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Publication History View all

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    ABSTRACT: As medicine progresses into a new era of personalised therapy, the use of monoclonal antibodies to treat a wide range of diseases lies at the heart of this new forefront. Since the licensing of the first monoclonal antibody for clinical use 30 years ago, the monoclonal antibody industry has expanded exponentially and is now valued at billions of dollars. With major advances in genetic sequencing and biomedical research, much research into monoclonal antibodies now focuses on identifying new targets for development and maximising their efficacy for use in clinical practice. However, a balance has to be struck with regards to reducing numbers of side-effects and overall economic cost, which arguably somewhat blighted their early clinical and commercial successes. Nowadays, there are approximately 30 monoclonal antibodies that have been approved for use in clinical practice with many more currently being tested in clinical trials. Some of the current major limitations include: the use of inefficient models for generation, a lack of efficacy and issues of cost-effectiveness. Some of the current research focuses on ways to improve the efficacy of existing monoclonal antibodies through optimising their effects and the addition of beneficial modifications. This review will focus on the history of monoclonal antibody development – how it has increasingly moved away from using laborious animal models to a more effective phage display system, some of the major drawbacks from a clinical and economical point of view and future innovations that are currently being researched to maximise their effectiveness for future clinical use.
    Annals of Medicine and Surgery 09/2014; 3(4):113-116. DOI:10.1016/j.amsu.2014.09.001
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    ABSTRACT: Introduction Calcitonin (CT) has recently been shown to display chondroprotective effects. Here, we investigate the putative mechanisms by which CT delivers these actions. Methods Immortalized C-28/I2 cells or primary adult human articular chondrocytes (AHAC) were cultured in high-density micromasses to investigate: (i) CT anabolic effects using qPCR and immuhistochemistry analysis; (ii) CT anti-apoptotic effects using quantitation of Bax/Bcl gene products ratio, TUNEL assay and caspase-3 expression; (iii) CT effects on CREB, COL2A1 and NFAT transcription factors. Results CT (10-10-10-8 nM) induced significant up-regulation of cartilage phenotypic markers (SOX9, COL2A1 and ACAN), with down-regulation of catabolic (MMP1 and MMP13 and ADAMTS5) gene products both in resting and inflammatory conditions. This was mirrored by an augmented production of type II collagen and accumulation of glycosaminoglycan- and proteoglycan-rich extracellular matrix in vitro. Mechanistic analyses revealed only partial involvement of cyclic AMP formation in these effects of CT. Congruently, using reporter assays for specific transcription factors, there was no indication for CREB activation, whereas the COL2A1 promoter was genuinely and directly activated by cell exposure to CT. Phenotypically, these mechanisms supported the ability of CT, whilst inactive on its own, to counteract the pro-apoptotic effects of IL-1β, demonstrated by TUNEL-positive staining of chondrocytes and ratio of BAX/BCL genes products. Conclusion These data may provide a novel lead for the development of CT-based chondroprotective strategies that rely on the engagement of mechanisms that lead to augmented chondrocyte anabolism and inhibited chondrocyte apoptosis.
    Biochemical Pharmacology 08/2014; 91(3). DOI:10.1016/j.bcp.2014.07.034
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    ABSTRACT: Emotions and feelings are the bricks of our social life and yet we often forget that they have a significant impact on our physical wellbeing. Indeed, a growing number of studies have shown that both an imbalanced or improved emotional state can significantly influence the way our immune system responds. In this commentary, we have summarized the most recent studies on the effects of different types of emotional states on the immune system and we have also explored the effects of mood modulator approaches on the immune response. We hope this commentary will prompt scientists and clinicians to think about the therapeutic value and potential of emotions and feelings in immune-related diseases. At the same time, we think that this commentary will shed some light on the scientific truth behind the very famous expression "It's in my blood" when we talk about feelings and personality.
