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Biomedical subjects

M S Irwin

Publications and source records attributed to M S Irwin.

14 recordsLinked to original sources
PubMed2006

Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma.

Cyclooxygenase-2 (COX-2) is upregulated in many tumors including neuroblastoma, and its overexpression has been implicated in resistance to p53-dependent apoptosis. Although p53 is rarely mutated in neuroblastoma, the p53 protein is rendered inactive via several mechanisms including sequestration in the cytoplasm. Here, we show that COX inhibitors inhibit the growth of neuroblastoma and when combined with low doses of chemotherapy, exert synergistic effects on neuroblastoma cells. Following COX inhibitor treatment, HDM2, which targets p53 for ubiquitin-mediated degradation, is downregulated, resulting in an attenuation of p53 ubiquitination and an increase in p53 half-life. The level of HDM2 phosphorylation at ser166, which influences both HDM2 and p53 subcellular distribution, is markedly diminished in response to COX inhibitors and is associated with increased p53 nuclear localization. Combining COX inhibitors with low-dose chemotherapy potentiates apoptosis and p53 stability, nuclear localization, and activity. p53 knockdown by siRNA resulted in the rescue of COX-inhibitor-treated cells, indicating that COX inhibitor-induced apoptosis is, at least in part, p53-dependent. Taken together, these results provide the first evidence that COX inhibitors enhance chemosensitivity in neuroblastoma via downregulating HDM2 and augmenting p53 stability and nuclear accumulation.

Antineoplastic Agents↗
PubMed2000

A common polymorphism acts as an intragenic modifier of mutant p53 behaviour.

The p73 protein, a homologue of the tumour-suppressor protein p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactivate p73. The binding of such mutants is influenced by whether TP53 (encoding p53) codon 72, by virtue of a common polymorphism in the human population, encodes Arg or Pro. The ability of mutant p53 to bind p73, neutralize p73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg. We found that the Arg-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes. Thus, inactivation of p53 family members may contribute to the biological properties of a subset of p53 mutants, and a polymorphic residue within p53 affects mutant behaviour.

Alleles↗
PubMed1998

Viral oncoproteins discriminate between p53 and the p53 homolog p73.

p73 is a recently identified member of the p53 family. Previously it was shown that p73 can, when overproduced in p53-defective tumor cells, activate p53-responsive promoters and induce apoptosis. In this report we describe the generation of anti-p73 monoclonal antibodies and confirm that two previously described p73 isoforms are produced in mammalian cells. Furthermore, we show that these two isoforms can bind to canonical p53 DNA-binding sites in electrophoretic mobility shift assays. Despite the high degree of similarity between p53 and p73, we found that adenovirus E1B 55K, simian virus 40 T, and human papillomavirus E6 do not physically interact with p73. The observation that viral oncoproteins discriminate between p53 and p73 suggests that the functions of these two proteins may differ under physiological conditions. Furthermore, they suggest that inactivation of p73 may not be required for transformation.

Adenoviridae↗
PubMed1997

Cold intolerance following peripheral nerve injury. Natural history and factors predicting severity of symptoms.

Cold intolerance can be severe and debilitating following injury to the hand. Little is known about its natural history and factors predicting symptom severity. We looked retrospectively at upper limb peripheral nerve injuries over a 12-year period. Information was obtained using a patient questionnaire and patient records. The incidence of cold intolerance was 83%. In 48% the onset of symptoms was within 1 month of the initial injury. At a mean follow-up of 51 months improved symptoms were reported by 21%, while 18% deteriorated. Patients were more likely to develop cold intolerance if they smoked and less likely if they suffered a sharp injury. A score defining the severity of cold induced symptoms, based on the information collected, was calculated for each patient. Significantly increased severity was associated with complete nerve division, median and ulnar nerve division and an associated vessel injury. Symptom improvement was significantly more likely in non-smokers and a deterioration most likely with a high severity score.

Adolescent↗
PubMed1997

Neuropathy in non-freezing cold injury (trench foot).

Non-freezing cold injury (trench foot) is characterized, in severe cases, by peripheral nerve damage and tissue necrosis. Controversy exists regarding the susceptibility of nerve fibre populations to injury as well as the mechanism of injury. Clinical and histological studies (n = 2) were conducted in a 40-year-old man with severe non-freezing cold injury in both feet. Clinical sensory tests, including two-point discrimination and pressure, vibration and thermal thresholds, indicated damage to large and small diameter nerves. On immunohistochemical assessment, terminal cutaneous nerve fibres within the plantar skin stained much less than in a normal control whereas staining to von Willebrand factor pointed to increased vascularity in all areas. The results indicate that all nerve populations (myelinated and unmyelinated) were damaged, possibly in a cycle of ischaemia and reperfusion.

Adult↗
PubMed1996

A valentine.

Explore the source record for details and available documents.

Adult↗
PubMed1996

Nature and mechanism of peripheral nerve damage in an experimental model of non-freezing cold injury.

