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M J Langman

Publications and source records attributed to M J Langman.

At least 37 records · Page 2Linked to original sources
PubMed1997

Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers.

We have compared the expression of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ten paired samples of normal and tumour colonic tissue with regard to both mRNA and protein. We have compared sensitivity of these tissues to IGF-I using primary cultures of epithelial cells of colonic mucosa, and we have examined the production of IGFs and IGFBPs by these cells. In the tissues, IGFBP-2 mRNA was expressed in all normal and cancer samples but other IGFBPs showed variable expression. mRNAs for IGF-I were expressed in all normal and cancer tissues but IGF-II mRNA was only detected in cancer tissue (3 out of 10). Immunostaining of sections of normal and cancer tissue was negative for IGF-I and IGF-II; IGFBP-2 was positive in 2 out of 10 cancer tissues and 7 out of 10 normal tissues; IGFBP-3 was positive in 7 out of 10 cancer tissues and 7 out of 10 normal tissues; and IGFBP-4 was positive in 5 out of 10 cancer tissues and 6 out of 10 normal tissues. In the cells in culture, cancer cells showed increased incorporation of [35S]methionine into protein and [3H]thymidine into DNA (P < 0.02) when treated with IGF-I. Western blotting of serum-free conditioned media from cells in culture showed that 8 out of 10 normal and 3 out of 10 cancer cultures produced a 32-kDa immunoreactive IGFBP-2. No IGFBP-3 was secreted by any culture but 24-kDa IGFBP-4 was found in 3 out of 10 normal and 5 out of 10 cancer tissues. Because of the discrepancy between mRNA and protein expression for IGFBP-2, degradation of native IGFBPs was assessed using tissue extracts. Colon cancer extracts were able to degrade exogenous IGFBP-2, IGFBP-3 and IGFBP-4, whereas normal tissue extracts were without effect on IGFBP-2. We conclude that IGFBPs are synthesized and secreted by cells of the colonic mucosa but that proteolysis of secreted IGFBP-2 occurs in colon cancer tissue. This selective degradation may confer a growth advantage.

Colon↗
PubMed1997

Differential expression of oestrogen receptor and oestrogen inducible genes in gastric mucosa and cancer.

BACKGROUND: Evidence exists for a role for oestrogen in gastric cancer. The incidence of gastric cancer is much higher in men than in woman, and a similar sex difference is also seen in a rat experimental model of gastric cancer. AIMS: Evidence for a functional oestrogen receptor in normal gastric mucosa and cancer has been sought. METHODS: Oestrogen receptor and the oestrogen inducible genes pS2 and ERD5 were sought by northern blot analysis and in situ hybridisation and immunohistochemistry. Oestrogen receptor protein was studied by enzyme immunoassay. RESULTS: mRNA for oestrogen receptor was detected in cancer and normal gastric mucosa. Enzyme immunoassay for oestrogen receptor showed a mean of 1.8 fmol/mg protein in cancer and 13.7 fmol/mg in paired normal mucosa. The oestrogen inducible genes pS2 and ERD5 were also detected in both cancer and normal mucosa, with expression localised to epithelium. Expression of pS2 was lower in cancer compared with normal mucosa, whereas ERD5 expression was higher in cancer. CONCLUSIONS: Significant amounts of oestrogen receptor were expressed in gastric mucosa with a lower amount in cancer. Oestrogen inducible genes were also expressed differentially but were not found to correlate closely with oestrogen receptor. Oestrogen receptor functionality remains to be demonstrated in the stomach.

Blotting, Northern↗
PubMed1997

Insulin-like growth factor binding proteins as mediators of IGF-I effects on colon cancer cell proliferation.

