, tyrosine kinase, was edited in livers of transgenic mice but not of controls. This result demonstrates that other mRNAs can be edited by the overexpressed editing enzyme and suggests that aberrant editing of hepatic mRNAs involved in cell growth and regulation is the cause of the tumorigenesis. Finally, these findings compromise the potential use of APOBEC-1 for gene therapy to lower plasma levels of low density lipoproteins.

APOBEC-1 Deaminase↗
PubMed1995

Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer.

BACKGROUND: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. PURPOSE: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. METHODS: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). RESULTS: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). CONCLUSIONS: In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.

Adult↗
PubMed1995

Identification of abnormal chromosomal complement in formalin-fixed, paraffin-embedded placental tissue.

The objective of this project was to assess the efficacy of fluorescence in situ hybridization (FISH) with chromosome-specific DNA probes to identify chromosome number in formalin-fixed, paraffin-embedded placental specimens. Using this approach, 75 per cent of the karyotypes in 20 formalin-fixed placental samples (comprising aneuploids, triploids, and normals) were correctly identified. As this technology improves, the ability to obtain information regarding chromosomal abnormalities in formalin-fixed, paraffin-embedded placental tissue should improve as well. This technology can potentially provide important cytogenetic information even when fresh tissue is not available for standard karyotypic analysis.

Chromosome Aberrations↗
PubMed1995

Anxiety sensitivity: theoretical perspectives and recent findings.

Anxiety sensitivity (AS) is the fear of anxiety-related sensations, which arises from beliefs that these sensations have harmful somatic, psychological or social consequences. According to Reiss (1991), AS is one of three fundamental fears that amplify or cause many common fears. AS also is thought to play an important role in causing panic attacks. The purpose of the present article is to review recent findings concerning the construct of AS and its place in the nomological network outlined by Reiss. Although the weight of evidence supports a unifactorial model of AS, recent findings suggest AS is multifactorial at the level of first-order factors, and these factors load on a single higher-order factor. People with elevated AS, compared to those with low AS, are more likely to have histories of panic attacks. AS is factorially distinct from other fundamental fears, and is more strongly related to agoraphobia than other common fears. AS can be regarded as a subfactor of trait anxiety, and is more strongly related to agoraphobia than other common fears. AS can be regarded as a subfactor of trait anxiety, although the question arises as to whether AS is a cause of trait anxiety. Important questions for further investigation concern the etiology of AS and whether it can be reduced to still more basic fears.

Anxiety↗
PubMed1995

Stimulus estimation and the overprediction of fear: a comment on two studies.

The overprediction of fear is the tendency to overestimate the amount of fear one will experience in a subjectively threatening situation. This bias is thought to promote excessive avoidance and limit the opportunity for corrective learning. The stimulus estimation model states that the overprediction of fear arises from the overprediction of the danger features of the stimulus and the underprediction of available safety resources. Two recent studies reportedly failed to support the model (Arntz, Hildebrande & van den Hout, Behaviour Research and Therapy, 32, 709-722, 1994; Telch, Valentiner & Bolte, Behaviour Research and Therapy, 32, 747-751, 1994). The present commentary shows that both studies suffered significant methodological problems and neither can be said to have tested the model. Criteria for evaluating the model are briefly discussed.

Anxiety Disorders↗
PubMed1995

MEG and ECoG localization accuracy test.

We tested the localization accuracy of magnetoencephalography (MEG) and electrocorticography (ECoG) for a current dipole in a saline filled sphere at depths ranging from 1 to 6 cm at 1 cm intervals. We used standard neuromagnetometer placements and subdural electrode grids, previously employed for patient studies, with precise measurements of sensor and electrode locations with a 3-dimensional spatial digitizer. MEG and ECoG had comparable accuracy with mean errors of 1.5 and 1.8 mm, respectively. It appears that use of the spatial digitizer increases accuracy for both MEG and EGoG localizations. The larger errors in the ECoG with increasing depths could be attributed to under-sampling of the spatial pattern of the field which spreads out with deeper sources. It should be noted that in clinical applications a grid of the dimensions used here would most typically be used for superficial sources on the cortex with depth recordings being preferred for investigations of deep epileptogenic activity. Results are encouraging for continued development of non-invasive MEG methods for further definition of epileptogenic zones in the brain.

