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Biomedical subjects

A L Thomas

Publications and source records attributed to A L Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2001

A phase II study of caelyx, liposomal doxorubicin: lack of activity in patients with advanced gastric cancer.

PURPOSE: A phase II study was designed to assess the efficacy and safety of Caelyx (liposomal doxorubicin) in patients with advanced or metastatic gastric cancer. METHODS: A total of 25 patients with gastric adenocarcinoma were treated with Caelyx 45 mg/m2 every 28 days as first-line therapy for advanced disease. Patients were treated until tumour progression or unacceptable toxicity. RESULTS: One patient was withdrawn from the study after experiencing a severe infusion reaction. Of the 24 evaluable patients, 1 had a partial response, 7 had stable disease and the others progressed. Side effects, in particular palmar-plantar erythrodysaesthesia and haematological toxicity, were minor. CONCLUSIONS: We conclude that while this dose and schedule of Caelyx in this patient group is acceptable, further studies with this regimen cannot be recommended due to the lack of antitumour activity seen.

Adenocarcinoma↗
PubMed2001

Recent advances in the nonsurgical treatment of upper gastrointestinal tract tumors.

Cancers of the esophagus, stomach and pancreas constitute a major cause of cancer death worldwide. Despite improvements in both surgical techniques and chemotherapy regimens these tumors remain a great therapeutic challenge and most patients still die of their disease, even after apparent 'curative resection'. There is a clear need for more effective treatments, particularly for patients with advanced disease, since this is the most common presenting stage. In this review we will discuss the clinical strategies in use and identify the best current treatment options based on randomized clinical trial data. Novel strategies under investigation are discussed and speculation made as to which will be standard treatments of the future.

Chemotherapy, Adjuvant↗
PubMed2000

Experimental analyses of sexual and natural selection on short tails in a polygynous warbler.

We believe that no experimental study has yet tested Darwin's idea that, as well as generating trait elaboration, intersexual selection might sometimes drive sex-biased trait reduction. Here we present the results of two experiments exploring the negative relationship between tail length and reproductive success in male golden-headed cisticolas (Cisticola exilis). In the first experiment, artificially shortening a male's tail produced a dramatic increase in his reproductive success, measured as either the number of females nesting or number of chicks Hedged on his territory. A second experiment, in which manipulated birds were flown through a maze, revealed that short tails also impose costs by reducing aerodynamic performance during slow-speed foraging flight. Because tail shortening yields reproductive benefits and viability costs, we conclude it has evolved via sexual selection. Disentangling exactly how short tails enhance male reproductive success is more difficult. Male-male competition appears partly responsible: aerodynamic theory predicts that tail reduction enhances high-speed flight and, in line with this, shortened-tail males spent more time engaged in high-speed aerial chases of rivals and defended higher-quality territories. However, shortened-tail males had higher reproductive success independent of territory quality and spent more time in aerial displays which may be directed at females. This suggests that tail shortening is also favoured via female choice based on male phenotype.

Animals↗
PubMed2000

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer: report of a phase I/II dose-escalating study.

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis.

Aged↗
PubMed2000

Chemotherapy for upper gastrointestinal tumours.

The aim of this review is to identify current chemotherapy treatment for tumours of the oesophagus, stomach, pancreas, and liver. The role of both neoadjuvant, adjuvant, and palliative chemotherapy regimens will be discussed. This review will be of interest to oncologists in clarifying current issues regarding chemotherapy, and to physicians in other medical specialties, to increase their general understanding of benefits and drawbacks of chemotherapy in this patient group.

Carcinoma, Hepatocellular↗
PubMed2000

Marimastat: the clinical development of a matrix metalloproteinase inhibitor.

Marimastat (BB-2516) is the first orally bioavailable matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed Phase I, II and some Phase III trials. In Phase I studies, which recruited patients with various malignancies, the main toxicity observed was mild to severe joint and muscle pain seen in > 60% of patients receiving a dose of marimastat > 50 mg b.i.d. The symptoms were reversible on discontinuation of the drug and their incidence has been reduced by using marimastat 10 mg b.i.d. In a number of Phase II studies in a variety of tumours, serum tumour markers were used as surrogate determinants of efficacy. Results were interpreted as indicating activity, but this has not yet translated into improved survival in the Phase III studies, which have been completed in pancreatic or gastric carcinoma and glioma. It is likely that these drugs will be most effective in the setting of minimal tumour volume such as in adjuvant treatment or maintenance therapy following response to standard cytotoxics. Therefore, the analysis of Phase III studies in small cell lung cancer (SCLC) where this hypothesis has been tested is awaited with interest. Marimastat can be safely co-administered with conventional cytotoxics and radiotherapy and Phase III studies using these approaches are currently ongoing.