    Biochemical Pharmacology 08/2014; 91(3). DOI:10.1016/j.bcp.2014.07.016
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    ABSTRACT: Background Long noncoding RNAs (lncRNAs) have been shown to be involved in the development and progression of lung cancer. However, the roles of lncRNAs in lung cancer are not well understood. Methodology/Principal Findings We used a high-throughput microarray to compare the lncRNA and messenger RNA (mRNA) expression profiles in lung adenocarcinoma and normal tissue (NT) samples. Several candidate adenocarcinoma-associated lncRNAs were verified by real-time quantitative reverse transcription polymerase chain reaction (PCR) analysis. Using abundant and varied probes, we were able to assess 30,586 lncRNAs and 26,109 mRNAs in our microarray. We found that 2,420 lncRNAs and 1,109 mRNAs were differentially expressed (≥2-fold change) in lung adenocarcinoma samples and NT, indicating that many lncRNAs were significantly upregulated or downregulated in lung adenocarcinoma. We also found, via quantitative PCR, that 19 lncRNAs were aberrantly expressed in lung adenocarcinoma compared with matched histologically normal lung tissues. Among these, LOC100132354 and RPLP0P2 were the most aberrantly expressed lncRNAs, as estimated by quantitative PCR in 100 pairs of lung adenocarcinoma and NT samples. Conclusions/Significance Our study ascertained the expression patterns of lncRNAs in lung adenocarcinoma by microarray. The results revealed that many lncRNAs were differentially expressed in lung adenocarcinoma tissues and NT, suggesting that they may play a key role in tumor development.
    PLoS ONE 08/2014; 9(8):e104044. DOI:10.1371/journal.pone.0104044
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    ABSTRACT: Objective To investigate the salt (sodium chloride) content in cheese sold in UK supermarkets. Study design We carried out a cross-sectional survey in 2012, including 612 cheeses available in UK supermarkets. Methods The salt content (g/100 g) was collected from product packaging and nutrient information panels of cheeses available in the top seven retailers. Results Salt content in cheese was high with a mean (±SD) of 1.7±0.58 g/100 g. There was a large variation in salt content between different types of cheeses and within the same type of cheese. On average, halloumi (2.71±0.34 g/100 g) and imported blue cheese (2.71±0.83 g/100 g) contained the highest amounts of salt and cottage cheese (0.55±0.14 g/100 g) contained the lowest amount of salt. Overall, among the 394 cheeses that had salt reduction targets, 84.5% have already met their respective Department of Health 2012 salt targets. Cheddar and cheddar-style cheese is the most popular/biggest selling cheese in the UK and has the highest number of products in the analysis (N=250). On average, salt level was higher in branded compared with supermarket own brand cheddar and cheddar-style products (1.78±0.13 vs 1.72±0.14 g/100 g, p<0.01). Ninety per cent of supermarket own brand products met the 2012 target for cheddar and cheddar-style cheese compared with 73% of branded products (p=0.001). Conclusions Salt content in cheese in the UK is high. There is a wide variation in the salt content of different types of cheeses and even within the same type of cheese. Despite this, 84.5% of cheeses have already met their respective 2012 targets. These findings demonstrate that much larger reductions in the amount of salt added to cheese could be made and more challenging targets need to be set, so that the UK can continue to lead the world in salt reduction.
    BMJ Open 08/2014; 4(8):e005051. DOI:10.1136/bmjopen-2014-005051
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    International Journal of Surgery (London, England) 07/2014; 12(9). DOI:10.1016/j.ijsu.2014.07.268
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    ABSTRACT: Individual bacteria and shifts in the composition of the microbiome have been associated with human diseases including cancer. To investigate changes in the microbiome associated with oral cancers, we profiled cancers and anatomically matched contralateral normal tissue from the same patient by sequencing 16S rDNA hypervariable region amplicons. In cancer samples from both a discovery and a subsequent confirmation cohort, abundance of Firmicutes (especially Streptococcus) and Actinobacteria (especially Rothia) was significantly decreased relative to contralateral normal samples from the same patient. Significant decreases in abundance of these phyla were observed for pre-cancers, but not when comparing samples from contralateral sites (tongue and floor of mouth) from healthy individuals. Weighted UniFrac principal coordinates analysis based on 12 taxa separated most cancers from other samples with greatest separation of node positive cases. These studies begin to develop a framework for exploiting the oral microbiome for monitoring oral cancer development, progression and recurrence.
