417 research outputs found

    Raman Spectroscopy Reveals New Insights into the Zonal Organization of Native and Tissue-Engineered Articular Cartilage.

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    Tissue architecture is intimately linked with its functions, and loss of tissue organization is often associated with pathologies. The intricate depth-dependent extracellular matrix (ECM) arrangement in articular cartilage is critical to its biomechanical functions. In this study, we developed a Raman spectroscopic imaging approach to gain new insight into the depth-dependent arrangement of native and tissue-engineered articular cartilage using bovine tissues and cells. Our results revealed previously unreported tissue complexity into at least six zones above the tidemark based on a principal component analysis and k-means clustering analysis of the distribution and orientation of the main ECM components. Correlation of nanoindentation and Raman spectroscopic data suggested that the biomechanics across the tissue depth are influenced by ECM microstructure rather than composition. Further, Raman spectroscopy together with multivariate analysis revealed changes in the collagen, glycosaminoglycan, and water distributions in tissue-engineered constructs over time. These changes were assessed using simple metrics that promise to instruct efforts toward the regeneration of a broad range of tissues with native zonal complexity and functional performance.M.S.B., J.-P.S.-P., and M.M.S. acknowledge the support of the Medical Research Council, the Engineering and Physical Sciences Research Council, and the Biotechnology and Biological Sciences Research Council UK Regenerative Medicine Platform Hubs “Acellular Approaches for Therapeutic Delivery” (MR/K026682/1) and “A Hub for Engineering and Exploiting the Stem Cell Niche” (MR/K026666/1). J.-P.S.-P. and M.M.S. were also supported by the Medical Engineering Solutions in the Osteoarthritis Centre of Excellence, funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (088844). J.-P.S.-P. would like to acknowledge the Value in People Award from the Wellcome Trust Institutional Strategic Support Fund (097816/Z/11/A). M.M.S. also acknowledges the support from the ERC Seventh Framework Programme Consolidator grant “Naturale CG” under Grant Agreement No. 616417

    Multi-Gene Expression Predictors of Single Drug Responses to Adjuvant Chemotherapy in Ovarian Carcinoma: Predicting Platinum Resistance

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    Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Standard therapy includes treatment with platinum-based combination chemotherapies yet there is no biomarker model to predict their responses to these agents. We here have developed and independently tested our multi-gene molecular predictors for forecasting patients' responses to individual drugs on a cohort of 55 ovarian cancer patients. To independently validate these molecular predictors, we performed microarray profiling on FFPE tumor samples of 55 ovarian cancer patients (UVA-55) treated with platinum-based adjuvant chemotherapy. Genome-wide chemosensitivity biomarkers were initially discovered from the in vitro drug activities and genomic expression data for carboplatin and paclitaxel, respectively. Multivariate predictors were trained with the cell line data and then evaluated with a historical patient cohort. For the UVA-55 cohort, the carboplatin, taxol, and combination predictors significantly stratified responder patients and non-responder patients (p = 0.019, 0.04, 0.014) with sensitivity = 91%, 96%, 93 and NPV = 57%, 67%, 67% in pathologic clinical response. The combination predictor also demonstrated a significant survival difference between predicted responders and non-responders with a median survival of 55.4 months vs. 32.1 months. Thus, COXEN single- and combination-drug predictors successfully stratified platinum resistance and taxane response in an independent cohort of ovarian cancer patients based on their FFPE tumor samples

    Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

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    In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L

    Fear of crime on the rail networks: Perceptions of the UK public and British Transport Police

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    Counter-terrorism on the rail network is vital to the security of the United Kingdom. The British Transport Police (BTP) employ covert and overt security measures to prevent crime, which includes: closed circuit television, armed police, unarmed polisce, police community support officers, police dogs, stops and searches and awareness campaigns. All security measures aim to deter crime while importantly reassuring the public. We surveyed both members of the public and BTP officers about the perceived effectiveness of current security measures, specifically with regards to fear of terrorism. Feelings of reassurance and the perceived effectiveness of security measures were positively related. The most effective and reassuring security measure was the use of armed police; whereas the least effective and reassuring was the use of awareness campaigns. However, interestingly, qualitative analyses suggested that an increase in armed police without informed awareness campaigns would have a negative impact on public reassurance by increasing fear

    Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer

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    Background: Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. Methods: We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. Results: We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m(2) with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. Conclusions: We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation

    Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment

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    The treatment of colorectal cancer is rapidly becoming a significant financial burden to health-care systems within economically developed nations. A current challenge for oncologists and health-care payers is to integrate new, often high-cost, biologic therapies into clinical practice. Inherent to this process is the consideration of cost-effectiveness. The aim of this study was to compare the cost-effectiveness of cetuximab plus irinotecan with an appropriate comparator from a National Health Service (NHS) perspective. This economic evaluation is a trial-based study of cetuximab vs active/best supportive care. Effectiveness estimates for the treatment groups were modelled from key clinical trials. Cunningham et al (2004) compared cetuximab/irinotecan with cetuximab monotherapy; Cunningham et al (1998) compared irinotecan monotherapy in a second-line setting with supportive care. Modelling was necessary owing to an absence of head-to-head clinical trial data of cetuximab/irinotecan vs current standard care. Costs were calculated for the study drugs received, associated administration, palliative chemotherapy for patients in the standard care arm and other nonchemotherapy resources. The discounted life-expectancy of patients treated with cetuximab/irinotecan was 0.91 life-years, and 0.47 discounted life-years for patients receiving active/best supportive care. Patients treated with cetuximab/irinotecan accumulated mean additional costs of £18 901 per patient relative to the comparator arm, with £11 802 attributable to cetuximab. The incremental cost per life-year gained with cetuximab/irinotecan therapy compared with active/best supportive care was £42 975. The incremental cost per quality adjusted life-year gained was £57 608. The incremental cost per life-year gained for cetuximab/irinotecan is relatively high compared with other health-care interventions. However, this result should be considered in the context of a number of factors specific to the treated patient population

    Production of phi mesons at mid-rapidity in sqrt(s_NN) = 200 GeV Au+Au collisions at RHIC

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    We present the first results of meson production in the K^+K^- decay channel from Au+Au collisions at sqrt(s_NN) = 200 GeV as measured at mid-rapidity by the PHENIX detector at RHIC. Precision resonance centroid and width values are extracted as a function of collision centrality. No significant variation from the PDG accepted values is observed. The transverse mass spectra are fitted with a linear exponential function for which the derived inverse slope parameter is seen to be constant as a function of centrality. These data are also fitted by a hydrodynamic model with the result that the freeze-out temperature and the expansion velocity values are consistent with the values previously derived from fitting single hadron inclusive data. As a function of transverse momentum the collisions scaled peripheral.to.central yield ratio RCP for the is comparable to that of pions rather than that of protons. This result lends support to theoretical models which distinguish between baryons and mesons instead of particle mass for explaining the anomalous proton yield.Comment: 326 authors, 24 pages text, 23 figures, 6 tables, RevTeX 4. To be submitted to Physical Review C as a regular article. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm
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