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Biomedical subjects

H R Matthews

Publications and source records attributed to H R Matthews.

At least 55 records · Page 3Linked to original sources
PubMed1995

Lack of correlation of P-glycoprotein expression with response to MIC chemotherapy in oesophageal cancer.

The multidrug resistance gene product P-glycoprotein (P-GP) was assessed immunohistochemically (by antibody JSB-1) in biopsy specimens from 27 oesophageal squamous carcinomas and 10 adenocarcinomas before treatment with mitomycin, ifosfamide and cisplatin (MIC). Tumours were assessed following treatment and correlation with response sought. Of the squamous carcinomas, 74% (20/27) responded to MIC but only one expressed P-GP before and after treatment. Of the adenocarcinomas, 30% (three of 10) responded. Seven of the 10 adenocarcinomas expressed P-GP before treatment but all 10 were P-GP positive after chemotherapy. The difference in prevalence and induction of P-GP between the histological types was highly significant and may correlate with the greater response to MIC seen in squamous carcinomas compared with adenocarcinomas. P-GP cannot be used as a predictive marker of response as tumours express it inconsistently with response to MIC. Resistance to MIC may be due to other mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Expression of HLA-ABC, HLA-DR and intercellular adhesion molecule-1 in oesophageal carcinoma.

AIM: To examine the expression of HLA-ABC and HLA-DR major histocompatibility (MHC) antigens and intercellular adhesion molecule (ICAM)-1 in normal, inflamed, metaplastic, and neoplastic oesophageal tissue and in freshly disaggregated tumours. METHODS: Sequential sections of frozen tissue and cytospins of freshly disaggregated tumour were stained using the ABC peroxidase system and monoclonal antibodies specific for HLA-ABC, HLA-DR and ICAM-1. RESULTS: Normal oesophageal tissue showed positive staining for HLA-ABC in the basal layers of the oesophageal squamous epithelium and on the epithelial cells of the submucosal oesophageal glands. HLA-DR and ICAM-1 were not detected in either of these cell types. In 20 of 37 (54%) carcinomas HLA-ABC was expressed weakly, with heterogeneous expression in nine (24%). Two tumours showed strong expression of HLA-ABC, but 15 of 37 (41%) were negative. HLA-DR and ICAM-1 were expressed weakly in six of 37 (16%) carcinomas without correlation with each other or with the expression of HLA-ABC. CONCLUSIONS: HLA-ABC is absent from a high proportion of oesophageal carcinomas (41%) and is otherwise variably and weakly expressed with strong expression in only a small fraction (3%). In other carcinomas there is a higher level of HLA-ABC expression. This discrepancy may partly explain the aggressive nature of oesophageal carcinomas. HLA-DR and ICAM-1 are not normally expressed on those cells from which oesophageal carcinomas are thought to arise. The limited expression found here could suggest a partial or inhibited immune response against oesophageal carcinoma. In vivo repressive factors may be involved.

Adenocarcinoma↗
PubMed1994

The effect of pH on the block by L-cis-diltiazem and amiloride of the cyclic GMP-activated conductance of salamander rods.

Block by L-cis-diltiazem and amiloride of the cyclic GMP-activated conductance was studied in inside-out patches excised from the salamander rod outer segment. When cytoplasmic pH was varied, the steady-state level of block by L-cis-diltiazem changed in the way that would be predicted if it were the protonated ammonium group that is responsible for effecting block. This is in contrast to the recent results of Haynes (J. gen. Physiol. 100, 783 (1992)) in catfish cones, where no such change was seen. Amiloride was found to block the conductance with a similar voltage dependence to that of L-cis-diltiazem. The dependence of amiloride block on cytoplasmic pH was found to be shifted relative to that of L-cis-diltiazem, consistent with the 1 pH-unit higher pKa value of amiloride and the idea that it is only the charged form of amiloride which can effect block. This suggests that the results seen with L-cis-diltiazem were indeed due to changes in the proportion of blocker in the protonated form, and not to effects of protons on the channel.

Ambystoma↗
PubMed1994

Expression of p53 protein in oesophageal carcinoma: clinicopathological correlation and prognostic significance.

Correlation of p53 expression with 5-year survival and histopathological parameters was examined immunohistochemically in two groups of 30 patients with oesophageal carcinoma (5-year survivors versus non-survivors). Tumour type, sex, operative procedure and age were matched. Some 64 per cent of squamous carcinomas and 79 per cent of adenocarcinomas were p53 positive. Normal squamous, normal glandular and metaplastic glandular epithelia were negative. Dysplastic squamous and glandular epithelium adjacent to tumours was positive when the tumour was positive and negative when it was not. Univariate analysis showed that nodal status (P = 0.001), and grade and depth of invasion (both P = 0.01) correlated with outcome. Correlation of tumour grade with outcome, when the most poorly differentiated area is used, is a novel finding for oesophageal carcinoma. The p53 status was not significantly associated with survival or any of these parameters.

Adenocarcinoma↗
PubMed1994

A phase II study of mitomycin, ifosfamide and cisplatin in operable and inoperable squamous cell carcinoma of the oesophagus.