    PLoS ONE 06/2014; 9(6):e98741. DOI:10.1371/journal.pone.0098741
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    ABSTRACT: Mast cells (MCs) expressing serine proteases; tryptase and chymase, are associated with fibrosis in various diseases. However, little is known about their involvement in oral submucous fibrosis (OSF). Our goal was to evaluate the role of MC tryptase and chymase in the pathogenesis of OSF and its malignant transformation. Immunohistochemical expression of MC tryptase and chymase was evaluated in 20 cases of OSF, 10 cases of oral squamous cell carcinoma (OSCC) and 10 cases of healthy controls. Subepithelial zone of Stage 1 and 2 while deep zone of Stage 3 and 4 OSF demonstrated increased tryptase positive MCs. OSCC revealed a proportionate increase in tryptase and chymase positive MCs irrespective of areas of distribution. An altered balance in the subepithelial and deep distribution of tryptase and chymase positive MCs play an important role in the pathogenesis of OSF and its malignant transformation.
    PLoS ONE 05/2014; 9(5):e98719. DOI:10.1371/journal.pone.0098719
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    ABSTRACT: Cartilage breakdown is the disabling outcome of rheumatic diseases, whether prevalently inflammatory such as rheumatoid arthritis or prevalently mechanical such as osteoarthritis (OA). Despite the differences between immune-mediated arthritides and OA, common mechanisms drive cartilage breakdown. Inflammation, chondrocyte phenotype and homeostatic mechanisms have recently been the focus of research and will be summarised in this review.
    Drug Discovery Today 05/2014; 19(8). DOI:10.1016/j.drudis.2014.05.014
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    ABSTRACT: To determine the relationship between the reduction in salt intake that occurred in England, and blood pressure (BP), as well as mortality from stroke and ischaemic heart disease (IHD). Analysis of the data from the Health Survey for England. England, 2003 N=9183, 2006 N=8762, 2008 N=8974 and 2011 N=4753, aged ≥16 years. BP, stroke and IHD mortality. From 2003 to 2011, there was a decrease in mortality from stroke by 42% (p<0.001) and IHD by 40% (p<0.001). In parallel, there was a fall in BP of 3.0±0.33/1.4±0.20 mm Hg (p<0.001/p<0.001), a decrease of 0.4±0.02 mmol/L (p<0.001) in cholesterol, a reduction in smoking prevalence from 19% to 14% (p<0.001), an increase in fruit and vegetable consumption (0.2±0.05 portion/day, p<0.001) and an increase in body mass index (BMI; 0.5±0.09 kg/m(2), p<0.001). Salt intake, as measured by 24 h urinary sodium, decreased by 1.4 g/day (p<0.01). It is likely that all of these factors (with the exception of BMI), along with improvements in the treatments of BP, cholesterol and cardiovascular disease, contributed to the falls in stroke and IHD mortality. In individuals who were not on antihypertensive medication, there was a fall in BP of 2.7±0.34/1.1±0.23 mm Hg (p<0.001/p<0.001) after adjusting for age, sex, ethnic group, education, household income, alcohol consumption, fruit and vegetable intake and BMI. Although salt intake was not measured in these participants, the fact that the average salt intake in a random sample of the population fell by 15% during the same period suggests that the falls in BP would be largely attributable to the reduction in salt intake rather than antihypertensive medications. The reduction in salt intake is likely to be an important contributor to the falls in BP from 2003 to 2011 in England. As a result, it would have contributed substantially to the decreases in stroke and IHD mortality.
    BMJ Open 04/2014; 4(4):e004549. DOI:10.1136/bmjopen-2013-004549
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