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Biomedical subjects

J A Cook

Publications and source records attributed to J A Cook.

At least 163 records · Page 9Linked to original sources
PubMed1994

Sequence dependence of paclitaxel (Taxol) combined with cisplatin or alkylators in human cancer cells.

Clinical trials combining paclitaxel with other active chemotherapy agents are currently underway. In vitro preclinical studies may assist in the selection of appropriate drug combinations or sequences for clinical investigation. We have used clonogenic cell survival assays and DNA flow cytometry to examine the effect of paclitaxel combined with melphalan, thiotepa, or cisplatin on the survival and cell-cycle parameters of human lung A549 and breast MCF-7 adenocarcinoma cells. A549 and MCF-7 cells were incubated with paclitaxel for 24 h, followed by a 1 h exposure to cisplatin, melphalan, or thiotepa. Both cell types were also incubated with cisplatin or an alkylator for 1 h followed by a 24 h paclitaxel exposure. When the paclitaxel exposure preceded either melphalan, thiotepa, or cisplatin, the cytotoxicity was additive for both cell lines tested. When cisplatin or alkylator exposure was given prior to the paclitaxel, cytotoxicity was also additive in MCF-7 cells. However, cisplatin or alkylators were antagonistic to paclitaxel cytotoxicity when they preceded the paclitaxel exposure in A549 cells (e.g., 2% survival with 100 nM paclitaxel vs. 7% survival with cisplatin and paclitaxel). Cell-cycle analysis revealed that exposure to 100 nM paclitaxel for 24 h blocked a majority of the cells into the G2/M phase (> or = 80% for A549 cells, 60-65% for MCF-7 cells). However, exposure to alkylators before incubation in paclitaxel reduced the proportion of A549 but not MCF-7 cells in G2/M--e.g., exposure to 30 micrograms/ml cisplatin prior to paclitaxel exposure caused only 25% of A549 and 55% of MCF-7 cells to block in G2/M.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1994

Nocturnal intermittent peritoneal dialysis.

Automated methods of peritoneal dialysis have developed as alternative methods of treatment to CAPD. We review our experience of 47 patients treated with nocturnal intermittent peritoneal dialysis (NIPD). Patients receive a nocturnal exchange of 15-25 litres of dialysate with the peritoneum left dry during the day. If biochemical control is inadequate, 1 litre of dialysate is left in during the day. Indications for NIPD included social reasons and CAPD failure due to poor ultrafiltration or problems related to raised intra-abdominal pressure. Some features of biochemical control were less good with NIPD compared with CAPD with higher phosphate (2.18 mmol/l versus 1.83 mmol/l, P < 0.001); creatinine (1256 mumol/l versus 1085 mumol/l, P < 0.001); and potassium (4.92 mmol/l versus 4.64 mmol/l, P = 0.056) in patients changing between CAPD and NIPD. Overall peritonitis rate on NIPD was one episode per 47.1 months compared with a rate of one episode per 17.5 months for patients commencing CAPD over the same period. Conversion from CAPD to NIPD was successful in all six cases for problems related to raised intra-abdominal pressure on CAPD and in six of nine patients transferred due to poor ultrafiltration. NIPD is a useful form of treatment and we believe that the increased cost is offset by the reduced peritonitis rate.

Adult↗
PubMed1993

Squamous carcinoma presenting as an enlarged cervical lymph node.

BACKGROUND: Patients presenting with an enlarged cervical lymph node containing squamous cell carcinoma are a difficult problem for head and neck surgeons. In most cases, the primary site lies in the head and neck region. The advent of fine-needle aspiration cytologic study means that this group of patients can be accurately identified in the clinic and investigated accordingly. METHODS: The current report studies the records of 267 such patients presenting to the Head and Neck Unit at The University of Liverpool over a 29-year period. RESULTS: The 5-year survival rate for all patients presenting with a cervical lymph node metastasis was 27%. The 5-year survival rate for patients with a detected primary in the head and neck was 31% and the primary site was identified during the patient's life time in all but 36 patients (13%). In 53% of patients, the primary site was discovered during routine clinical examination, and in a further 16% it was discovered at panendoscopy. Most diagnostic tests proved relatively unhelpful but 10 patients in our series had the primary site discovered by radiograph and 9 of these had carcinoma of the lung. In the current study when the primary site was discovered it was in the head and neck region in 74% of patients. Primary sites other than head and neck occurred in 11% of the patients and no 5-year survivors existed. Multivariate analysis suggested that open biopsy of the lymph node metastasis appeared to have an adverse effect on survival as did advanced age and advanced N stage. The late diagnosis of the primary site, if it proved to be in the head and neck region, on the other hand, had a positive association with survival. CONCLUSIONS: Patients presenting with a lymph node metastasis in the head and neck region from an unknown primary have a prognosis identical to that of other patients with head and neck squamous carcinoma with neck node metastases. The prognosis for patients in whom the primary site is never discovered or in whom the primary site is not head and neck, however, is disastrous. If the primary tumor proves to be in the head and neck region, treatment is worthwhile since almost a third of patients are cured of their disease. When the primary carcinoma is not in the head and neck region, treatment must be considered palliative.