Non-freezing cold injury (NFCI), so called trench foot, is a condition characterised by a peripheral neuropathy, developing when the extremities are exposed for prolonged periods to wet conditions at temperatures just above freezing. Classically, military personnel are affected, with 14% of casualties in the Falklands conflict afflicted. Clinically, NFCI is characterised by a well-defined acute clinical picture and chronic sequelae. Little is known regarding the pathophysiology and treatment of this condition. Opinions vary as to the type of nerve fibres most susceptible to damage and proposed mechanisms of injury include direct axonal damage, ischaemia and ischaemia/reperfusion. A series of investigations has been performed to clarify which populations of nerve fibres are more susceptible to damage, and to elucidate the exact mechanism of nerve injury. An in vivo rabbit hind limb model, subjected to 16 h of cold immersion (1-2 degrees C), provided the basis of this study. Nerve specimens were examined by semi-thin sectioning for myelin fibre counts, by electron microscopy to assess the unmyelinated fibre population, and fine nerve terminals in plantar skin were assessed immunohistochemically. The results showed that large myelinated fibres were preferentially damaged, while small myelinated and unmyelinated fibres were relatively spared. Nerve damage was found to start proximally and extend distally with time. Serial temperature measurements identified a warm-cold interface in the upper tibial region of immersed limbs. As this was the initial site of injury, this suggested that a dynamic balance exists in the cold immersed limb between the protective effects of cooling and the damaging effects of ischaemia. The non-invasive technique of near infrared spectroscopy was used to measure changes in tissue oxygen supply and utilisation and blood volume. The findings supported the hypothesis that an interface is created at the site of initial nerve damage in the upper tibia, where cyclical ischaemia-reperfusion injury occurs.

Animals↗
PubMed1995

Near infra-red spectroscopy: a non-invasive monitor of perfusion and oxygenation within the microcirculation of limbs and flaps.

Reliable early detection of adverse circulatory changes within a flap following free tissue transfer and early re-exploration are vital to minimise flap failure. Most surgeons rely on clinical assessment to monitor these changes but techniques such as plethysmography and laser Doppler have their advocates. These methods are limited however to measuring changes close to the surface. Near infra-red spectroscopy (NIRS) is a relatively new, non-invasive technique which allows continuous monitoring of concentration changes in oxy-, deoxy- and total haemoglobin (HbO2, Hb and HbT), as well as oxidised cytochrome aa3, through tissue up to 10 cm in depth. Information is provided on tissue oxygen supply, cellular oxygen utilisation, blood volume and perfusion status. A study has been performed in 10 rabbit hind limbs to assess the ability of NIRS to detect and distinguish between venous, arterial and total vascular occlusion. Clear patterns of change have been identified which allow rapid detection of vascular occlusion with accurate prediction of site. Arterial occlusions were characterised by an increase in Hb with a corresponding decrease in HbO2 and HbT. Venous occlusions resulted in an increase in HbT with relatively minor fluctuations in Hb and HbO2. Simultaneous occlusion of both artery and vein produced similar changes to those of arterial occlusion except that HbT decreased only minimally. These findings suggest that NIRS has a potentially useful role in the monitoring of free flaps, with the great advantage that perfusion can be measured to a considerable depth and information provided on the oxygenation profiles both accurately and non-invasively.

Animals↗
PubMedDate not supplied

Amelanotic lentigo malignant melanoma: a case report and review of the literature.

A patient with an amelanotic lentigo malignant melanoma is presented which manifested itself initially as an erythematous flare with the subsequent development of nodules. The diagnosis was only made histologically. A computer search of the literature revealed 6 previous cases, and a review of these rare tumours is presented.

Erythema↗
PubMedDate not supplied

Role of the newer p53 family proteins in malignancy.

The most recently identified members of the p53 family, p63 and p73, share certain structural and functional similarities with p53. Both p63 and p73 can bind to canonical p53-DNA-binding sites, transactivate the promoters of known p53 target genes and induce apoptosis. Despite these similarities there are many important differences. In contrast to p53, p63 and p73 give rise to multiple distinct protein isoforms that have different functional properties. Upstream signaling pathways involved in the activation of p63 and p73 differ from those involved in p53 activation. Only a subset of the DNA damaging agents that induce p53 can induce p73. Cellular and viral oncoproteins can discriminate between p53 and the newer family members. In addition, the levels of p63 and p73 are affected by certain states of cellular differentiation. Finally, it is becoming clear that the newest members of the p53 family are not classical tumor suppressor genes. In contrast to the high prevalence of p53 mutations in human cancers, p63 and p73 mutations are rare. Indeed, levels of p73 increase during malignant progression. In addition, unlike p53-/- mice, mice lacking p63 and p73 do not develop tumors, but instead have significant developmental abnormalities. Mutations in p63 have also been detected in humans with the ectodermal dysplastic syndrome EEC. Further studies are required to determine whether qualitative or quantitative differences in the expression of p63 and p73 isoforms are important in the development of human cancers.

Animals↗