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Biomedical subjects

M Saunders

Publications and source records attributed to M Saunders.

At least 73 records · Page 4Linked to original sources
PubMed1997

A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer.

BACKGROUND AND PURPOSE: Continuous, hyperfractionated, accelerated radiotherapy (CHART) has shown promise of improved tumour control and reduced late morbidity in pilot studies and has now been tested in a multicentre randomised controlled clinical trial. MATERIAL AND METHODS: Patients with squamous cell cancer in the main sites within the head and neck region with the general exception of early T1 N0 tumours were entered into the study by 11 centres. There was a 3:2 randomisation to either CHART, where a dose of 54 Gy was given in 36 fractions over 12 days, or to conventional therapy where 66 Gy was given in 33 fractions over 6.5 weeks. A total of 918 patients were included over a 5 year period from March 1990. RESULTS: ACUTE MORBIDITY: Acute radiation mucositis was more severe with CHART, occurred earlier but settled sooner and was in nearly all cases healed by 8 weeks in both arms. Skin reactions were less severe and settled more quickly in the CHART treated patients. TUMOUR CONTROL AND SURVIVAL: Life table analyses of loco-regional control, primary tumour control, nodal control, disease-free interval, freedom from metastasis and survival showed no evidence of differences between the two arms. In exploratory subgroup analyses there was evidence of a greater response to CHART in younger patients (P = 0.041) and poorly differentiated tumours appeared to fare better with conventional radiotherapy (P = 0.030). In the larynx there was evidence of a trend towards increasing benefit with more advanced T stage (P = 0.002). LATE TREATMENT RELATED MORBIDITY: Osteoradionecrosis occurred in 0.4% of patients after CHART and 1.4% of patients after conventional radiotherapy. The incidence of chondritis or cartilage necrosis was similar in both arms. Life table analysis showed evidence of reduced severity in a number of late morbidities in favour of CHART. These were most striking for skin telangiectasia, superficial and deep ulceration of the mucosa and laryngeal oedema. CONCLUSION: Similar local turnout control was achieved by CHART as compared with conventional radiotherapy despite the reduction in total dose from 66 to 54 Gy supporting the importance of repopulation as a cause of radiation failure. The effects seen in advanced laryngeal cancer and those related to histological differentiation need further study. Reduced late morbidity is a factor which together with patient preference should be considered in the decision as to the programme of radiotherapy to employ in the curative treatment of head and neck cancer.

Adult↗
PubMed1997

Sodium salicylate inhibits cyclo-oxygenase-2 activity independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid.

Acetylsalicylic acid (aspirin) is the drug most commonly self-administered to reduce inflammation, swelling, and pain. The established mechanism of action of aspirin is inhibition of the enzyme cyclo-oxygenase (COX). Once taken, aspirin is rapidly deacetylated to form salicylic acid, which may account, at least in part, for the therapeutic actions of aspirin. However, where tested, salicylic acid has been found to be a relatively inactive inhibitor of COX activity in vitro, despite being an effective inhibitor of prostanoids formed at the site of inflammation in vivo. Recently, the identification of a cytokine-inducible isoform of COX, COX-2, has led to the suggestion that salicylate produces its anti-inflammatory actions by inhibiting COX-2 induction through actions on nuclear factor kappaB (NF-kappaB). We have used interleukin 1beta-induced COX-2 in human A549 cells to investigate the mechanism of action of salicylate on COX-2 activity. Sodium salicylate inhibited prostaglandin E2 release when added together with interleukin 1beta for 24 hr with an IC50 value of 5 microg/ml, an effect that was independent of NF-kappaB activation or COX-2 transcription or translation. Sodium salicylate acutely (30 min) also caused a concentration-dependent inhibition of COX-2 activity measured in the presence of 0, 1, or 10 microM exogenous arachidonic acid. In contrast, when exogenous arachidonic acid was increased to 30 microM, sodium salicylate was a very weak inhibitor of COX-2 activity with an IC50 of >100 microg/ml. Thus, sodium salicylate is an effective inhibitor of COX-2 activity at concentrations far below those required to inhibit NF-kappaB (20 mg/ml) activation and is easily displaced by arachidonic acid.

