Surgery (RMH) - Research Publications
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ItemNo Preview AvailableVascular endothelial growth factor d is dispensable for development of the lymphatic system(AMER SOC MICROBIOLOGY, 2005-03)Vascular endothelial growth factor receptor 3 (Vegfr-3) is a tyrosine kinase that is expressed on the lymphatic endothelium and that signals for the growth of the lymphatic vessels (lymphangiogenesis). Vegf-d, a secreted glycoprotein, is one of two known activating ligands for Vegfr-3, the other being Vegf-c. Vegf-d stimulates lymphangiogenesis in tissues and tumors; however, its role in embryonic development was previously unknown. Here we report the generation and analysis of mutant mice deficient for Vegf-d. Vegf-d-deficient mice were healthy and fertile, had normal body mass, and displayed no pathologic changes consistent with a defect in lymphatic function. The lungs, sites of strong Vegf-d gene expression during embryogenesis in wild-type mice, were normal in Vegf-d-deficient mice with respect to tissue mass and morphology, except that the abundance of the lymphatics adjacent to bronchioles was slightly reduced. Dye uptake experiments indicated that large lymphatics under the skin were present in normal locations and were functional. Smaller dermal lymphatics were similar in number, location, and function to those in wild-type controls. The lack of a profound lymphatic phenotype in Vegf-d-deficient mice suggests that Vegf-d does not play a major role in lymphatic development or that Vegf-c or another, as-yet-unknown activating Vegfr-3 ligand can compensate for Vegf-d during development.
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ItemPatients' preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile?(SPRINGERNATURE, 2005-12-12)Adjuvant endocrine therapy improves recurrence and survival rates, but has side effects and is inconvenient. The aim of this study was to determine the preferences of premenopausal women who had adjuvant endocrine therapy in a randomised trial. In all, 85 (or eighty-five) women completed semistructured interviews 6-30 months after finishing adjuvant endocrine therapy. Hypothetical scenarios based on known potential survival times (5 or 15 years) and rates (60% or 80% at 5 years) without adjuvant endocrine therapy were used to determine the smallest gains women judged necessary to make their adjuvant endocrine therapy worthwhile. Although a third of the women considered gains of 1% in survival rates or 6 months in survival times sufficient to make their adjuvant endocrine therapy worthwhile, more than half the women required gains of at least 5% in survival rates or 3 years in survival time as necessary to make adjuvant endocrine therapy worthwhile. Larger benefits were required by women who had longer treatment, worse side effects, and by those who were treated with goserelin alone. The route of administration (tablet vs injection) did not affect preferences and some women judged small benefits sufficient to make their adjuvant endocrine therapy worthwhile, but many women required larger benefits than their counterparts in similar studies of preferences for adjuvant chemotherapy.
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ItemNew computational tools for brassica genome research.(Hindawi Limited, 2004)With the increasing quantities of Brassica genomic data being entered into the public domain and in preparation for the complete Brassica genome sequencing effort, there is a growing requirement for the structuring and detailed bioinformatic analysis of Brassica genomic information within a user-friendly database. At the Plant Biotechnology Centre, Melbourne, Australia, we have developed a series of tools and computational pipelines to assist in the processing and structuring of genomic data, to aid its application to agricultural biotechnology research. These tools include a sequence database, ASTRA, a sequence processing pipeline incorporating annotation against GenBank, SwissProt and Arabidopsis Gene Ontology (GO) data and tools for molecular marker discovery and comparative genome analysis. All sequences are mined for simple sequence repeat (SSR) molecular markers using 'SSR primer' and mapped onto the complete Arabidopsis thaliana genome by sequence comparison. The database may be queried using a text-based search of sequence annotation or GO terms, BLAST comparison against resident sequences, or by the position of candidate orthologues within the Arabidopsis genome. Tools have also been developed and applied to the discovery of single nucleotide polymorphism (SNP) molecular markers and the in silico mapping of Brassica BAC end sequences onto the Arabidopsis genome. Planned extensions to this resource include the integration of gene expression data and the development of an EnsEMBL-based genome viewer.
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ItemNegative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase.(Rockefeller University Press, 2004-06-07)A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn-/- bone marrow-derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn-/- mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn-/- mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcepsilonRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcepsilonRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn-/- mice because both lyn-/- and lyn-/- fyn-/- mice showed high IgE levels. Thus, lyn-/- mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.
