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Biomedical subjects

A Meagher

Publications and source records attributed to A Meagher.

14 recordsLinked to original sources
PubMed2006

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer.

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Elective surgery after acute diverticulitis.

BACKGROUND: Diverticulitis is a common condition. Practice guidelines from many organizations recommend bowel resection after two attacks. The evidence for such a recommendation is reviewed. METHODS: A Medline literature search was performed to locate English language articles on surgery for diverticular disease. Further articles were obtained from the references cited in the literature initially reviewed. RESULTS: Most people with diverticulosis are asymptomatic. Diverticular disease occurs in over 25 per cent of the population, increasing with age. After one episode of diverticulitis one-third of patients have recurrent symptoms; after a second episode a further third have a subsequent episode. Perforation is commonest during the first episode of acute diverticulitis. After recovering from an episode of diverticulitis the risk of an individual requiring an urgent Hartmann's procedure is one in 2000 patient-years of follow-up. Surgery for diverticular disease has a high complication rate and 25 per cent of patients have ongoing symptoms after bowel resection. CONCLUSION: There is no evidence to support the idea that elective surgery should follow two attacks of diverticulitis. Further prospective trials are required.

Acute Disease↗
PubMed2001

Microsatellite-stable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer.

Chromosomal instability and microsatellite instability represent the major pathways for colorectal cancer (CRC) progression. However, a significant percentage of CRC shows neither pattern of instability, and thus represents a potentially distinctive form of the disease. Flow cytometry was used to determine the degree of DNA aneuploidy in 46 consecutive sporadic colorectal cancers. Microsatellite status was determined by PCR amplification using standard markers, while immunostaining was used to examine the expression of p53. K- ras status was determined by restriction-mediated PCR assay. Twenty-five (54%) tumours were aneuploid, 14 (30%) were diploid and microsatellite-stable and seven (15%) were diploid and microsatellite-unstable. Tumours with microsatellite instability were more likely to be right sided, to occur in women and to be associated with an improved survival. Aneuploid tumours were significantly more common in men and were likely to be left sided. The diploid microsatellite-stable (MSS) tumours did not show a sex or site predilection, but were strongly associated with the presence of metastatic disease at the time of diagnosis. Our data suggests that diploid, MSS tumours represent a biologically and phenotypically distinct subset of colorectal carcinoma, and one that is associated with the early development of metastases. We suggest that the genetic stability that characterizes these tumours may favour the maintenance of an invasive phenotype, and thus facilitate disease progression. These findings may have important implications for treatment options in this disease subset.

Aged↗
PubMed2001

Microsatellite instability and the clinicopathological features of sporadic colorectal cancer.

BACKGROUND AND AIMS: In this study, we prospectively examined the clinical significance of the microsatellite instability (MSI) phenotype in sporadic colorectal cancer, and investigated methods for effective identification of these tumours in routine pathology practice. METHODS: DNA was extracted from 310 tumours collected from 302 consecutive individuals undergoing curative surgery for sporadic colorectal cancer. Microsatellite status was determined by polymerase chain reaction amplification using standard markers, while immunostaining was used to examine expression of MLH1, MSH2, and p53. RESULTS: Eleven per cent of tumours showed high level instability (MSI-H), 6.8% had low level instability (MSI-L), and the remainder were stable. MSI-H tumours were significantly more likely to be of high histopathological grade, have a mucinous phenotype, and to harbour increased numbers of intraepithelial lymphocytes. They were also more likely to be right sided, occur in women, and be associated with improved overall survival. In total, 25 (8%) tumours showed loss of staining for MLH1 and a further three tumours showed absence of staining for MSH2. The positive and negative predictive value of immunohistochemistry in the detection of MSI-H tumours was greater than 95%. CONCLUSIONS: We conclude that the MSI-H phenotype constitutes a pathologically and clinically distinct subtype of sporadic colorectal cancer. Immunohistochemical staining for MLH1 and MSH2 represents an inexpensive and accurate means of identifying such tumours.

Adult↗
PubMed2000

Phase I clinical trial of the chimeric monoclonal antibody (c30.6) in patients with metastatic colorectal cancer.