Cerebral Cortex↗
PubMed1995

Influence of 12 weeks of training by brisk walking on postprandial lipemia and insulinemia in sedentary middle-aged women.

The purpose of this study was to examine the influence of brisk walking on postprandial lipemia in 26 sedentary women aged 41 to 55 years. The lipemic response to a high-fat meal (mean +/- SEM: 73.8 +/- 1.3 g fat, 66% energy; 81.8 +/- 1.4 g carbohydrate) was determined pretraining and posttraining. Blood samples were obtained in the fasted state and hourly for 6 hours after the meal. Serum was analyzed for triacylglycerol (TAG), total cholesterol, high-density lipoprotein (HDL) and HDL2 cholesterol, apolipoproteins (apos) A-I and B, nonesterified fatty acids (NEFA), glucose, and insulin. Subjects were randomly assigned to one of two groups: walkers (n = 13) followed a program of brisk walking (average of 21 +/- 1 [range, 17 to 27] min.d-1 at 1.76 +/- 0.02 m.s-1), whereas controls (n = 13) maintained their habitual life-style. Procedures were repeated 12 weeks later, with 48 hours between the last training session and determination of postprandial lipemia. Eleven walkers and 13 controls completed the study. Responses over time were compared between groups (Mann-Whitney U, P < .05). Brisk walking improved endurance fitness and decreased body fatness, but had no influence on peak TAG concentration (walkers, 1.6 +/- 0.2 v 1.6 +/- 0.2 mmol.L-1; controls, 1.9 +/- 0.3 v 2.1 +/- 0.3) or the area under the TAG/time curve after the test meal. The area under the insulin/time curve decreased in walkers relative to controls. These results suggest that in sedentary women aged 41 to 55, brisk walking attenuates the serum insulin response, but not the lipemic response, to consumption of a high-fat mixed meal when these responses are determined 48 hours after the last exercise bout.

Adaptation, Physiological↗
PubMed1995

Multiple DNA binding modes of anthracene-9-carbonyl-N1-spermine.

The poly(dAdT)2 complex of anthracene-9-carbonyl-N1-spermine, a spermine derivative terminally substituted with an anthracene moiety, has been studied using fluorescence, linear dichroism, circular dichroism, normal absorption spectroscopy (as a function of temperature) and computer modelling. For comparison, some data are also provided for the same ligand with poly(dGdC)2 and calf thymus DNA. Following detailed fluorescence and CD spectroscopic studies, we propose that anthracene-9-carbonyl-N1-spermine intercalates in at least two different binding orientations with poly(dAdT)2. Based on computer simulation data, we deduce that the ligand can intercalate from both the minor groove and the major groove. In contrast, intercalation with poly(dGdC)2 probably occurs only from the major groove. At high ligand concentrations, the CD spectra suggest anthracene-anthracene interactions, whilst the LD data point towards a groove-bound anthracene. Again from computer simulations, we propose binding modes consistent with these observations. Other data from the LD spectra suggest a sequential nature to the binding of the ligand to calf thymus DNA, with GC-rich sites being occupied first. At low ligand concentrations, anthracene-9-carbonyl-N1-spermine is able to stabilize poly(dAdT)2 against thermal decomposition, but not as effectively as spermine. The reverse is found to be true with calf thymus DNA. Both the anthracene-9-carbonyl-N1-spermine and spermine complexes of poly(dAdT)2 show pre-melt transitions in their melting curves. The anthracene-9-carbonyl-N1-spermine complex with poly(dAdT)2 also shows a post-melt transition.

Antineoplastic Agents↗
PubMed1995

Improving visualization of distal and terminal ileum during the small bowel meal: an evaluation of fluoroscopic manoeuvres.