Animals↗
PubMed1997

The effects of cyclosporin A, dexamethasone and other immunomodulatory drugs on induced expression of IL-3, IL-4 and IL-8 mRNA in a human mast cell line.

We examined by RT-PCR the effect of a number of immunomodulatory compounds on cytokine gene expression at the level of mRNA in the HMC-1 human leukemic mast cell line. Resting cells expressed relatively low constitutive levels of mRNA for the cytokine genes IL-3, IL-4 and IL-8, and mRNA levels for each of these cytokines were significantly enhanced after 4-h stimulation with the calcium ionophore ionomycin. Treatment of the cells with the immunosuppressant CsA at 10(-5) M produced a significant inhibition of ionomycin-induced expression of IL-3, IL-4 and IL-8 mRNA, and at 10(-6) M produced a significant inhibition of induced expression of IL-3 and IL-8 but not IL-4. At both concentrations of CsA, expression of IL-3 was inhibited to a greater extent than that of the other two cytokines. Treatment of the cells with the corticosteroid DEX at 10(-5) M but not 10(-6) M significantly reduced the ionomycin-induced expression of IL-3 but not IL-4 or IL-8 mRNA. Progesterone and methotrexate were both inactive in modulation of induced cytokine expression in this cell line. In conclusion, this study shows that cytokine expression, particularly of IL-3, is inhibited in a human mast cell line by CsA and DEX. These findings may be relevant to the anti-allergic action of these drugs.

Adjuvants, Immunologic↗
PubMed1996

Interactions between the histidine stimulation of cadmium and zinc influx into human erythrocytes.

1. Histidine (2-40 mM) stimulated cadmium uptake into human erythrocytes incubated in the presence of 1% bovine serum albumin to ensure that the free, ionic cadmium concentration was low. 2. The histidine-stimulated cadmium uptake correlated with the calculated concentration of the cadmium-bis-histidine complex rather than the cadmium-mono-histidine complex or free ionic cadmium. 3. The histidine stimulation of cadmium uptake was saturable and stereospecific. D-Histidine (10 mM) had no effect. 4. Cadmium and zinc were both able to inhibit 65Zn2+ uptake into erythrocytes incubated in the presence of 40 mM L-histidine. The relationships between the percentage inhibition of 65Zn2+ uptake and the calculated concentrations of cadmium-bis-histidine and zinc-bis-histidine were very similar, which suggests that the metal histidine complexes compete for a common transport mechanism. 5. Pretreatment of the erythrocytes with N-ethylmaleimide using a protocol which is known to inhibit the system y+ amino acid transport mechanism had no effect on the histidine stimulation of metal transport.

Animals↗
PubMed1996

Effects of Ara-C on neutral sphingomyelinase and mitogen- and stress-activated protein kinases in T-lymphocyte cell lines.

Neutral sphingomyelinase (SMase) can be activated by extracellular signals to produce ceramide, which may affect mitogen-activated protein kinase (MAPK) activities. Neutral SMase activity was assessed in membranes from Jurkat, a human T-cell line, and EL4, a murine T-cell line. Ara-C activated SMase with 10 minutes in both Jurkat and EL4 cells, while phorbol ester (PMA) had no effect. PMA, but not Ara-C or ceramides, activated ERK MAPKS, in Jurkat and EL4. PMA acted synergistically with ionomycin to activate JNK MAPKs in Jurkat and EL4 within 10 minutes. Ara-C activated JNKs only after prolonged incubation (90-120 minutes). Thus, ceramide is not a positive signal for ERK activation in T-cell lines. The effects of Ara-C on JNK activity may be mediated through secondary response pathways.

Animals↗
PubMed1996

Familial juvenile systemic granulomatosis (Blau's syndrome).

Blau's syndrome refers to the rare familial presentation of a sarcoid-like granulomatous disease classically involving the skin, uveal tract and joints, in the absence of pulmonary manifestations. The onset is in childhood, and the mode of inheritance is thought to be autosomal dominant. We report a 15-year-old female and her 22-month-old daughter who presented with clinical features similar to those of Blau's syndrome. In addition to the skin, eye and joint disease, the mother also developed neurological involvement. In both patients long-term systemic corticosteroids were required to control the disease.

Adolescent↗
PubMed1995

The effects of mercuric chloride on growth, cytokine and MHC class II gene expression in a human leukemic mast cell line.