The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 and histamine receptor 2 blockers. Other side effects were mild and predictable. Biodistribution studies showed a rapid and intensive hepatic uptake. At the 50 mg/m2 level the half-life and maximum serum concentration were 81 +/- 15 h and 7.9 microg/ml, respectively. One patient developed a low-level human anti-c30.6 response. Tumor response was assessed by computed tomography, positron emission tomography scanning, and serial carcinoembryonic antigen measurements. There were no partial responses, although positron emission tomography scanning demonstrated some reduction in tumor activity in three individuals. The chimerized c30.6 antibody is not immunogenic in humans and appears worthy of further study. It does, however, produce a unique profile of side effects that can be well controlled with premedication.

Adult↗
PubMed1998

Appendicitis in HIV-positive patients.

BACKGROUND: The aim of the present study was to review the experience of appendicitis in human immunodeficiency virus (HIV)-positive patients. METHODS: A retrospective analysis of all HIV-positive patients operated on for suspected acute appendicitis during a 10-year period at St Vincent's Hospital was performed. These patients were compared to a group of 60 age- and sex-matched patients with no HIV risk factors who were operated on during the same time period. RESULTS: On presentation the clinical findings were similar in both groups, with two notable exceptions. No HIV-positive patient had an elevated white cell count. The present study demonstrated a significant delay in presentation of the HIV-positive group to the Emergency Department, possibly explaining the higher appendiceal perforation rate in this group. There were no cases of HIV-related diseases mimicking acute appendicitis. There was no mortality, and morbidity was higher in the seropositive group. CONCLUSIONS: HIV-positive patients with a history suggestive of acute appendicitis should not be treated differently from the normal population. Morbidity and mortality can be minimized by prompt surgical treatment.

Acute Disease↗
PubMed1997

Surgical management of ileosigmoid fistulas in Crohn's disease.

UNLABELLED: Ileosigmoid fistulas are found in Crohn's disease and may present a surgical dilemma. PURPOSE: This study was designed to examine surgical practice to determine types of intervention, enumerate complications, and elicit guidelines for surgical management. METHOD: The medical records of patients with ileosigmoid fistula and Crohn's disease from 1975 to 1995 were reviewed. RESULTS: Ninety patients (44 men) were studied. A preoperative diagnosis of ileosigmoid fistula was made in 77 percent of patients. Sigmoid repair was performed in 43 patients (47.8 percent), sigmoid resection in 32 patients (35.6 percent), 12 patients (13.3 percent) underwent more extensive procedures, and 3 patients (3.3 percent) either had surgery elsewhere or were observed. The fistula was never directly responsible for a stoma. The repair and resection groups were similar with respect to age, length of Crohn's disease, and preoperative symptoms. There was no significant difference between groups in the incidence of postoperative complications; there were no postoperative deaths. Average length of stay was 8.3 days following repair and 9.9 days after resection. Reasons for resection included significant purulence or inflammation, a large fistula defect, a defect on the mesenteric border of the sigmoid, and active sigmoid Crohn's disease. Surgeon's assessment of the presence of Crohn's disease in the sigmoid correlated with pathologic examination and was aided by knowledge of recent endoscopic appearance and biopsy results; intraoperative frozen section and colonoscopy were helpful in distinguishing serosal inflammation from active Crohn's disease. CONCLUSION: Contrast studies identified 77 percent of ileosigmoid fistulas preoperatively. Performing repair rather than resection does not increase the risk of complications, if standard surgical principles are followed. Preoperative or intraoperative endoscopy assists the surgical evaluation of the sigmoid.

Adolescent↗
PubMed1997

Pathological and genetic correlates of apoptosis in the progression of colorectal neoplasia.