Age Factors↗
PubMed1993

Glutathione depletion by L-buthionine sulfoximine antagonizes taxol cytotoxicity.

Taxol is a naturally occurring chemotherapeutic agent that is active against a variety of tumors. Taxol is believed to act by binding tightly to microtubules and preventing their disaggregation. Others have shown that depletion of cellular glutathione results in the disaggregation of microtubules, presumably by allowing the oxidation of some or all of the cysteine residues in tubulins. We studied the effect of glutathione (GSH) depletion by L-buthionine sulfoximine (L-BSO) on taxol cytotoxicity in two human tumor lines. After a 24-h incubation in 5 mM L-BSO, the breast adenocarcinoma line MCF-7 and the lung adenocarcinoma line A549 were exposed to varying concentrations of taxol for 24 h. GSH levels were undetectable in cells treated with L-BSO. At the highest concentrations of taxol (50 nM), control MCF-7 cells had 10% cell survival and control A549 cells had only 1% cell survival as assessed by clonogenic assay. Pretreatment with 5 mM L-BSO resulted in a 3-fold increase in survival of MCF-7 cells and a 10-fold increase in survival of A549 cells. Pretreatment with L-BSO had no effect on taxol uptake into A549 or MCF-7 cells, as assessed by measurement of binding of [3H]taxol to cells. Following exposure to 37 nM taxol for 24 h, both cell lines had over 80% of their population in G2/M and bromodeoxyuridine labeling showed that taxol markedly reduced the percentage of cells in S phase. L-BSO pretreatment had no effect on the cell cycle in either cell line in the absence of taxol. However, in cells treated with taxol, L-BSO increased the percentage of cells in S phase by 3-fold in both cell lines. We conclude that depletion of cellular GSH by L-BSO results in resistance to taxol in MCF-7 and A549 cells. Resistance to taxol mediated by GSH depletion is not due to alterations in cellular uptake of taxol by L-BSO. L-BSO increased the S-phase fraction of taxol-treated cells in both cell lines. These data suggest that GSH depletion interferes with cell cycle changes induced by taxol. The alteration in taxol-induced cell cycle effects may account for the resistance to taxol produced by L-BSO.

Buthionine Sulfoximine↗
PubMed1993

Thromboxane A2 receptors in equine monocytes: identification of a new subclass of TXA2 receptors.

Thromboxane (TX) A2 has been implicated as an important pathophysiologic mediator of a variety of cardiovascular diseases. Monocytes synthesize TXA2 and it modulates their function. This study sought to characterize monocyte TXA2 receptors. Radioligand binding studies were performed on membranes prepared from equine peripheral blood monocytes using [125I]BOP, a TXA2 receptor agonist. [125I]BOP bound to a single class of binding sites (Kd = 1.0 +/- 0.3 nM and Bmax = 389 +/- 191 fmol/mg protein; n = 5). Several TXA2 receptor agonists and antagonists competed for binding with [125I]BOP. I-BOP produced a concentration-dependent inhibition of endotoxin-induced tumor necrosis factor (TNF) activity (IC50 = 9.6 +/- 2.5 nM; n = 5). In contrast to its effects in platelets and vascular smooth muscle, I-BOP significantly increased cAMP formation in monocytes (EC50 = 22 +/- 3.6 nM; n = 4). The TXA2 receptor antagonists SQ29548 (5.6 microM) and L657925 (0.13 microM) significantly blocked I-BOP-stimulated cAMP formation but did not block 250 nM prostaglandin E2-stimulated cAMP formation. These data support the presence of a TXA2 receptor in equine peripheral blood monocytes. Activation of this receptor results in suppression of endotoxin-induced TNF formation and stimulation of cAMP production. Increased cAMP production after receptor activation suggests that this receptor may represent a unique subclass of TXA2 receptors.