Arachidonic Acid↗
PubMed1997

In vivo validation of whole body composition estimates from dual-energy X-ray absorptiometry.

We validated whole body composition estimates from dual-energy X-ray absorptiometry (DEXA) against estimates from a four-component model to determine whether accuracy is affected by gender, race, athletic status, or musculoskeletal development in young adults. Measurements of body density by hydrostatic weighing, body water by deuterium dilution, and bone mineral by whole body DEXA were obtained in 172 young men (n = 91) and women (n = 81). Estimates of body fat (%Fat) from DEXA (%FatDEXA) were highly correlated with estimates of body fat from the four-component model [body density, total body water, and total body mineral (%Fatd,w,m); r = 0.94, standard error of the estimante (SEE) = 2.8% body mass (BM)] with no significant difference between methods [mean of the difference +/- SD of the difference = -0.4 +/- 2.9 (SD) % BM, P = 0.10] in women and men. On the basis of the comparison with %Fatd,w,m, estimates of %FatDEXA were slightly more accurate than those from body density (r = 0.91, SEE = 3.4%; mean of the difference +/- SD of the difference = -1.2 +/- 3.4% BM). Differences between %FatDEXA and %Fatd,w,m were weakly related to body thickness, as reflected by BMI (r = -0.34), and to the percentage of water in the fat-free mass (r = -0.51), but were not affected by race, athletic status, or musculoskeletal development. We conclude that body composition estimates from DEXA are accurate compared with those from a four-component model in young adults who vary in gender, race, athletic status, body size, musculoskeletal development, and body fatness.

Absorptiometry, Photon↗
PubMed1996

Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction.

Interleukin-6 (IL-6) induces tyrosine phosphorylation and activation of the latent transcription factor Stat3 in HepG2 cells. Mutation of Stat3 tyrosine 705 to phenylalanine (Y705F) inhibits IL-6-induced tyrosine phosphorylation of this Stat3 mutant in transfected HepG2 cells. In cotransfections of HepG2 cells, the Stat3 mutant Y705F causes a reduction of the tyrosine phosphorylation of wild type Stat3-FLAG. Moreover, Y705F inhibits the action of endogenous Stat3 in cotransfected cells, reducing IL-6 induction of a Stat3-responsive reporter construct. Y705F therefore acts as a dominant negative mutation of Stat3.

Amino Acid Sequence↗
PubMed1996

Successful treatment of HTLV-1-associated acute adult T-cell leukaemia lymphoma by allogeneic bone marrow transplantation.

HTLV-1-associated acute adult T-cell leukaemia-lymphoma (ATL) is a highly aggressive malignant disorder with a median survival of 6 months or less. We describe an Afro-Caribbean female with very poor prognosis ATL who underwent chemotherapy with a 4 d infusion schedule of cyclophosphamide, doxorubicin and etoposide, followed by successful allogeneic bone marrow transplantation (BMT) from her HTLV-1-negative histocompatible sister. The patient remains in complete remission 23 months after BMT and has 100% donor haemopoiesis with no evidence of HTLV-1 infection on PCR testing. We suggest that allo-BMT can prolong disease free survival or may even be curative in HTLV patients.

Adult↗
PubMed1996

Predicting distant failure in nasopharyngeal cancer.

