Surgery (St Vincent's) - Research Publications
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ItemNo Preview AvailableGata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14(AMER SOC MICROBIOLOGY, 2011-11)The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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ItemThe delicate balance of melanoma immunotherapy(WILEY, 2013-08)The strategy of immune modulation for the treatment of cancer is being refined with the introduction of multiple new therapeutic agents into the clinic. Melanoma is a disease where many of these agents have demonstrated efficacy. The mechanisms of action of these agents exploit the counter-regulatory mechanisms of the immune response. However, these agents are also associated with immune-related adverse events (IRAEs), which represent tissue-specific inflammatory responses. These IRAEs highlight the delicate balance of immunologic homeostasis and, with some interventions, may occur more frequently in patients who sustain a therapeutic response. This review will discuss melanoma immunogenicity and immunotherapy. Furthermore, the spectrum and distinction between a reversible immune adverse event and autoimmunity will be highlighted.
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ItemElectrical probing of cortical excitability in patients with epilepsy(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011-12)Standard methods for seizure prediction involve passive monitoring of intracranial electroencephalography (iEEG) in order to track the 'state' of the brain. This paper introduces a new method for measuring cortical excitability using an electrical probing stimulus. Electrical probing enables feature extraction in a more robust and controlled manner compared to passively tracking features of iEEG signals. The probing stimuli consist of 100 bi-phasic pulses, delivered every 10 min. Features representing neural excitability are estimated from the iEEG responses to the stimuli. These features include the amplitude of the electrically evoked potential, the mean phase variance (univariate), and the phase-locking value (bivariate). In one patient, it is shown how the features vary over time in relation to the sleep-wake cycle and an epileptic seizure. For a second patient, it is demonstrated how the features vary with the rate of interictal discharges. In addition, the spatial pattern of increases and decreases in phase synchrony is explored when comparing periods of low and high interictal discharge rates, or sleep and awake states. The results demonstrate a proof-of-principle for the method to be applied in a seizure anticipation framework. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction.
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ItemA new class of animal collagen masquerading as an insect silk(NATURE PORTFOLIO, 2013-10-04)Collagen is ubiquitous throughout the animal kingdom, where it comprises some 28 diverse molecules that form the extracellular matrix within organisms. In the 1960s, an extracorporeal animal collagen that forms the cocoon of a small group of hymenopteran insects was postulated. Here we categorically demonstrate that the larvae of a sawfly species produce silk from three small collagen proteins. The native proteins do not contain hydroxyproline, a post translational modification normally considered characteristic of animal collagens. The function of the proteins as silks explains their unusual collagen features. Recombinant proteins could be produced in standard bacterial expression systems and assembled into stable collagen molecules, opening the door to manufacture a new class of artificial collagen materials.
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ItemTowards scalable production of a collagen-like protein from Streptococcus pyogenes for biomedical applications(BMC, 2012-11-05)BACKGROUND: Collagen has proved valuable as biomedical materials for a range of clinical applications, particularly in wound healing. It is normally produced from animal sources, such as from bovines, but concerns have emerged over transmission of diseases. Recombinant collagens would be preferable, but are difficult to produce. Recently, studies have shown that 'collagens' from bacteria, including Streptococcus pyogenes, can be produced in the laboratory as recombinant products, and that these are biocompatible. In the present study we have established that examples of bacterial collagens can be produced in a bioreactor with high yields providing proof of manufacture of this important group of proteins. RESULTS: Production trials in shake flask cultures gave low yields of recombinant product, < 1 g/L. Increased yields, of around 1 g/L, were obtained when the shake flask process was transferred to a stirred tank bioreactor, and the yield was further enhanced to around 10 g/L by implementation of a high cell density fed-batch process and the use of suitably formulated fully defined media. Similar yields were obtained with 2 different constructs, one containing an introduced heparin binding domain. The best yields, of up to 19 g/L were obtained using this high cell density strategy, with an extended 24 h production time. CONCLUSIONS: These data have shown that recombinant bacterial collagen from S. pyogenes, can be produced in sufficient yield by a scalable microbial production process to give commercially acceptable yields for broad use in biomedical applications.