Animals↗
PubMed1993

A randomised phase II trial of epirubicin and 5-fluorouracil versus cisplatinum in the palliation of advanced and recurrent malignant tumour of the salivary glands.

Sixteen patients with advanced and recurrent malignant salivary gland tumours were admitted to a randomised trial and the response assessed. Seven patients received Epirubicin/5-Fluorouracil and none of these patients responded. Nine patients received Cisplatinum and only one patient had a partial response. The trial suggests that chemotherapy has no place in the treatment of advanced salivary gland malignant tumours.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines.

The cytotoxicity of paclitaxel against eight human tumour cell lines has been studied with in vitro clonogenic assays. The fraction of surviving cells fell sharply after exposure for 24 h to paclitaxel concentrations ranging from 2 to 20 nM; the paclitaxel IC50 was found to range between 2.5 and 7.5 nM. Increasing the paclitaxel concentration above 50 nM, however, resulted in no additional cytotoxicity after a 24 h drug exposure. Cells incubated in very high concentrations of paclitaxel (10,000 nM) had an increase in survival compared with cells treated with lower concentrations of the drug. Prolonging the time of exposure of cells to paclitaxel from 24 to 72 h increased cytotoxicity from 5 to 200 fold in different cell lines. Exponentially growing cells were more sensitive to paclitaxel than were cells in the plateau phase of growth. Cremophor EL, the diluent in which the clinical preparation of paclitaxel is formulated, antagonised paclitaxel at concentrations of 0.135% (v/v). These data suggest that paclitaxel will be most effective clinically when there is prolonged exposure of tumour to the drug. Further, it appears that modest concentrations (i.e., 50 nM) should be as effective as higher concentrations of paclitaxel. Finally, we have noted that Cremophor EL is a biologically active diluent and, at high concentrations (0.135% v/v), can antagonise paclitaxel cytotoxicity.

Adenocarcinoma↗
PubMed1993

Implications of tumour in resection margins following surgical treatment of squamous cell carcinoma of the head and neck.

Presence of tumour at the resection margin following primary surgical treatment for squamous cell carcinoma of the head and neck is thought to adversely affect prognosis. To confirm this we performed a review of 478 patients treated by primary surgery for squamous cell carcinoma of the head and neck and sub-divided them into those exhibiting positive margins and those with negative margins following resection. Uni-variate and multi-variate statistical methods were used to analyse survival figures and a variety of parameters associated with the presence of positive resection margins. We found 5-year survival was decreased if resection margins were found to be positive (P < 0.025). The presence of positive resection margins was also significantly associated with time to tumour recurrence (P < 0.001) and survival with nodal recurrence (P < 0.001). Other factors which were significantly associated with survival using Cox's multi-variate analysis were site of tumour (P < 0.005), nodal extracapsular rupture (P < 0.05), histology (P < 0.05) and pathological T-stage (P < 0.05). Uni-variate analysis revealed no significant associations between the presence of positive margins and the patient's age, sex, tumour site, degree of tumour differentiation, and nodal status, though using multiple logistic regression, the general condition of the patient (P < 0.01) and the tumour site P < 0.05) were significantly related. The results support the concept that every effort should be made to obtain negative resection margins when undertaking primary ablative surgery for squamous cell carcinoma of the head and neck.

Carcinoma, Squamous Cell↗
PubMed1993

The effect of histamine challenge on nasal airflow sensation.

Objective nasal airflow resistance, as measured by the rhinomanometer, and the subjective sensation of nasal patency are usually regarded as showing poor correlation. However, previous population studies comparing nasal resistance and subjective nasal airflow sensation have failed to take into account the great individual variation in resting nasal resistance. To investigate the potential relationship between the two parameters, 20 healthy volunteers underwent histamine nasal challenge tests. Nasal resistance prior to the intra-nasal administration of histamine ('resting' nasal resistance, NRR) was compared with nasal resistance when the subject reported a subjective sensation of nasal blockage ('obstructed' nasal resistance, NR0) and the two were found to be significantly correlated using the Spearman rank correlation method (rs = 0.648, P = 0.002). Linear regression analysis using the method of least squares demonstrated an association between the two variables (P = 0.029), conforming to the formula NR0 = 1.26NR+0.478, (resistance units kPa.s.l-1). Subjective and objective measurements of nasal patency may be much more closely related than has previously been reported.