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ItemPostchemoembolisation syndrome - tumour necrosis or hepatocyte injury?(NATURE PUBLISHING GROUP, 2003-10-20)Transarterial chemoembolisation of liver tumours is typically followed by elevated body temperature and liver transaminase enzymes. This has often been considered to indicate successful embolisation. The present study questions whether this syndrome reflects damage to tumour cells or to the normal hepatic tissue. The responses to 256 embolisations undertaken in 145 patients subdivided into those with hepatocyte-derived (primary hepatocellular carcinoma) and nonhepatocyte-derived tumours (secondary metastases) were analysed to assess the relative effects of tumour necrosis and damage to normal hepatocytes in each group. Cytolysis, measured by elevated alanine aminotransferase, was detected in 85% of patients, and there was no difference in the abnormalities in liver function tests measured between the two groups. Furthermore, cytolysis was associated with a higher rate of postprocedure symptoms and side effects, and elevated temperature was associated with a worse survival on univariate analysis. Multivariate analysis demonstrated that there was no benefit in terms of survival from having elevated temperature or cytolysis following embolisation. Cytolysis after chemoembolisation is probably due to damage to normal hepatocytes. Temperature changes may reflect tumour necrosis or necrosis of the healthy tissue. There is no evidence that either a postchemoembolisation fever or cytolysis is associated with an enhanced tumour response or improved long-term survival in patients with primary or secondary liver cancer.
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ItemNo Preview AvailableUnintended pregnancy and induced abortion among unmarried women in China: a systematic review.(Springer Science and Business Media LLC, 2004-01-22)BACKGROUND: Until recently, premarital examination for both men and women was a legal requirement before marriage in China. Researchers have carried out surveys of attendees' sexual activity, pregnancy and abortion before their marriages, trying to map out reproductive health needs in China, according to this unique population-based data. To systematically identify, appraise and summarise all available studies documenting pregnancy and induced abortion among unmarried Chinese women attending premarital examinations. METHODS: We searched the Chinese Biomedical Literature Index from 1978 to 2002; PUBMED; and EMBASE. Trials were assessed and data extracted by two people independently. RESULTS: Nine studies, of which seven were conducted in the urban areas, one in the rural areas, and one in both urban and rural areas, met the inclusion criteria. In the seven studies in urban areas, the majority of unmarried women had experienced sexual intercourse, with estimates ranging from 54% to 82% in five studies. Estimates of a previous pregnancy ranged from 12% to 32%. Abortion rates were high, ranging between 11 to 55% in 8 studies reporting this, which exclude the one rural study. In the three studies reporting both pregnancy and abortion, most women who had become pregnant had an induced abortion (range 86% to 96%). One large rural study documented a lower low pregnancy rate (20%) and induced abortion rate (0.8%). CONCLUSIONS: There is a large unmet need for temporary methods of contraception in urban areas of China.
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ItemEngineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR(NATURE PUBLISHING GROUP, 2005-03-28)We report the generation of a chimeric monoclonal antibody (ch806) with specificity for an epitope on the epidermal growth factor receptor (EGFR) that is different from that targeted by all other anti-EGFR therapies. Ch806 antibody is reactive to both de2-7 and overexpressed wild-type (wt) EGFR but not native EGFR expressed in normal tissues at physiological levels. Ch806 was stably expressed in CHO (DHFR -/-) cells and purified for subsequent characterisation and validated for use in preliminary immunotherapy investigations. Ch806 retained the antigen binding specificity and affinity of the murine parental antibody. Furthermore, ch806 displayed enhanced antibody-dependent cellular cytotoxicity against target cells expressing the 806 antigen in the presence of human effector cells. Ch806 was successfully radiolabelled with both iodine-125 and indium-111 without loss of antigen binding affinity or specificity. The radioimmunoconjugates were stable in the presence of human serum at 37 degrees C for up to 9 days and displayed a terminal half-life (T(1/2beta)) of approximately 78 h in nude mice. Biodistribution studies undertaken in BALB/c nude mice bearing de2-7 EGFR-expressing or amplified EGFR-expressing xenografts revealed that (125)I-labelled ch806 failed to display any significant tumour retention. However, specific and prolonged tumour localisation of (111)In-labelled ch806 was demonstrated with uptake of 31%ID g(-1) and a tumour to blood ratio of 5 : 1 observed at 7 days postinjection. In vivo therapy studies with ch806 demonstrated significant antitumour effects on established de2-7 EGFR xenografts in BALB/c nude mice compared to control, and both murine 806 and the anti-EGFR 528 antibodies. These results support a potential therapeutic role of ch806 in the treatment of suitable EGFR-expressing tumours, and warrants further investigation of the potential of ch806 as a therapeutic agent.