Human colon cancer cell lines COLO205, HT29 and SW620 are known to secrete insulin-like growth factor II (IGF-II) and its modulatory binding proteins (IGFBPs). We have characterised the sensitivity of these cell lines to exogenous IGF-I and have examined the effects of their autocrine IGFBPs on these responses. Cells cultured in serum-free medium were treated with 1-100 ng/ml IGF-I, or des(1,3)IGF-I, a truncated IGF-I with low affinity for IGFBPs. DNA synthesis was determined by 24 h incorporation of 3H-thymidine. Experiments were repeated in the presence of 24 h cell-conditioned media containing endogenous IGFBPs. In all 3 cell lines, cell-conditioned media reduced sensitivity to IGF-I but not to des(1,3)IGF-I suggesting that IGFBPs in the cell-conditioned media of colon cells inhibit IGF-I action. IGFBPs in the cell layer and 24 h cell-conditioned media were identified by Western ligand and antibody analyses. IGFBP-4 was secreted by all cell lines and IGFBP-2 from the COLO205 and SW620 cells lines but not the HT29 cells. No IGFBP-3 was secreted by any of the cell lines but IGFBP-3 was found in the cell layer in all of the cell lines. When endogenous secreted IGFBPs were removed, cell lines were consistently more sensitive to IGF-I than des(1,3)IGF-I suggesting that IGFBP-3 associated with the cell layer enhances responses to IGF-I. This is in contrast to the effects of the secreted IGFBPs. Differential modulating actions of IGFBPs may be important in regulating colon cell turnover.

Cell Division↗
PubMed1997

Expression of oestrogen receptor and oestrogen-inducible genes in pancreatic cancer.

BACKGROUND: Previous studies have not been able to demonstrate convincingly whether the human pancreas expresses oestrogen receptor and whether there is any benefit from antioestrogen therapy in advanced pancreatic cancer. METHODS: Oestrogen receptor expression was assessed in normal human pancreas and pancreatic cancer tissue by enzyme immunoassay, Northern blot analysis, in situ hybridization and immunohistochemistry. The expression of the oestrogen-inducible proteins, progesterone receptor, pS2 and ERD5 was also examined. RESULTS: A mean of 1.0 (range 0-2.4) fmol oestrogen receptor per mg protein was detected in normal pancreas and 0.5 (range 0-1.2) fmol mg-1 in pancreatic cancer. Messenger RNA for oestrogen receptor was detected in both normal and cancerous pancreas. In situ hybridization and immunohistochemistry, however, failed to localize oestrogen receptor expression. Mean (range) expression of progesterone receptor in normal and neoplastic pancreas was 1.9 (0.5-3.5) and 2.5 (0.3-9.3) fmol mg-1 respectively. pS2 and ERD5 were also expressed in normal tissue and pancreatic cancer, and expression was localized to ductular epithelium. CONCLUSION: The amount of oestrogen receptor detected in pancreatic tissue was small, and may account for previous difficulties in its detection. The extent to which it is functional in both the normal and malignant pancreas warrants further investigation.

Adult↗
PubMed1996

Antiproliferative responses to two human colon cancer cell lines to vitamin D3 are differently modified by 9-cis-retinoic acid.

1 alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] exerts antiproliferative actions in colorectal cancer, but their underlying molecular mechanisms have not been determined. 1,25(OH)2D3 regulates target gene transcription via a specific nuclear vitamin D receptor (VDR), which mediates hormone action preferentially as a heterodimer with 9-cis-retinoic acid receptors (RXRs). We investigated the actions of 1,25(OH)2D3 and 9-cis-retinoic acid (RA) in two human colon cancer cell lines, HT-29 and Caco-2. Both expressed mRNAs encoding VDR, RXR alpha, and RXR gamma, and VDR was regulated posttranscriptionally in Caco-2 cells. There was an antiproliferative response of both cell lines to 1,25(OH)2D3. 9-cis-RA exerted antiproliferative effects on Caco-2 cells but blocked 1,25(OH)2D3 actions in HT-29 cells. The 1,25(OH)2D3-responsive gene 25-hydroxyvitamin D3 24-hydroxylase was induced in both cell lines b 1,25(OH)2D3 but in only HT-29 cells by 9-cis-RA. 1,25(OH)2D3 and 9-cis-RA cotreatment enhanced 24-hydroxylase expression in HT-29 cells only. The 24-hydroxylase enzyme is known to result in catabolism of 1,25(OH)2D3 and attenuation of its actions. Increased 24-hydroxylase activity in HT-29 cells, but not in Caco-2 cells, in response to 9-cis-RA may account for some of the complex cell-specific responses demonstrated in these studies.