Administration, Intranasal↗
PubMed1993

Laser treatment of rhinitis--1 year follow-up.

Laser cautery of the inferior turbinates for the treatment of rhinitis has been shown to be as effective as sub-mucosal diathermy in the short-term and to produce less morbidity. However, the long-term effects are unknown. A cohort of patients who were treated by either of these methods were reviewed 1 year after treatment. Subjective and objective measurements of airway obstruction were performed using a linear analogue scale and a nasal peak inspiratory flowmeter. The results obtained were compared with those recorded pre-operatively, 3 days post-operatively and 6 days post-operatively. In contrast to the results of sub-mucous diathermy of the inferior turbinates for the treatment of rhinitis, the reduction in subjective nasal airway obstruction obtained by laser cautery to the inferior turbinates is maintained 1 year after surgery. Neither method of turbinate reduction was associated with a sustained objective improvement in nasal airway patency as measured by peak nasal inspiratory flow rate determinations.

Adolescent↗
PubMed1993

Electromagnetic stimulation as a treatment of tinnitus: a pilot study.

This paper reports the results of a study to determine whether pulsed electromagnetic stimulation, applied over the mastoid bone, caused an improvement in the level of tinnitus in long-standing tinnitus sufferers. Fifty-eight patients from the Liverpool Tinnitus Association volunteered to take part in a double-blind placebo controlled trial. Active and placebo devices were randomly allocated to these patients on their first visit. At the end of one week of treatment, each patient noted whether their tinnitus had completely disappeared, was improved, unchanged or made worse by the treatment Forty-five per cent of the patients who completed the trial were improved by the active device, but only 9% by placebo (P = 0.0013, Mann-Whitney test). We suggest that electromagnetic stimulation may be an effective treatment in some tinnitus sufferers.

Adult↗
PubMed1993

Non-squamous malignancy in lymph nodes: the occult primary.

The present study presents 105 patients seen at a head and neck specialist clinic with a neck gland which subsequently proved to be a non-squamous malignancy. Of the 105 patients, 50 patients were eventually found to have a tumour in the head and neck region, 30 to have a distant primary and in 25 no primary site was ever found. The majority of patients were diagnosed in the clinic after careful examination and most of the remainder were diagnosed during endoscopy/biopsy. Chest radiography was the most useful investigation for diagnosing primary tumours of the lung. The 5-year-survival for the whole group of 105 patients was 28% (95% CI 17-39). The 5-year-survival for the head and neck primary tumour group was 44% (95% CI 25-60). The median survival of patients with a distant primary tumour was only a 6 months, there was one 5-year-survivor. The median survival for those in whom the primary was never discovered was 18 months. However, a reasonable proportion of these patients survived, five being alive at 5 years. The difference between survival for the three groups was statistically significant (P < 0.001). The most common histological type was undifferentiated/anaplastic tumours (37 out of 105) and this was followed by adenocarcinoma (33 out of 105). There was a significant difference in the survival between these two groups (chi 2 = 2.02, d.f. = 1, P = NS). Multi-variate analysis suggested that survival was better in the older age group and was affected by histology (P = 0.0093, P = 0.0332 respectively). The present study suggests that the treatment of patients in whom the primary site is eventually found to be in the head and neck region is rewarding with the same survival as a similar group of patients with squamous cell carcinoma. Sixty of the group of 105 patients had excision biopsies of the neck node and this did not affect survival.

Adenocarcinoma↗
PubMed1993

Effects of two magainin peptides on eicosanoid release from rat peritoneal macrophages.