In a prospective study of 78 patients with nasopharyngeal cancer, we examined the prognostic significance of T stage, histology, parapharyngeal involvement, and lymph node dimensions, size, and level concerning distant metastasis. AU patients were treated with radical radiotherapy alone and completed 3 to 7 years of follow-up. In univariate analysis of time to metastasis, there was a significant difference stratifying for T stage (T1 and 2 versus T3 and 4), node dimensions (less than 6 versus more than or equal to 6 cm), neck level (above versus below the thyroid notch), and parapharyngeal involvement, but not for bilaterality of lymphadenopathy. Histology was an important prognostic factor related to distant metastasis since none of the 24 World Health Organization class I cases showed distant metastasis versus 14 (26%) of 54 patients with World Health Organization class II/III carcinoma. A multivariate duration model of time to metastasis within the later histologic group suggested that lymph node dimensions, node level, and T stage were the most important factors related to distant metastases, with the hazard ratios being 3.98, 3.23, and 1.76, respectively. Multivariate analysis within the T3- to T4-stage group showed that node dimension was the only significant variable, with an associated hazard ratio of 4.09. Cases with upper-neck lymphadenopathy and node dimensions of less than 6 cm had a distant metastasis rate of <5%. We conclude that adjuvant chemotherapy for nasopharyngeal cancer is justified in T3- and T4-staged cases with nonkeratinizing or undifferentiated histology and with lymph nodes larger than 6 cm and/or located below the thyroid notch.

Adult↗
PubMed1996

Clinical results of hypoxic cell radiosensitisation from hyperbaric oxygen to accelerated radiotherapy, carbogen and nicotinamide.

The 40-year history of hypoxic cell sensitisation can be traced from hyperbaric oxygen to the present clinical studies with carbogen, nicotinamide and accelerated radiotherapy. A meta-analysis by Overgaard (1995) included 10703 cases entered into 83 randomised controlled trials and showed an overall improvement in local tumour control of 4.6% (P = 0.00001) and in survival of 2.8% (P = 0.005). Hyperbaric oxygen gave a 6.6% (P = 0.003) improvement in local control and hypoxic cell sensitisers 3.9% (P = 0.04). Despite this, the only hypoxic cell-sensitising method in routine clinical use is the giving of nimorazole in supraglottic and pharyngeal carcinomas. Acute, as well as chronic hypoxia has been recognised and nicotinamide, the amide derivative of B3 is believed to prevent the former. Thus ARCON (accelerated radiotherapy, carbogen and nicotinamide) has been introduced in the clinic in an effort to overcome tumour proliferation, chronic and acute hypoxia, respectively. The success of future randomised controlled trials would be improved greatly if methods were available to measure the concentration of hypoxic cells in tumours before treatment and thus select those where benefit may be gained. The use of ARCON recognises that tumour cell proliferation is an important cause of failure in addition to hypoxia. However, intrinsic radiosensitivity may also need to be taken into account in the future. Clinical trials aim to improve the therapeutic ratio and thus the study of morbidity is as important as local tumour control. International collaboration is essential if randomised controlled trials are to be carried out within reasonable periods of time.

Blood Transfusion↗
PubMed1995

Recombination-dependent DNA replication stimulated by double-strand breaks in bacteriophage T4.

We analyzed the mechanism of recombination-dependent DNA replication in bacteriophage T4-infected Escherichia coli using plasmids that have sequence homology to the infecting phage chromosome. Consistent with prior studies, a pBR322 plasmid, initially resident in the infected host cell, does not replicate following infection by T4. However, the resident plasmid can be induced to replicate when an integrated copy of pBR322 vector is present in the phage chromosome. As expected for recombination-dependent DNA replication, the induced replication of pBR322 required the phage-encoded UvsY protein. Therefore, recombination-dependent plasmid replication requires homology between the plasmid and phage genomes but does not depend on the presence of any particular T4 DNA sequence on the test plasmid. We next asked whether T4 recombination-dependent DNA replication can be triggered by a double-strand break (dsb). For these experiments, we generated a novel phage strain that cleaves its own genome within the nonessential frd gene by means of the I-TevI endonuclease (encoded within the intron of the wild-type td gene). The dsb within the phage chromosome substantially increased the replication of plasmids that carry T4 inserts homologous to the region of the dsb (the plasmids are not themselves cleaved by the endonuclease). The dsb stimulated replication when the plasmid was homologous to either or both sides of the break but did not stimulate the replication of plasmids with homology to distant regions of the phage chromosome. As expected for recombination-dependent replication, plasmid replication triggered by dsbs was dependent on T4-encoded recombination proteins. These results confirm two important predictions of the model for T4-encoded recombination-dependent DNA replication proposed by Gisela Mosig (p. 120-130, in C. K. Mathews, E. M. Kutter, G. Mosig, and P. B. Berget (ed.), Bacteriophage T4, 1983). In addition, replication stimulated by dsbs provides a site-specific version of the process, which should be very useful for mechanistic studies.