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ItemQuantifying trade-offs:: quality of life and quality-adjusted survival in a randomised trial of chemotherapy in postmenopausal patients with lymph node-negative breast cancer(NATURE PUBLISHING GROUP, 2004-11-29)We evaluated quality of life (QL) and quality-adjusted survival in International Breast Cancer Study Group Trial IX, a randomised trial including 1669 eligible patients receiving tamoxifen for 5 years or three prior cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 57 months tamoxifen. During the time with CMF toxicity (Tox), without symptoms and toxicity (TWiST), and following relapse (Rel), patients scored their QL indicators and a utility indicator for subjective health estimation between 'perfect' and 'worst' health. Scores were averaged within Tox, TWiST and Rel and transformed to utilities. Mean durations for the three transition times were weighted with utilities to obtain mean quality-adjusted TWiST (Q-TWiST). Patients receiving CMF reported significantly worse scores for most QL domains at month 3, but less hot flushes. After completing chemotherapy, there were no differences by treatment groups. Benefits evaluated by Q-TWiST favoured the additional chemotherapy. CMF provided 3 more months of Q-TWiST for patients with ER-negative tumours, but CMF provided no benefit in Q-TWiST for patients with ER-positive tumours. Q-TWiST analysis based on patient ratings is feasible in large-scale cross-cultural clinical trials.
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ItemProteomic analysis of colorectal cancer: prefractionation strategies using two-dimensional free-flow electrophoresis(HINDAWI LTD, 2005-06)This review deals with the application of a new prefractionation tool, free-flow electrophoresis (FFE), for proteomic analysis of colorectal cancer (CRC). CRC is a leading cause of cancer death in the Western world. Early detection is the single most important factor influencing outcome of CRC patients. If identified while the disease is still localized, CRC is treatable. To improve outcomes for CRC patients there is a pressing need to identify biomarkers for early detection (diagnostic markers), prognosis (prognostic indicators), tumour responses (predictive markers) and disease recurrence (monitoring markers). Despite recent advances in the use of genomic analysis for risk assessment, in the area of biomarker identification genomic methods alone have yet to produce reliable candidate markers for CRC. For this reason, attention is being directed towards proteomics as a complementary analytical tool for biomarker identification. Here we describe a proteomics separation tool, which uses a combination of continuous FFE, a liquid-based isoelectric focusing technique, in the first dimension, followed by rapid reversed-phase HPLC (1-6 min/analysis) in the second dimension. We have optimized imaging software to present the FFE/RP-HPLC data in a virtual 2D gel-like format. The advantage of this liquid based fractionation system over traditional gel-based fractionation systems is the ability to fractionate large quantity protein samples. Unlike 2D gels, the method is applicable to both high-M(r) proteins and small peptides, which are difficult to separate, and in the case of peptides, are not retained in standard 2D gels.
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ItemSustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity(ROCKEFELLER UNIV PRESS, 2002-12-16)Genetic ablation of the Lyn tyrosine kinase has revealed unique inhibitory roles in B lymphocyte signaling. We now report the consequences of sustained activation of Lyn in vivo using a targeted gain-of-function mutation (Lyn(up/up) mice). Lyn(up/up) mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. Lyn(up/up) B cells are characterized by the constitutive phosphorylation of negative regulators of B cell antigen receptor (BCR) signaling including CD22, SHP-1, and SHIP-1, and display attributes of lymphocytes rendered tolerant by constitutive engagement of the antigen receptor. However, exaggerated positive signaling is also apparent as evidenced by the constitutive phosphorylation of Syk and phospholipase Cgamma2 in resting Lyn(up/up) B cells. Similarly, Lyn(up/up) B cells show a heightened calcium flux in response to BCR stimulation. Surprisingly, Lyn(up/up) mice develop circulating autoreactive antibodies and lethal autoimmune glomerulonephritis, suggesting that enhanced positive signaling eventually overrides constitutive negative signaling. These studies highlight the difficulty in maintaining tolerance in the face of chronic stimulation and emphasize the pivotal role of Lyn in B cell signaling.