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ItemControlling the Molecular Structure and Physical Properties of Artificial Honeybee Silk by Heating or by Immersion in Solvents(PUBLIC LIBRARY SCIENCE, 2012-12-21)Honeybee larvae produce silken cocoons that provide mechanical stability to the hive. The silk proteins are small and non-repetitive and therefore can be produced at large scale by fermentation in E. coli. The recombinant proteins can be fabricated into a range of forms; however the resultant material is soluble in water and requires a post production stabilizing treatment. In this study, we describe the structural and mechanical properties of sponges fabricated from artificial honeybee silk proteins that have been stabilized in aqueous methanol baths or by dry heating. Aqueous methanol treatment induces formation of ß-sheets, with the amount of ß-sheet dictated by methanol concentration. Formation of ß-sheets renders sponges insoluble in water and generates a reversibly compressible material. Dry heat treatments at 190°C produce a water insoluble material, that is stiffer than the methanol treated equivalent but without significant secondary structural changes. Honeybee silk proteins are particularly high in Lys, Ser, Thr, Glu and Asp. The properties of the heat treated material are attributed to generation of lysinoalanine, amide (isopeptide) and/or ester covalent cross-links. The unique ability to stabilize material by controlling secondary structure rearrangement and covalent cross-linking allows us to design recombinant silk materials with a wide range of properties.
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ItemA Preclinical Evaluation of Alternative Synthetic Biomaterials for Fascial Defect Repair Using a Rat Abdominal Hernia Model(PUBLIC LIBRARY SCIENCE, 2012-11-20)INTRODUCTION: Fascial defects are a common problem in the abdominal wall and in the vagina leading to hernia or pelvic organ prolapse that requires mesh enhancement to reduce operation failure. However, the long-term outcome of synthetic mesh surgery may be unsatisfactory due to post-surgical complications. We hypothesized that mesh fabricated from alternative synthetic polymers may evoke a different tissue response, and provide more appropriate mechanical properties for hernia repair. Our aim was to compare the in vivo biocompatibility of new synthetic meshes with a commercial mesh. METHODS: We have fabricated 3 new warp-knitted synthetic meshes from different polymers with different tensile properties polyetheretherketone (PEEK), polyamide (PA) and a composite, gelatin coated PA (PA+G). The rat abdominal hernia model was used to implant the meshes (25 × 35 mm, n = 24/ group). After 7, 30, 60, 90 days tissues were explanted for immunohistochemical assessment of foreign body reaction and tissue integration, using CD31, CD45, CD68, alpha-SMA antibodies. The images were analysed using an image analysis software program. Biomechanical properties were uniaxially evaluated using an Instron Tensile® Tester. RESULTS: This study showed that the new meshes induced complex differences in the type of foreign body reaction over the time course of implantation. The PA, and particularly the composite PA+G meshes, evoked a milder early inflammatory response, and macrophages were apparent throughout the time course. Our meshes led to better tissue integration and new collagen deposition, particularly with the PA+G meshes, as well as greater and sustained neovascularisation compared with the PP meshes. CONCLUSION: PA, PA+G and PEEK appear to be well tolerated and are biocompatible, evoking an overlapping and different host tissue response with time that might convey mechanical variations in the healing tissue. These new meshes comprising different polymers may provide an alternative option for future treatment of fascial defects.
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ItemInternational Preoperative Rectal Cancer Management: Staging, Neoadjuvant Treatment, and Impact of Multidisciplinary Teams(SPRINGER, 2010-11)BACKGROUND: Little is known regarding variations in preoperative treatment and practice for rectal cancer (RC) on an international level, yet practice variation may result in differences in recurrence and survival rates. METHODS: One hundred seventy-three international colorectal centers were invited to participate in a survey of preoperative management of rectal cancer. RESULTS: One hundred twenty-three (71%) responded, with a majority of respondents from North America, Europe, and Asia. Ninety-three percent have more than 5 years' experience with rectal cancer surgery. Fifty-five percent use CT scan, 35% MRI, 29% ERUS, 12% digital rectal examination and 1% PET scan in all RC cases. Seventy-four percent consider threatened circumferential margin (CRM) an indication for neoadjuvant treatment. Ninety-two percent prefer 5-FU-based long-course neoadjuvant chemoradiation therapy (CRT). A significant difference in practice exists between the US and non-US surgeons: poor histological differentiation as an indication for CRT (25% vs. 7.0%, p = 0.008), CRT for stage II and III rectal cancer (92% vs. 43%, p = 0.0001), MRI for all RC patients (20% vs. 42%, p = 0.03), and ERUS for all RC patients (43% vs. 21%, p = 0.01). Multidisciplinary team meetings significantly influence decisions for MRI (RR = 3.62), neoadjuvant treatment (threatened CRM, RR = 5.67, stage II + III RR = 2.98), quality of pathology report (RR = 4.85), and sphincter-saving surgery (RR = 3.81). CONCLUSIONS: There was little consensus on staging, neoadjuvant treatment, and preoperative management of rectal cancer. Regular multidisciplinary team meetings influence decisions about neoadjuvant treatment and staging methods.
