Medicine & Health

Publication Search Results

Now showing 1 - 10 of 19
  • (2007) Hitchins, Megan P.; Lin, Vita Ap; Buckle, Andrew; Cheong, Kayfong; Halani, Nimita; Ku, Su; Kwok, Chau-To; Packham, Deborah; Suter, Catherine M.; Meagher, Alan; Stirzaker, Clare; Clark, Susan; Hawkins, Nicholas; Ward, Robyn L.
    Journal Article
    Biallelic promoter methylation and transcriptional silencing of the MLH1 gene occurs in the majority of sporadic colorectal cancers exhibiting microsatellite instability due to defective DNA mismatch repair. Long-range epigenetic silencing of contiguous genes has been found on chromosome 2q14 in colorectal cancer. We hypothesized that epigenetic silencing of MLH1 could occur on a regional scale affecting additional genes within 3p22, rather than as a focal event. We studied the levels of CpG island methylation and expression of multiple contiguous genes across a 4 Mb segment of 3p22 including MLH1 in microsatellite-unstable and -stable cancers, and their paired normal colonic mucosa. We found concordant CpG island hypermethylation, H3-K9 dimethylation and transcriptional silencing of MLH1 and multiple flanking genes spanning up to 2.4 Mb in microsatellite-unstable colorectal cancers. This region was interspersed with unmethylated genes, which were also transcriptionally repressed. Expression of both methylated and unmethylated genes was reactivated by methyltransferase and histone deacetylase inhibitors in a microsatellite-unstable colorectal carcinoma cell line. Two genes at the telomeric end of the region were also hypermethylated in microsatellite-stable cancers, adenomas, and at low levels in normal colonic mucosa from older individuals. Thus, the cluster of genes flanking MLH1 that was specifically methylated in the microsatellite-unstable group of cancers extended across 1.1 Mb. Our results show that coordinate epigenetic silencing extends across a large chromosomal region encompassing MLH1 in microsatellite-unstable colorectal cancers. Simultaneous epigenetic silencing of this cluster of 3p22 genes may contribute to the development or progression of this type of cancer.

  • (2007) Hitchins, Megan P.; Wong, Justin J.L.; Suthers, Graeme; Suter, Catherine M.; Martin, David I.K.; Hawkins, Nicholas; Ward, Robyn L.
    Journal Article
    Persons who have hypermethylation of one allele of MLH1 in somatic cells throughout the body (a germ-line epimutation) have a predisposition for the development of cancer in a pattern typical of hereditary nonpolyposis colorectal cancer. By studying the f

  • (2007) Hettiaratchi, A.; Hawkins, Nicholas; McKenzie, G.; Ward, Robyn L.; Hunt, J.E.; Wakefield, D.; Di Girolamo, N.
    Journal Article
    Matrix metalloproteinase (MMP) overexpression has been implicated in the pathogenesis of colorectal carcinoma (CRC). Accumulating evidence suggests that MMP promoter single nucleotide polymorphisms ( SNPs) effecting gene transcription are associated with

  • (2007) Wong, Justin; Hawkins, Nicholas; Ward, Robyn
    Journal Article
    Recent advances in basic and clinical science have driven epigenetics to the forefront of cancer research. Together with genetic changes, the disruption of epigenetic mechanisms is now established as a hallmark of cancer in humans. Colorectal cancer, long a classic model for the genetic basis of cancer, is now providing researchers with the opportunity to view epigenetic events in the context of neoplasia in humans. Knowledge of the heritable changes in gene expression that result from epigenetic events is of increasing relevance to clinical practice, particularly in terms of diagnostic and prognostic molecular markers, as well as novel therapeutic targets.

  • (2007) Mikhail, S; Zwar, N; Vagholkar, Sanjyot; Dennis, Sarah; Day, Richard
    Journal Article
    Objectives: To examine the effect of the debate on the safety of non-steroidal anti-inflammatory drugs (NSAIDs) on decision making by Australian general practitioners and patients with osteoarthritis (OA), and to explore issues concerning the use of NSAIDs from both prescriber and consumer perspectives. Design and setting: A qualitative study in which five focus groups (three for GPs, and two for patients with OA) were conducted between 15 May and 4 August 2006 in south-western Sydney. Participants: Five advanced general practice registrars, six experienced GPs, and 20 patients with OA aged 54-85 years. Main outcome measures: Key themes and issues identified by content analysis of focus group transcripts. Results: GPs reported adopting a cautious approach to prescribing NSAIDs because of uncertainty about safety and medicolegal concerns. They were sceptical about information provided by the pharmaceutical industry and found the literature about the safety of NSAIDs confusing. Time was identified as a major barrier to adequate discussion with patients, and explaining the risk to patients in a meaningful way was perceived as a challenge. Patients wanted information and sought it from a range of sources, most commonly pharmacists and GPs. Most patients made active decisions about using or not using NSAIDs, with some favouring physical function over safety. Patients were also using other forms of treatment including alternative medicine. Conclusion: Our findings reflect the need to provide clear, unbiased information about NSAIDs to help both GPs and patients negotiate this decision-making dilemma.

