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Canberra, Australia

Hemmings C.,ACT Pathology | Hemmings C.,University of Western Australia
Pathology | Year: 2010

The cancer stem cell hypothesis suggests that malignant tumours may arise from a limited number of specialised cells possessing the key 'stem' properties of self-renewal and the ability to produce differentiated progeny. Such cells purportedly constitute a small fraction of most tumours but have greater potential to produce new tumours than their 'non-stem' counterparts. However, they have proven difficult to identify and characterise in most malignancies. Cancer stem cells are liable to be resistant to most forms of conventional chemotherapy and radiation and so may help to explain tumour recurrence after a seemingly good response to initial therapy. This review examines the evidence for the existence of such cells, the therapeutic implications of this hypothesis, and problems posed by it, as well as outlining the concept of the stem cell niche and its possible role in tumour development and progression. © 2010 Royal College of Pathologists of Australasia. Source

Subramaniam K.,Gastroenterology and Hepatology Unit | Pavli P.,Gastroenterology and Hepatology Unit | Llewellyn H.,ACT Pathology | Chitturi S.,Gastroenterology and Hepatology Unit
Current Drug Safety | Year: 2012

Introduction: Glatiramer acetate (Copaxone), a polypeptide has been approved for treating patients with active relapsing-remitting multiple sclerosis. Case Presentation: We report the first case of severe acute hepatitis after commencing treatment for multiple sclerosis with glatiramer acetate. A 31-year-old female with multiple sclerosis presented with anorexia, lethargy and jaundice five weeks after commencing glatiramer acetate. She had never received beta-interferon treatment. Investigations revealed a bilirubin of 0.109 mmol/L (0.002-0.02 mmoL/L) and prothrombin time of 21 secs (9-15 secs). Her liver function tests were normal before commencing glatiramer acetate. A liver biopsy performed approximately 6 weeks after commencement of glatiramer acetate showed predominantly centrilobular hepatocyte necrosis with portal-venous bridging, along with mild portal and interface hepatitis. The necrosis was not accompanied by an acute inflammatory or chronic inflammatory infiltrate. The features were not suggestive of autoimmune hepatitis but consistent with drug toxicity. The liver tests returned to normal within 2 months after cessation of glatiramer acetate. Conclusion: Physicians should be aware that glatiramer acetate can be associated with uncommon but yet significantly severe liver toxicity. © 2012 Bentham Science Publishers. Source

McGill D.,Canberra Hospital | McGill D.,Australian National University | Talaulikar G.,Australian National University | Potter J.M.,Australian National University | And 2 more authors.
Clinica Chimica Acta | Year: 2010

Background: Cardiac biomarkers are emerging as a potentially powerful prognostic tool for renal-dialysis patients. The optimal biomarker and/or combination of biomarkers for predicting mortality remain uncertain. This study evaluates the prognostic value of the new high-sensitivity troponin T (TnT) assay compared to established biomarkers. Methods: All patients had blood sampled for prospective assessment of the prognostic value of traditional risk markers including albumin and CRP, and cardiac biomarkers BNP, NT-proBNP, TnT and TnI. Patients were closely monitored clinically. Mortality and morbidity outcomes were documented for a national morbidity and mortality database. Stored samples were subsequently used to measure TnT with a new high-sensitivity assay. Results: After a median of 30. months from blood collection, NT-proBNP was the most powerful predictor of all-cause mortality, along with albumin. After a median of 46.7. months the new high-sensitive TnT assay was the only cardiac biomarker predictive of all-cause mortality. TnT was detectable in all dialysis patients using the high-sensitive TnT assay with a cut-point of 24.15. ng/L below which all patients survived. Conclusions: The new hs-TnT is the most powerful biomarker for prognostic classification for all-cause mortality of all the commonly used biomarkers for our renal-dialysis population. Our study also suggests that cardiac biomarkers have a different prognostic ability for different time frames with NT-proBNP being a better predictor for early mortality and troponin for later mortality. © 2010 Elsevier B.V. Source

Gan L.T.,Australian National University | Van Rooyen D.M.,Australian National University | Koina M.E.,ACT Pathology | McCuskey R.S.,University of Arizona | And 2 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Free cholesterol (FC) accumulates in non-alcoholic steatohepatitis (NASH) but not in simple steatosis. We sought to establish how FC causes hepatocyte injury. Methods In NASH-affected livers from diabetic mice, subcellular FC distribution (filipin fluorescence) was established by subcellular marker co-localization. We loaded murine hepatocytes with FC by incubation with low-density lipoprotein (LDL) and studied the effects of FC on JNK1 activation, mitochondrial injury and cell death and on the amplifying roles of the high-mobility-group-box 1 (HMGB1) protein and the Toll-like receptor 4 (TLR4). Results In NASH, FC localized to hepatocyte plasma membrane, mitochondria and ER. This was reproduced in FC-loaded hepatocytes. At 40 μM LDL, hepatocyte FC increased to cause LDH leakage, apoptosis and necrosis associated with JNK1 activation (c-Jun phosphorylation), mitochondrial membrane pore transition, cytochrome c release, oxidative stress (GSSG:GSH ratio) and ATP depletion. Mitochondrial swelling and crystae disarray were evident by electron microscopy. Jnk1-/- and Tlr4-/- hepatocytes were refractory to FC lipotoxicity; JNK inhibitors (1-2 μM CC-401, CC-930) blocked apoptosis and necrosis. Cyclosporine A and caspase-3 inhibitors protected FC-loaded hepatocytes, confirming mitochondrial cell death pathways; in contrast, 4-phenylbutyric acid, which improves ER folding capacity did not protect FC-loaded hepatocytes. HMGB1 was released into the culture medium of FC-loaded wild type (WT) but not Jnk1-/- or Tlr4-/- hepatocytes, while anti-HMGB1 anti-serum prevented JNK activation and FC lipotoxicity in WT hepatocytes. Conclusions These novel findings show that mitochondrial FC deposition causes hepatocyte apoptosis and necrosis by activating JNK1; inhibition of which could be a novel therapeutic approach in NASH. Further, there is a tight link between JNK1-dependent HMGB1 secretion from lipotoxic hepatocytes and a paracrine cytolytic effect on neighbouring cholesterol-loaded hepatocytes operating via TLR4. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

Patel A.,ACT Pathology
Australian Journal of Medical Science | Year: 2012

An 89-year-old lady presented to the Emergency Department with abdominal pain, vomiting, confusion and fever. A spiral pleomorphic anaerobic Gram-negative bacillus was isolated from blood, confirmed as Anaerobiospirillum succiniciproducens by the bioMérieux API Rapid ID 32A bacterial identification system. As a commensal of dogs and cats, Anaerobiospirillum spp. are rare causes of gastrointestinal illness and bacteraemia in humans. There is no consensus on antibiotic therapy. However, accurate laboratory diagnosis of Anaerobiospirillum spp. will aid in understanding of its epidemiology, treatment and ultimately lead to a decrease in patient morbidity and mortality. Source

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