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ItemThe effectiveness of neuromuscular warm-up strategies, that require no additional equipment, for preventing lower limb injuries during sports participation: a systematic review(BIOMED CENTRAL LTD, 2012-07-19)BACKGROUND: Lower limb injuries in sport are increasingly prevalent and responsible for large economic as well as personal burdens. In this review we seek to determine which easily implemented functional neuromuscular warm-up strategies are effective in preventing lower limb injuries during sports participation and in which sporting groups they are effective. METHODS: Seven electronic databases were searched from inception to January 2012 for studies investigating neuromuscular warm-up strategies and injury prevention. The quality of each included study was evaluated using a modified version of the van Tulder scale. Data were extracted from each study and used to calculate the risk of injury following application of each evaluated strategy. RESULTS: Nine studies were identified including six randomized controlled trials (RCT) and three controlled clinical trials (CCT). Heterogeneity in study design and warm-up strategies prevented pooling of results. Two studies investigated male and female participants, while the remaining seven investigated women only. Risk Ratio (RR) statistics indicated 'The 11+' prevention strategy significantly reduces overall (RR 0.67, confidence interval (CI) 0.54 to 0.84) and overuse (RR 0.45, CI 0.28 to 0.71) lower limb injuries as well as knee (RR 0.48, CI 0.32 to 0.72) injuries among young amateur female footballers. The 'Knee Injury Prevention Program' (KIPP) significantly reduced the risk of noncontact lower limb (RR 0.5, CI 0.33 to 0.76) and overuse (RR 0.44, CI 0.22 to 0.86) injuries in young amateur female football and basketball players. The 'Prevent Injury and Enhance Performance' (PEP) strategy reduces the incidence of anterior cruciate ligament (ACL) injuries (RR 0.18, CI 0.08 to 0.42). The 'HarmoKnee' programme reduces the risk of knee injuries (RR 0.22, CI 0.06 to 0.76) in teenage female footballers. The 'Anterior Knee Pain Prevention Training Programme' (AKP PTP) significantly reduces the incidence of anterior knee pain (RR 0.27, CI 0.14 to 0.54) in military recruits. CONCLUSIONS: Effective implementation of practical neuromuscular warm-up strategies can reduce lower extremity injury incidence in young, amateur, female athletes and male and female military recruits. This is typically a warm-up strategy that includes stretching, strengthening, balance exercises, sports-specific agility drills and landing techniques applied consistently for longer than three consecutive months. In order to optimize these strategies, the mechanisms for their effectiveness require further evaluation.
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ItemLower limb biomechanics during running in individuals with achilles tendinopathy: a systematic review(BMC, 2011-05-30)BACKGROUND: Abnormal lower limb biomechanics is speculated to be a risk factor for Achilles tendinopathy. This study systematically reviewed the existing literature to identify, critique and summarise lower limb biomechanical factors associated with Achilles tendinopathy. METHODS: We searched electronic bibliographic databases (Medline, EMBASE, Current contents, CINAHL and SPORTDiscus) in November 2010. All prospective cohort and case-control studies that evaluated biomechanical factors (temporospatial parameters, lower limb kinematics, dynamic plantar pressures, kinetics [ground reaction forces and joint moments] and muscle activity) associated with mid-portion Achilles tendinopathy were included. Quality of included studies was evaluated using the Quality Index. The magnitude of differences (effect sizes) between cases and controls was calculated using Cohen's d (with 95% CIs). RESULTS: Nine studies were identified; two were prospective and the remaining seven case-control study designs. The quality of 9 identified studies was varied, with Quality Index scores ranging from 4 to 15 out of 17. All studies analysed running biomechanics. Cases displayed increased eversion range of motion of the rearfoot (d = 0.92 and 0.67 in two studies), reduced maximum lower leg abduction (d = -1.16), reduced ankle joint dorsiflexion velocity (d = -0.62) and reduced knee flexion during gait (d = -0.90). Cases also demonstrated a number of differences in dynamic plantar pressures (primarily the distribution of the centre of force), ground reaction forces (large effects for timing variables) and also showed reduced peak tibial external rotation moment (d = -1.29). Cases also displayed differences in the timing and amplitude of a number of lower limb muscles but many differences were equivocal. CONCLUSIONS: There are differences in lower limb biomechanics between those with and without Achilles tendinopathy that may have implications for the prevention and management of the condition. However, the findings need to be interpreted with caution due to the limited quality of a number of the included studies. Future well-designed prospective studies are required to confirm these findings.