  • (2007) Ha, Hong
    Idiopathic Membranous nephropathy (MN) is a common cause of nephrotic syndrome in humans, and many patients progress to end-stage kidney disease. The best available animal model of MN is active Heymann nephritis (HN) in which rats are immunized with renal tubular antigen (RTA) in complete Freund's adjuvant (CFA). Rats develop heavy proteinuria, a key measure of glomerular damage, and the disease is histologically identical to human MN. It has been thought that HN is mediated by antibody-based mechanisms. More recent evidence demonstrates a critical role for cytotoxic T cells. This thesis aims to further examine the role of T cell responses in active HN. First, the effect of the anti-CD3 monocIonal antibody (mAb) G4.18 was investigated. Anti-CD3 given 4 weeks after immunization prevented the development of proteinuria, delayed anti-RTA antibody responses, and reduced glomerular infiltration of CD8+ T cells and macrophages, but did not affect glomerular deposition of IgG or complement. Increased mRNA expression of the Th2 cytokines IL-4 and IL-5 was detected in draining lymph nodes. These findings suggest that immune deviation to a Th2 response reduces glomerular injury in HN. Second, the role of CD4+ T cells in immune tolerance was examined. Rats were given RTA in incomplete Freund's adjnvant (lFA) to induce tolerance to RTA, and three weeks later were immunized with RTA in CFA. Anti-CD4 mAb therapy at the time of RTA1IFA treatment had no effect on subsequent proteinuria or anti-RTA autibodies. Third, the role of IL-4 in this model of immune tolerance was examined. Anti-IL-4 mAb therapy blocked the induction of tolerance, and led to the development of proteinuria. Finally, the effect of treatment with IL-4 and IL-5 was examined. Treatment with these cytokines separately or together after immunization blocked the development of proteinuria, without a consistent effect on anti-RTA antibodies. These results demonstrate a central role for T cell regulation in HN, and show that immune deviation to a Th2 response is protective against glomerular injury. The findings may have implications in the future for focused therapeutic intervention in human idiopathic MN.

  • (2007) Chung, Sylvia; Wei, Ai-Qun; Connor, David; Webb, Graham; Molloy, Tim; Pajic, Marina; Diwan, Ashish
    Journal Article
    Study Design. Nonviral transfection of nucleus pulposus cells with a telomerase expression construct to assess the effects on cellular lifespan, function, karyotypic stability, and transformation properties. Objectives. To investigate whether telomerase gene therapy can extend the cellular lifespan while retaining functionality of nucleus pulposus cells in a safe manner. Summary of Background Data. Degeneration of the intervertebral disc is an age-related condition in which cells responsible for the maintenance and health of the disc deteriorate with age. Telomerase can extend the cellular lifespan and function of other musculoskeletal tissues, such as the heart, bones, and connective tissues. Therefore, extension of the cellular lifespan and matrix production of intervertebral disc cells may have the potential to delay the degeneration process. Methods. Ovine nucleus pulposus cells were lipofectamine transfected in vitro with a human telomerase reverse transcriptase (hTERT) expression construct. Cellular lifespan and matrix transcript levels were determined by cumulative population doublings and real-time RT-PCR, respectively. G1-cell cycle checkpoint, p53 functionality, growth of transfected cells in anchorage-independent or serum starvation conditions, and karyotypic analysis were performed. Results. Transfection was achieved successfully with 340% +/- 7% ( mean +/- SD) relative telomerase activity in hTERT- transfected cells. hTERT transfection enabled a 50% extension in mean cellular lifespan and prolonged matrix production of collagen 1 and 2 for more than 282 days. Karyotypic instability was detected but G1-cell cycle checkpoint and p53 was functionally comparable to parental cells with no growth in serum starvation or anchorage-independent conditions. Conclusions. Telomerase can extend the cellular lifespan of nucleus pulposus cells and prolong the production of extracellular matrix. Safety is still unresolved, as karyotypic instability was detected but no l

  • (2007) Jin, Feng Yi; Prestage, Garrett; Imrie, John; Kippax, Susan; Pell, Catherine; Donovan, Basil; Templeton, David; Cunningham, Philip; Cunningham, Amy; Mindel, Adrian; Kaldor, John; Grulich, Andrew
    Conference Paper

  • (2007) Jin, F; Prestage, Garrett; Mao, Limin; Kippax, Susan; Pell, Catherine; Donovan, Basil; Cunningham, Philip; Templeton, David; Kaldor, John; Grulich, Andrew
    Journal Article

  • (2007) Jin, F; Prestage, Garrett; Zablotska, I; Rawstorne, Patrick; Kippax, Susan; Donovan, Basil; Cunningham, Philip; Templeton, David; Kaldor, John; Grulich, Andrew
    Journal Article
    Background/objectives: Higher levels of sexual risk behaviours have been reported in HIV positive than in HIV negative homosexual men. In clinic based studies, higher rates of sexually transmitted infections (STIs) have also been reported. We compared rates of common STIs between HIV positive and HIV negative homosexual men from two ongoing community based cohort studies in Sydney, Australia. Methods: Participants in the two cohorts were recruited using similar community based strategies. They were interviewed face to face annually after enrolment. Comprehensive sexual health screening, including hepatitis A and B, syphilis, gonorrhoea, and chlamydia (in urethra and anus) was offered to participants in both cohorts. Results: In participants in the HIV positive cohort, 75% were hepatitis A seropositive, 56% had serological evidence of previous or current hepatitis B infection, and 24% had evidence of vaccination against hepatitis B infection. 19% of men tested positive for syphilis and 4% had evidence of recent infections. Compared with men in the HIV negative cohort, after adjustment for age, HIV positive participants had significantly higher prevalence of previous or current hepatitis B infection, syphilis, and anal gonorrhoea. Conclusion: This finding supports the need for frequent STI testing in HIV positive men to prevent morbidity and to decrease the risk of ongoing HIV transmission.