We have examined the effects of mercuric chloride (HgCl2) on growth and IL-4, IL-8, TNF-alpha and MHC class II gene expression in the HMC-1 human leukemic mast cell line. Proliferation, measured by [3H]thymidine incorporation or production of a formazan product (MTT assay), was substantially inhibited by HgCl2 at concentrations of 10(-6) M and above. Inspection of the DNA by agarose gel electrophoresis from HgCl2-treated cells revealed that it was intact, indicating inhibition of DNA synthesis, but not denaturation. HgCl2 inhibited expression of mRNA for IL-8, TNF-alpha and MHC class II at 4 x 10(-6) M and inhibited expression of IL-4 mRNA at 8 x 10(-6) M and above. At a concentration of 10(-5)M, HgCl2 almost completely blocked mRNA expression for IL-4, IL-8, TNF-alpha and MHC class II, but produced negligible inhibition of expression of mRNA encoding the housekeeping gene beta-actin, thus demonstrating selective toxicity for the cytokine and MHC class II genes studied. Pre-exposure of the cells to human recombinant IL-4 prior to treatment with HgCl2 had no effect on expression levels of any of the genes examined. The effects seen in this study are consistent with previous reports showing immunotoxic effects of HgCl2 on other cell types, therefore, the HMC-1 mast cell line may prove useful in further studies of mast cell cytokine gene expression and the mechanisms involved in cytokine gene toxicity.

Base Sequence↗
PubMed1995

The effect of histidine and cysteine on zinc influx into rat and human erythrocytes.

1. The effect of histidine and cysteine on the initial rate of zinc influx into rat and human erythrocytes in the presence of bovine serum albumin has been investigated. 2. The L-enantiomers of both amino acids promoted zinc influx into rat erythrocytes in a dose-dependent manner. L-Histidine, but not L-cysteine, also promoted zinc uptake into human erythrocytes. D-Histidine did not promote zinc uptake in either rat or human erythrocytes. In rat erythrocytes D-cysteine was significantly less effective than L-cysteine. 3. The stimulation of zinc influx into rat erythrocytes by 20 mM L-histidine was approximately 4.1 times that seen with human erythrocytes. 4. The influx of zinc in the presence of varying concentrations of L-histidine was linearly related to the calculated concentration of the zinc-bis-histidine complex but not to that of the zinc-mono-histidine complex or the free ionic zinc concentration. 5. These results are discussed in relation to the nature of the transport mechanisms involved.

Animals↗
PubMed1995

An analysis of beta-lactam-derived antigens on spleen cell and serum proteins by ELISA and Western blotting.

Penicillins and related beta-lactam antibiotics are known to conjugate to proteins to generate potentially antigenic (haptenic) determinants. In the present study, we used a rabbit polyclonal antibody raised against benzylpenicillin (BP) to investigate the capacity of six penicillins and one cephalosporin to generate haptenic groups in vitro on cultured mouse spleen cells and on serum proteins in the culture medium. All of the drugs tested, namely, BP, amoxicillin (AMX), ampicillin (AMP), cephalothin (CEP), cloxacillin (CLX), flucloxacillin (FLX), and phenoxymethylpenicillin (PMP) generated antigens in a concentration-dependent manner on cell and serum proteins, which could be detected by ELISA, although antigens generated by BP, CEP, FLX, or PMP in either cell- or serum-conjugated form were more readily detected than those generated by AMX, AMP, or CLX. Western blot analysis revealed that BP-derived antigens were generated relatively slowly on cell proteins (maximum binding was not yet reached after 8 h), compared to serum proteins (maximum binding within 1 h). BP, CEP, and PMP all generated similar distinctive patterns of immunostaining of electrophoresed cell or serum proteins which did not reflect the relative abundance of different proteins as revealed by Coomassie brilliant blue staining. FLX, CLX, AMP, and AMX did not generate antigens that could be detected on Western blots. In conclusion, we have shown that various beta-lactam antibiotics generate antigens on cell and serum proteins that can be detected and characterized immunochemically with polyclonal antiserum. Further application of these methods may offer potential for further identification of immunologically relevant cellular and serum antigens generated by these drugs.

Animals↗
PubMed1994

Attenuation of p53 expression protects against focal ischemic damage in transgenic mice.

Apoptosis or programmed cell death may be involved in neuronal death in the cerebral cortex after a permanent focal ischemic insult. Studies indicate that protein p53 is a major determinant of the cellular mechanism that leads to programmed cell death. Wild-type C57 mice and two groups of transgenic C57 mice, one homozygous and the other heterozygous for a p53 null gene, were subjected to middle cerebral artery occlusion. As expected, the wild-type mice had a large, consistent infarct volume (22.11 +/- 4.59 mm3; n = 10). Both transgenic groups had significantly less ischemic damage than the wild-type control group. However, unexpectedly, the heterozygous group had the least amount of ischemic damage (16.12 +/- 1.71 mm3, n = 11; 27% reduction in infarct size). The ischemic damage in the homozygous group (18.72 +/- 3.48 mm3, n = 9) was significantly less than in the wild-type control (15% reduction in infarct size) but significantly more than in the heterozygous group. Thus, although the absence of p53 expression was protective, greater protection was afforded by reduced expression of p53. These data suggest that attenuated p53 expression may be protective after an ischemic event.

Animals↗