This study evaluated a variety of fluoroscopic manoeuvres used during small bowel meals for assessment of the terminal ileum and pelvic loops of small bowel. The purpose was to identify those manoeuvres which provide maximum diagnostic yield. Fifty-six consecutive patients undergoing small bowel meal and pneumocolon entered the study. The individual manoeuvres were graded and their contribution to diagnostic quality determined. An analysis of variance was used to determine the diagnostic value of the manoeuvres. There was a significant difference in the diagnostic quality provided by the different manoeuvres. Compression of the terminal ileum with the 'F spoon' and of the pelvic bowel loops with the compression paddle in the supine position provided the best diagnostic information in single contrast. The double contrast images obtained with the pneumocolon contributed most to the diagnostic quality of the examination. The results enable us to recommend a sequence of manoeuvres which are most likely to provide diagnostic views of the terminal ileum and pelvic ileal loops yielding maximum information and optimizing use of fluoroscopic time.

Barium Sulfate↗
PubMed1995

Activity of cefepime against ceftazidime-resistant gram-negative bacilli using low and high inocula.

Cefepime is a broad-spectrum cephalosporin that is reported to have enhanced activity against ceftazidime-resistant Gram-negative bacilli. In this study the effects of varying inoculum size on in-vitro susceptibility to cefepime and other selected antimicrobial agents were determined by agar dilution MICs and in time-kill studies. Among strains of Pseudomonas aeruginosa (n = 55) and Enterobacter spp (n = 56) that had previously been identified as ceftazidime-resistant, 73% and 96% were susceptible to cefepime (MIC < or = 16 mg/L), respectively, when tested with an inoculum of 10(4) cfu. However, with an inoculum of 10(7) cfu, 98% and 100% of strains were resistant, respectively. Furthermore, the bactericidal activity of cefepime against ceftazidime-resistant isolates was also inoculum-dependent. In time-kill studies, bactericidal action was obtained only at the lowest concentration of organisms (10(4) cfu/mL). beta-Lactamase extracted from an isolate of P. aeruginosa that demonstrated an inoculum effect had a lower affinity for cefepime than for ceftazidime. Overall, cefepime proved to be more resistant to hydrolysis by the beta-lactamase. However, differences in kinetics of the beta-lactamase against cefepime or ceftazidime do not appear to be of consequence in determining susceptibility of P. aeruginosa and Enterobacter spp. at high bacterial densities, since most strains with chromosomally-mediated beta-lactamase are highly resistant.

Cefepime↗
PubMed1995

In vivo labelling with halogenated pyrimidines of squamous cell carcinomas and adjacent non-involved mucosa of head and neck region.

The frequency and distribution of labelled cells were studied immunohistochemically in 37 squamous cell carcinomas (SCC) of head and neck after in vivo infusion of IdUrd and BrdUrd. Tumours were classified according to their labelling patterns. Low and moderate grade SCC consisted of tumour islands separated by interstitial tissue. In some tumours labelled cells only appeared near the basal layer while in others proliferative cells were evenly distributed within the neoplastic island. In anaplastic carcinomas labelled cells were distributed either randomly or around blood vessels (cord structures). While the basal layer in adjacent normal epithelium contained very few labelled cells (LI = 1.6 +/- 0.2%), the LI of basal cells in tumour islands were much higher than the average LI of the tumour (47.2 +/- 2.8% and 23.8 +/- 1.6%, respectively). In patients who had received cytotoxic therapy up to two months before the biopsy, the LI in the basal layer of normal epithelium was 19.0 +/- 3.5%. In sequential biopsies obtained 1-2 weeks after the infusion of IdUrd and BrdUrd some labelled tumour cells were found in necrotic foci and in pearl structures. Additionally, in six tumours, we found areas of cells labelled with IdUrd alone, even though the IdUrd infusion had been followed by a BrdUrd infusion 1 h later. This is in agreement with the phenomenon of intermittent tumour blood flow described earlier in experimental tumours.

Biomarkers, Tumor↗