Antineoplastic Agents↗
PubMed1995

Safety of acid-suppressing drugs.

There is an extensive literature on the adverse effects of drugs that inhibit gastric acid secretion. This study presents a critical examination of interactions between antisecretory drugs and other compounds, the frequency of serious adverse effects relating to various body systems, the safety of antisecretory drugs in pregnancy, and longer-term safety data from postmarketing surveillance studies. While interactions with some other drugs, alcohol, and certain carcinogens are of potential concern, in practice clinically significant reactions appear to be rare if they occur at all. A small number of major side-effects have been documented, but they occur rarely, and postmarketing surveillance has not detected other longer-term sequelae. Safety of these drugs in pregnancy is not established, as data are so few. It is concluded that antisecretory agents, by comparison with most other classes of drugs, are remarkably well tolerated.

Female↗
PubMed1995

1,25-Dihydroxyvitamin D3 and retinoid X receptor expression in human colorectal neoplasms.

Epidemiological studies suggest that 1,25-dihydroxyvitamin D3 (D3) protects against colorectal carcinogenesis. Animal and in vitro studies show an antiproliferative effect of D3 in a variety of tumours including those of large bowel origin. D3 actions are mediated by D3 receptors (VDR) alone or by VDR in conjunction with retinoid X receptors (RXRs) in all D3 responsive tissues. The expression of mRNAs encoding VDR and RXRs in normal and malignant human colorectum was determined. Full length VDR (4.6 kB), RXR alpha (5.5 kB), and RXR gamma (3.5 and 7 kB) mRNAs were expressed in all tissues, but RXR beta mRNA was not expressed in any. VDR expression was reduced in 12 carcinomas relative to paired normal mucosa, and RXR alpha expression was reduced in nine. There was no correlation between VDR or RXR alpha expression and the site, grade of differentiation, or Dukes's staging of the tumour. The finding of persistent VDR and RXR coexpression in all colorectal tumours provides a rational basis for exploring a role for D3 in the treatment of colorectal malignancy.

Blotting, Northern↗
PubMed1995

Rising death rate from non-malignant disease of the oesophagus (NMOD) in England and Wales.

Between 1968 and 1991, the number of deaths from non-malignant oesophageal disease (NMOD) (International Classification of Diseases code 530), recorded by the Office of Population Censuses and Surveys (OPCS) in England and Wales, trebled in women, from 118 to 340 (5 to 13 per million) and doubled in men, from 131 to 251 (5.5 to 10 per million). Calculation of age specific death rates, shows the increase to result from a rise in mortality in those over 75 years and age standardised mortality confirms a rise in overall frequency from 2.9 to 7.0 deaths per million men and 5.2 to 13.1 per million women. Between 1974 and 1988 when specific diagnoses were coded, deaths from oesophageal ulcer rose from 1.5 to 2.5 per million. In men, the death rate from oesophageal stricture increased from 2.5 to 3 per million and in women from 3.5 to 6 per million. Mortality from oesophageal perforation did not change (1 per million). Some of these changes reflect the increasing age of the population in general, but further explanations are required. Review of 84 sets of case notes from a total of 281 inpatients whose coded diagnoses had included NMOD and who had died suggested that in 28 (33%) death was actually due to NMOD, and in seven of these endoscopic intervention was responsible. The certified underlying cause of death was compared with that suggested from case note review in 62 cases; death from NMOD was substantially underestimated. This study concludes that a rising death rate attributed to NMOD is underestimated on death certificates and that endoscopic intervention explains only a few of the cases.