We have evaluated the effect of mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 (MIC) in two groups of patients with squamous or undifferentiated carcinoma of the oesophagus, as either preoperative or primary treatment. Response was assessed by barium swallow, CT scan, and measurement of metastases where present. Toxicity was acceptable and there were no chemotherapy related deaths. In the operated group, five of 23 patients (22%) showed a complete response (three confirmed histologically) and nine (39%) showed a partial response following two courses of MIC. Resection was completed in 21 patients, with three hospital deaths (14%). Of the 18 patients who were discharged from hospital, eight have died at 4-24 months (median 13) from the start of treatment and 10 are alive at 5-35 months, with known recurrence in one. In the non-operated group, five of 20 patients (25%) showed a response, one complete, following one to four (mean 2.6) courses of MIC. Nineteen patients have died (at median 5 months), and one, who had a complete response, is alive and free from disease at 29 months. Neo-adjuvant therapy with MIC in squamous carcinoma of the oesophagus has shown encouraging early results, with acceptable toxicity.

Aged↗
PubMed1994

Effects of chemotherapy on ultrastructure of oesophageal squamous cell carcinoma.

Seven oesophageal squamous carcinomas, treated with pre-operative chemotherapy (mitomycin-C, ifosfamide and cisplatin-MIC), with a course finishing 21 days prior to resection, were examined by electronmicroscopy. In one treated case detailed light microscopy failed to reveal any tumour. Five of the remaining six tumours showed cytotoxic damage in that apoptosis and unusual necrotic changes were observed in almost all the neoplastic cells. These features were not seen in untreated cases. In four additional cases, who received one pulse of MIC followed by biopsy or resection within 3-6 days, apoptotic changes were very pronounced and extensive and most neoplastic cells presented unusual degeneration with characteristic derangement of the cytoskeleton, destruction of organelles and accumulation of glycogen. The ultrastructural appearance of 18 untreated resected oesophageal squamous carcinomas was studied for comparison with the treated tumours. The study has demonstrated ultrastructural changes resulting from chemotherapy. Results suggest that the regimen is more effective against squamous carcinomas than against adenocarcinomas of the oesophagus, as judged by comparison with the results of a previous study.

Adult↗
PubMed1993

Protein phosphatases 1, 2A, and 2C are protein histidine phosphatases.

Eukaryotic cellular proteins contain phosphohistidine. To search for protein histidine phosphatases, protein histidine kinase from Saccharomyces cerevisiae was used to phosphorylate histone H4 on histidine at position 75 in the H4 amino acid sequence. Incubation of the phosphorylated histone H4 with either protein phosphatase 1, 2A, or 2C resulted in extensive removal of phosphate from the phosphorylated histone. Thus, protein phosphatases 1, 2A, and 2C are histidine phosphatases as well as serine/threonine phosphatases. Calcium/calmodulin-regulated protein phosphatase (protein phosphatase 2B) did not remove phosphate from phosphohistidine. The histidine phosphatase reaction was tested for a magnesium requirement and effects of inhibitor-1 and okadaic acid. In all cases, the protein phosphatases behaved as they do in their serine/threonine phosphatase activity. Extracts of the yeast, S. cerevisiae, contain protein histidine phosphatase activity. Quantitative measurement of phosphatase activity shows that the activity against phosphohistidine is a major activity of protein phosphatases 1, 2A, and 2C.

Carrier Proteins↗
PubMed1993

Protein phosphatase assay suitable for acid-labile substrates.

A sensitive protein phosphatase assay suitable for acid-labile substrates has been developed. The assay involves incubation of the phosphatase with a 32P-labeled phosphoprotein substrate, quenching the reaction, and then filtering through an ultrafilter that retains substrate and allows the released phosphate to flow through. The released phosphate is counted. The use of a slightly alkaline quenching solution makes the assay suitable for all phosphoamino acids that are stable near physiological pH, including the acid-labile phosphoamino acids. The process is made very convenient by the use of disposable microcon-3 ultrafiltration devices. Radioactive waste is limited to reaction tubes, the microcon-3s, pipette tips, and the scintillation vials and fluid.

Acids↗
PubMed1993

Studies of the DNA binding properties of histone H4 amino terminus. Thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 "tail" to DNA.

The effect of acetylation on the DNA binding properties of the rigidly conserved histone H4 amino-terminal tail has been studied in detail using the technique of thermal denaturation. The quantitative DNA-binding parameters for both the non- and fully acetylated H4 amino terminus have been determined from thermal denaturation data for complexes of the peptides bound to mixed sequence 146-base pair DNA. We find that under dilute buffer conditions (5 mM Tris-HCl) the binding constant for the non-acetylated peptide to double-stranded DNA is 5 x 10(11) M-1 and that acetylation of lysine residues in the peptide reduces the binding constant to 1 x 10(5) M-1. The dramatic differences observed in the binding constants for the non- and fully acetylated peptides are probably due to the effect of acetylation on the even distribution of positively charged residues in the H4 amino terminus. In other experiments, the binding of both peptides to a 30-base pair oligonucleotide has been studied in solution with varying concentrations of sodium, magnesium, and phosphate ions. These experiments demonstrate that both magnesium and phosphate ions have strong effects on the binding of the H4 tail to DNA, especially weakening the binding of the acetylated peptide. For instance, the dissociation of the non-acetylated peptide from DNA requires 6 mM magnesium, yet the binding of the acetylated peptide is abolished in only 30 microM magnesium. The modulation of the DNA binding interactions of the H4 amino terminus by physiologically relevant ionic conditions, in addition to the effect of acetylation, can be important in the regulation of chromatin structure and function.