PURPOSE: Apoptosis is commonly observed in a variety of human tumors, and some of the genetic events which control this process have been identified in vitro. The aim of this study was to determine the frequency of apoptosis in colorectal neoplasms and to examine its relationship to a number of pathological parameters, to the presence of mutations in the p53 tumor suppressor gene, and to overexpression of the bcl-2 oncoprotein. METHODS: A total of 109 colorectal neoplasms (26 adenomas 83 carcinomas) were examined. An in situ end-labelling assay was used to detect apoptosis in paraffin-embedded tumor sections, and scores were determined by light microscopy. The p53 and bcl-2 status were determined by immunohistochemistry. RESULTS: Apoptotic frequency increased with tumor progression. Normal mucosa contained significantly fewer apoptotic cells than adenomas or carcinomas. Similarly adenomas showed less apoptosis than carcinomas, and the frequency of apoptosis increased with Dukes' stage. Overall, changes in apoptotic frequency were inversely related to the level of bcl-2 expression, but were not related to the p53 status of the tumors. CONCLUSIONS: The frequency of apoptosis in colorectal neoplasia appears to increase in the course of tumor progression in association with a decline in bcl-2 expression, but is not influenced by p53 gene mutations.

Adenocarcinoma↗
PubMed1996

Characterisation and clinicopathological correlates of serum anti-p53 antibodies in breast and colon cancer.

The humoral immune response to p53 was determined in 54 individuals with colon or breast cancer and 50 healthy subjects, in an attempt to better understand the origin and significance of anti-p53 serum antibodies. The presence of anti-p53 antibodies in serum was determined by enzyme-linked immunosorbent assay using purified recombinant human p53, and results were validated by immunoprecipitation of radiolabelled p53. Immunohistochemical analysis of 28 tumours was performed to detect the accumulation of p53 protein. Antibodies against p53 were significantly more common in patients with colorectal (10 of 42) and breast (2 of 12) cancer than in healthy individuals (2 of 50). They were of both the IgM (7 of 11) and IgG (4 of 11) isotypes. There was no significant difference in prevalence of serum antibodies against p53 with respect to the p53 immunohistochemical status of the tumour or to other pathological features, including the presence of lymph node and distant metastases. These findings provide indirect evidence that, rather than arising as a result of a specific immune response, anti-p53 antibodies in individuals with cancer may represent elevated levels of naturally occurring polyreactive antibodies.

Adult↗
PubMed1987

Seasonal variation in the form of iron in the liver of Spitsbergen reindeer: a Mössbauer spectroscopic study.

Mössbauer spectra have been obtained from samples of the liver of Spitsbergen reindeer at different times of the year. Most of the iron is in a very similar form to that of the iron storage materials ferritin and haemosiderin. The data reflect the large differences in the amount of iron found in the liver at different times of the year and also indicate that there are only relatively small differences in the chemical and physical form of the iron found in the liver at different times of the year.

Animals↗
PubMed1987

Iron(III) clusters bound to horse spleen apoferritin: an X-ray absorption and Mössbauer spectroscopy study that shows that iron nuclei can form on the protein.

Ferritin is a complex of a hollow, spherical protein and a hydrous, ferric oxide core of less than or equal to 4500 iron atoms inside the apoprotein coat; the apoprotein has multiple (ca. 12) binding sites for monoatomic metal ions, e.g., Fe(II), V(IV), Tb(III), that may be important in the initiation of iron core formation. In an earlier study we observed that the oxidation of Fe(II) vacated some, but not all, of the metal-binding sites, suggesting migration of some Fe during oxidation, possibly to form nucleation clusters; some Fe(III) remained bound to the protein. Preliminary extended X-ray absorbance fine structure (EXAFS) analysis of the same Fe(III)-apoferritin complex showed an environment distinct from ferritin cores, but the data did not allow a test of the Fe cluster hypothesis. In this paper, with improved EXAFS data and with Mössbauer data on the same complex formed with 57Fe, we clearly show that the Fe(III) in the distinctive environment is polynuclear (Fe atoms with Fe-Fe = 3.5 A and TB = 7 K). Moreover, the arrangement of atoms is such that Fe(III) atoms appear to have both carboxylate-like ligands, presumably from apoferritin, and oxo bridges to the other iron atoms. Thus the protein provides sites not only for initiation but also for nucleation of the iron core. Sites commodious enough and with sufficient conserved carboxylate ligands to accommodate such a nucleus occur inside the protein coat at the subunit dimer interfaces. Such Fe(III)-apoferritin nucleation complexes can be used to study the properties of the several members of the apoferritin family.

Animals↗