Magainins are novel polycationic peptides with broad-spectrum antimicrobial activity, including activity against gram-negative bacteria. Gram-negative bacteremia can elicit endotoxic shock that is associated with the increased formation of eicosanoids. Inhibition of eicosanoid synthesis has been shown to improve the outcome of experimental endotoxic shock. The aim of the present study was to test the in vitro effects of two magainin peptides, MSI-97 (M1) and MSI-98 (M2), on eicosanoid synthesis by rat peritoneal macrophages (M phi) stimulated by Salmonella enteritidis lipopolysaccharide (LPS; 50 micrograms/ml) and Salmonella minnesota lipid A (5 micrograms/ml) and to compare their effects on LPS reactivity with a metachromatic dye. M1 (100 micrograms/ml) significantly (P < 0.05) reduced LPS-stimulated synthesis of thromboxane B2 (TXB2), without changing 6-keto-prostaglandin F1 alpha in M phi. Similarly, M2 (10 micrograms/ml) significantly attenuated M phi synthesis of TXB2 stimulated by either LPS or lipid A. However, at a higher concentration (100 micrograms/ml), M2 but not M1 significantly augmented LPS-induced increases in TXB2 and 6-keto-prostaglandin F1 alpha. Polymyxin B (40 micrograms/ml) inhibited LPS production and lipid A-stimulated TXB2 production. M1 (100 micrograms/ml) and polymyxin B (10 and 40 micrograms/ml) also inhibited calcium ionophore A23187 (10 microM)-induced synthesis of TXB2. The lipid A moiety of LPS reacts with dimethylmethylene blue dye, providing a metachromatic assay of LPS. This metachromatic reaction with lipid A was significantly reduced by polymyxin B and M2 at all concentrations. M1 was effective only at the highest M1:lipid A concentration ratio (2:1). Thus, M1 and M2 share some similarities with polymyxin B in inhibiting lipid A reactivity with the dye, which suggests that these magainins may also bind to lipid A. However, M1 was devoid of any inhibitory effects on dye reactivity with S. enteritidis LPS and M2 was inhibitory at only one concentration ratio (1:5). In conclusion, the varied effects of the magainin peptides on LPS, lipid A, and M phi eicosanoid synthesis appear to depend on the type of peptide used and on its concentration.

Amino Acid Sequence↗
PubMed1993

Conservative genome size and rapid chromosomal evolution in the South American tuco-tucos (Rodentia: Ctenomyidae).

Genome size (the amount of DNA per cell) was measured by flow-cytometric analysis in seven species of a chromosomally variable rodent genus: Ctenomys boliviensis, C. conoveri, C. frater, C. leucodon, C. lewisi, C. opimus, and C. steinbachi. The mean genome size of these species was 7.19 pg DNA and little inter- and intra-specific variation was observed. Genome size was not correlated with diploid number, suggesting that chromosomal evolution at this level is independent of total DNA content. A hypothetical taxonomic unit optimization procedure was carried out using genome size change on a Wagner tree derived from allozyme data. Allozyme evolution and genome size change are linked by a weak, but significant, negative correlation suggestive of preferential genic evolution in the absence of genome size evolution.

Animals↗
PubMed1993

Prostaglandins, thromboxanes, leukotrienes, and cytochrome P-450 metabolites of arachidonic acid.

Arachidonic acid is metabolized via three major enzymatic pathways: cyclooxygenase, lipoxygenase, and cytochrome P-450. The cyclooxygenase pathway gives rise to the prostaglandins and thromboxane A2. The lipoxygenase pathway produces the leukotrienes and 5-, 12-, and 15-hydroxyeicosatetraenoic acids. The cytochrome P-450 pathway metabolites are oxygenated metabolites of arachidonic acid. Synthesis of several of the cyclooxygenase and lipoxygenase metabolites are increased in circulatory shock. A potential role for several of these compounds in the pathophysiologic sequelae of endotoxic and septic shock has been implied from a combination of animal and human studies. There are no studies that have explored a potential role for cytochrome P-450 metabolites in the pathogenesis of circulatory shock.

Animals↗
PubMed1993

One-step purification of recombinant human papillomavirus type 16 E7 oncoprotein and its binding to the retinoblastoma gene product.

Six derivatives of the human papillomavirus type 16 E7 gene were constructed, each of which encoded a peptide at the amino terminus of the E7 protein capable of chelating metal ions, for use in subsequent purification of the proteins by chelating peptide-immobilized metal ion affinity chromatography (CP-IMAC). Five of the six chelating peptides examined contained six amino acids, and each varied in the number of histidine and tryptophan residues. The CP-E7 proteins were expressed in Escherichia coli, and the cysteine residues were blocked in the form of S-sulfonate groups. This series of CP-E7 proteins was purified in a single chromatographic step using CP-IMAC. The efficiency of purification correlated with the number of histidine and tryptophan residues present in the CP. The purified CP-E7 proteins bound to the human retinoblastoma gene product, pRB, in in vitro co-immunoprecipitation assays and immobilized CP-E7 binding assays. The efficiency of E7-pRB binding was not altered by the presence of a CP at the N-terminus of E7 nor by the S-sulfonate groups within E7.

Amino Acid Sequence↗