Acetylation↗
PubMed1993

Polyamines, chromatin structure and transcription.

Nucleosomes are the basic elements of chromatin structure. Polyamines, such as spermine and spermidine, are small ubiquitous molecules absolutely required for cell growth. Photoaffinity polyamines bind to specific locations in nucleosomes and can change the helical twist of DNA in nucleosomes. Acetylation of polyamines reduces their affinity for DNA and nucleosomes, thus the helical twist of DNA in nucleosomes could be regulated by cells through acetylation. I suggest that histone and polyamine acetylation act synergistically to modulate chromatin structure. On naked DNA, the photoaffinity spermine bound preferentially to a specific 'TATA' sequence element, suggesting that polyamines may be involved in the unusual chromatin structure in this region. Further work is needed to test whether the specificities shown by photoaffinity polyamines are also shown by cellular polyamines; such experiments are now feasible.

Affinity Labels↗
PubMed1993

Primary immotile oesophagus in young patients.

Since 1984 we have identified 14 patients under the age of 45 years with severe, unexplained loss of oesophageal motility. The ages at presentation ranged from 20 to 42 years and nine were female. Barium swallow was normal in eight patients and showed minor abnormalities in six. Twenty-four hour pH studies were normal in all patients and the only endoscopic abnormality was minimal oesophagitis in three. Upper oesophageal sphincter resting pressures and cervical motility were normal except in one patient. Motility in the body of the oesophagus was severely reduced in all patients with a mean peristaltic amplitude of 10 mmHg. Lower oesophageal sphincter resting pressures were reduced in 11 patients and normal in three, with incomplete sphincter relaxation in three. All patients have been followed up for a minimum of 3 years without progression of their symptoms or the development of a secondary cause. Six patients have undergone repeat manometry and pH studies with no changes. We conclude that there is a group of young patients who appear to undergo severe primary loss of oesophageal motility for reasons that have not yet been identified. It is important to identify these patients so that inappropriate surgery can be avoided.

Adult↗
PubMed1993

Circular myotomy and Belsey repair for acquired shortening of the oesophagus.

Fourteen patients with shortening of the oesophagus due to chronic reflux oesophagitis have been treated by a combination of an oesophageal lengthening procedure with a standard anti-reflux repair. Their ages ranged from 18 to 78 years and eight were male. Thirteen patients had a reflux stricture (with additional penetrating ulcer in six) and one had a columnar-lined oesophagus. A complete circular myotomy was performed just below the level of the aortic arch, in combination with a Belsey Mark IV anti-reflux repair. There were no deaths post-operatively but one patient required re-operation for haemorrhage and one underwent oesophageal dilatation before discharge. All patients have now been followed up for over 5 years. Nine patients have required no further treatment for their oesophageal problems, two required two early dilatations each, two required multiple dilatations and one required oesophageal resection for stricture. We suggest that this combination merits further evaluation in the management of patients with short oesophagus due to reflux.

Adolescent↗
PubMed1993

Histopathological findings in oesophageal carcinoma with and without preoperative chemotherapy.

AIMS: To investigate the pathological effects of preoperative chemotherapy on oesophageal carcinoma. METHODS: Qualitative and quantitative changes in oesophageal carcinoma after preoperative chemotherapy were assessed by examination of biopsy specimens before treatment and resected specimens. RESULTS: Of 13 patients with adenocarcinoma treated with 5-fluorouracil, adriamycin, and mitomycin (FAM), nine showed minor histological changes compared with 14 control cases. All 12 patients with squamous carcinoma treated with preoperative mitomycin, ifosfamide, and cisplatin (MIC) showed noticeable histological changes when compared with the 13 control cases. Changes included complete ablation (n = 1) and partial regression (n = 5) of the tumour. A quantitative estimate of the proportion of tumour to stroma showed no difference between control adenocarcinomas and those treated with chemotherapy. There was, however, a significant reduction (p < 0.01) in the proportion of tumour to stroma in the treated squamous group compared with the controls. There was no relation between the degree of response in squamous carcinomas and the degree of differentiation of the tumour. Patients in which squamous carcinomas responded well, as assessed quantitatively, showed a tendency to better survival at one year. CONCLUSIONS: Histopathological changes attributable to chemotherapy can be observed in oesophageal carcinoma. The response of squamous carcinoma to MIC is histologically more evident than that of adenocarcinoma to FAM. A quantitative technique may be useful in assessing the effect of chemotherapy in oesophageal squamous carcinoma.

Adenocarcinoma↗