Aged↗
PubMed1995

Late mortality in elderly patients surviving acute peptic ulcer bleeding.

Acute peptic ulcer bleeding is associated with a substantial short term mortality but it is generally assumed that in the modern era of effective medical treatment the longer term prognosis is good. This study evaluated 487 patients aged over 60 years who were discharged from Nottingham University and City Hospitals after admission for acute peptic ulcer bleeding during 1986-91 and 480 age and sex matched community controls. Follow up information was obtained from hospital and general practitioner records and from the National Health Service central register. Mortality was compared with control mortality and with rates expected for England and Wales. During a mean follow up of 34 months 142 (29%) of 487 patients died compared with 58 (12%) of 480 community controls and with 81.5 deaths expected (observed/expected (O/E) = 1.74, 95% confidence limits (CL) 1.5 to 2.1). Six years after admission the actuarial survival estimate was only 50% for ulcer patients compared with 76% for community controls and 69% expected. The increased mortality was similar in men and women and was greatest in the 60-74 year age group. Much of the excess mortality was accounted for by deaths from cancer (O/E 34/19.7 = 1.73; CL 1.2 to 2.4), from respiratory disease (O/E 28/10.9 = 2.57; CL 1.7 to 3.7), and in men from vascular disease (O/E 31/22.4 = 1.38; CL 0.9 to 2.0). Eight deaths resulted from recurrent ulcer complications and four deaths from gastric cancers undetected at the index admission. In conclusion, patients discharged after peptic ulcer bleeding had a substantially reduced life expectancy. The increased mortality was predominantly due to a variety of smoking related diseases rather than recurrent peptic ulcer complications. Deaths from recurrent peptic ulcer complications were infrequent and were less than reported in earlier years possibly reflecting prolonged and widespread used of H2 receptor antagonists.

Acute Disease↗
PubMed1995

Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin--analysis of gastrointestinal bleeding during the UK-TIA trial.

From 1979 to 1985 2435 patients having had transient ischaemic attacks (TIAs) or minor ischaemic strokes, were enrolled in the UK TIA trial and were randomised to receive either aspirin 300 mg, daily or aspirin 1200 mg or placebo. Analysis of reported upper gastrointestinal bleeding events (defined as haematemesis or melaena, or both) showed a risk of bleeding in a dose dependent manner, odds ratios (95% CI) for 300 mg of aspirin = 3.3 (1.2 to 9.0) and for 1200 mg = 6.4 (2.5 to 16.5) and, as would be expected, an increased risk of hospitalisation because of bleeding also in a dose dependent manner, odds ratio = 3.6 (0.7 to 17.2) for 300 mg and 8.7 (2.0 to 37.6) for 1200 mg. Further analysis suggested greater risks of bleeding from duodenal ulcers than gastric ulcers and that bleeding is more likely early in the course of treatment with aspirin used as secondary prevention. There was also an increased risk of lower gastrointestinal bleeding, defined as fresh blood per rectum for both doses of aspirin, odds ratio 1.8 (0.5 to 6.1) for 300 mg of aspirin, and 1.5 (0.4 to 5.3) for 1200 mg of aspirin.

Aspirin↗
PubMed1995

Nonsteroidal anti-inflammatory drug-induced gastric damage: epidemiology.

Although figures vary considerably, the ingestion of aspirin or other non-aspirin non-steroidal anti-inflammatory drugs is associated with an increased risk of gastric ulceration, ulcer bleeding, ulcer complications and of death by a factor of around 3. Evidence for duodenal ulcer (DU) disease is less convincing, but the risk of complications of DU disease, bleeding and perforation, are increased to much the same extent as for gastric ulcer. Whether this increase in complications for DU represents exacerbation of an existing DU diathesis remains unresolved.

Aged↗