Bacteriophage T4↗
PubMed1994

Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity.

A motif essential for the transcriptional activation function 2 (AF-2) present in the E region of retinoic acid receptor (RAR) alpha and 9-cis retinoic acid receptor (RXR) alpha has been characterized as an amphipathic alpha-helix whose main features are conserved between transcriptionally active members of the nuclear receptor superfamily. This conserved motif, which can activate autonomously in the absence of ligand in animal and yeast cells, can be swapped between nuclear receptors without affecting the ligand dependency for activation of transcription, thus indicating that a ligand-dependent conformational change is necessary to reveal the AF-2 activation potential within the E region of the nuclear receptor. Interestingly, we show that the precise nature of the direct repeat response element to which RAR/RXR heterodimers are bound can affect the activity of the AF-2s of the heterodimeric partners, as well as the relative efficiency with which all-trans and 9-cis retinoic acids activate the RAR partner.

Amino Acid Sequence↗
PubMed1994

Prediction of survival in a hospital-based continuing care unit.

Prediction of survival can be relevant in palliative care in those units with selective admission policies and limited resources, for planning patient management and in discharge planning for those patients expected to go home. In this study, factors most predictive of prognosis were identified. Those factors shown to have no effect on survival included the performance of investigations or procedures, anti-cancer therapy, morphine dose on admission and original admitting ward. Patients admitted primarily for pain control had a significant survival advantage over those patients admitted for palliation of some other symptom. Actual survival correlated well with predicted outcome. Factors most predictive of relative risk of death in a multivariate analysis were dyspnoea, decubitus ulcers, predicted outcome, interventions and a diagnosis of lung cancer. When symptoms alone were analysed, dyspnoea and immobility carried the highest relative risk of death.

Adult↗
PubMed1993

Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids.

The binding of endogenous retinoids and stereoisomers of retinoic acid (RA) to the retinoid nuclear receptors, RA receptor (RARs) and retinoid X receptors (RXRs), was characterized using nucleosol preparations from transiently transfected COS-1 cells. Among several stereoisomers of RA tested, including 7-cis-, 9-cis-, 11-cis-, 13-cis-, and all-trans-RA, only 9-cis-RA effectively competes with 9-cis-[3H]RA binding to the RXRs. Additionally, the endogenous retinoid trans-didehydro-RA (t-ddRA) does not interact with RXRs, whereas the 9-cis form of ddRA competes effectively. RXRs (alpha, beta, and gamma) bind 9-cis-RA with dissociation constants (Kd) of 15.7, 18.3, and 14.1 nM, respectively. In contrast to the selectivity of RXRs for 9-cis-RA, RARs bind both t-RA and 9-cis-RA with high affinity, exhibiting Kd values in the 0.2-0.7 nM range for both ligands. Unlike RARs, the cellular RA binding proteins CRABPI or CRABPII bind t-RA but do not bind 9-cis-RA. Consistent with the binding data, 9-cis-RA and 9-cis-ddRA transcriptionally activate both GAL4-RXR and GAL4-RAR chimeric receptors with EC50 values of 3-20 nM for 9-cis-RA and 9-cis-ddRA, whereas t-RA and t-ddRA efficiently activate only GAL4-RAR chimeric receptors. Thus, 9-cis forms of endogenous retinoids can contribute to the pleiotropic effects of retinoids by interacting with both the RARs and RXRs.

Animals↗
PubMed1993

Need for a comparative performance standard for dry powder inhalers.

The efficacy of dry powder inhalers is dependent on the inspiratory flow rate at which they are used. The resistance to airflow through five different dry powder inhaler devices was measured. The devices were shown to vary significantly, with the Turbohaler having the highest resistance. We suggest that the performance of dry powder inhalers should be assessed at comparable pressure drops producing clinically relevant inspiratory flow rates for each device.

Nebulizers and Vaporizers↗