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News Article | February 16, 2017
Site: www.eurekalert.org

The University of Liverpool, in partnership with AKL Research and Development Ltd, is to lead on a clinical trial to test a potential new drug treatment for osteoarthritis. Osteoarthritis (OA) is the most common type of arthritis in the UK, affecting more than eight million people*, and is the leading cause of joint pain and stiffness in older people. As part of their research and development programme, AKL identifies promising phytochemicals, found in natural products, which are capable of being synthesized. Trials have identified two molecules which act synergistically and have been brought together to create 'APPA', a patented drug. In a variety of pre-clinical animal testing trials, APPA has clearly demonstrated significant pain relief from OA, improved functionality and the slowing of cartilage destruction. Having successfully passed preclinical toxicology studies, formal human studies can now start. The clinical trial is due to commence shortly at the Liverpool Clinical Trials Unit (LCTU) led by rheumatologist Professor Robert Moots from the University's Institute of Ageing and Chronic Disease. Professor Moots, said: "The severe pain from OA is usually managed with prescription drugs that are often not effective and that also, in many cases, induce unacceptable side effects. In many cases, major joint replacement surgery is needed to help deal with the pain. This is surely wrong. "This drug has huge potential to provide an effective treatment for OA. A reliable and easy way to treat OA has clear potential to save large amounts of money for the NHS and greatly improve the lifestyle and health of patients. "Working with research and development companies like AKL is crucial for the development and introduction of new treatments to benefit patients now and in future generations. We are excited to move this programme of trials forward." Research on how APPA affects human cells, especially activated neutrophils, is being led by Professor Steven Edwards at the University's Institute of Integrative Biology. Professor Edwards, said: "Neutrophils are the most abundant type of white blood cells and form an essential part of our immune system. There is now considerable evidence to show that neutrophils are activated in inflammatory diseases. They are however a "two-edged sword": they are required to protect us from infections but their inappropriate activation can result in irreversible damage in inflammatory diseases. "The 'holy grail' of anti-inflammatory targeting of neutrophils is specifically to block their tissue-damaging activities, but not compromise their ability to protect us. Work is ongoing but to date it appears that APPA does not target the host defence properties of neutrophils but does block their pro-inflammatory activities". David Sharples, CEO, AKL, said: "Professor Moots is leading this important clinical trial and that, in conjunction with Professor Edwards' research on APPA's novel modes of action, should provide the robust evidence we need to help bring this drug to market. There remains a high unmet need for an effective, well tolerated OA drug, so understandably we are very excited by APPA's prospects". AKL Research & Development Limited ("AKL") is an emerging pharmaceutical development company with a pioneering approach to drug development. AKL identifies and validates the active phytochemicals found in natural products. Synthetic versions of these compounds, whose safety and efficacy in their natural form have already been established in non-prescription markets are then taken to proof of concept through robust clinical evaluation. AKL's strategy of using well-characterised active compounds considerably improves the chances of successfully completing preclinical toxicity studies, avoiding unexpected side effects and demonstrating efficacy. It is AKL's intention to access global markets via a partner following proof of concept. The Company is based at the Stevenage Bioscience Catalyst, Stevenage, Herts UK. http://www. Professor Moots combines his clinical work as a consultant rheumatologist at Aintree University Hospital, with internationally recognised research into the causes and treatment of rheumatic diseases. Recently his group has been designated as a European Centre of Excellence for Rheumatology Research. Professor Steven Edwards is the Professor of Biochemistry at the Institute of Integrative Biology, University of Liverpool.

News Article | December 6, 2016
Site: www.eurekalert.org

New research from the University of Liverpool has identified the role of a specific protein in the human body that can help prevent the survival and spread of eye cancer, by initiating cancer 'cell-suicide'. The new findings may help revolutionise the approach to metastatic uveal melanoma (UM) - a cancer that arises from the pigment cells (melanocytes) in the eye, and for which there is currently no effective treatment. Metastasis is the spread of a cancer or other disease from one organ or part of the body to another without being directly connected with it. This occurs in about half of the patients with UM. Although rare, UM is the most common primary eye cancer in adults. While the primary tumour can often be treated very effectively, up to 50% of patients develop metastases most often in the liver, for whom no effective therapy is available. Apoptosis, or programmed cell death, is a rapid and irreversible process to efficiently eliminate dysfunctional cells. A hallmark of cancer is the ability of malignant cells to evade apoptosis. Dr Luminita Paraoan, from the University's Department of Eye and Vision Science in the Institute of Ageing and Chronic Disease, has published new findings in the British Journal of Cancer that identify the requirement of a protein called p63 for the initiation of apoptosis in UM. Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of each chromosome. One part of chromosome 3 contains the gene for the protein p63. Unfortunately people with aggressive (resistant to apoptosis) UM do not have this part and therefore do not have the p63 protein. Dr Paraoan's research found that if the p63 gene is used in combination with another gene, called p53, they can effectively target UM and start the process of apoptosis in the cancerous cells. The p53 gene is from a class of genes called tumour suppressors which are mutated in cases of cancer. Tumour suppressor genes are protective genes. Normally, they limit cell growth by monitoring how quickly cells divide into new cells, repairing damaged DNA, and controlling when a cell dies. When a tumour suppressor gene is mutated, for example in cancer cases, cells grow uncontrollably and may eventually form a mass called a tumour. Therefore p53 itself is ineffective in starting the process of apoptosis of cancer calls in UM. Of her research Dr Luminita said: "The study highlights for the first time the requirement of p63 in the initiation of apoptosis in UM". "Our findings have broad-ranging implications for other cancers in which apoptosis is evaded or is problematic. They will hopefully prove advantageous in designing therapeutic approaches to cancerous tumours that are currently resistant to chemotherapy and radiotherapy." The paper, entitled 'p63 is required beside p53 for PERP-mediated apoptosis in uveal melanoma', can be found here.

News Article | November 21, 2016
Site: www.newscientist.com

Artist Nick Laessing has been learning more than is entirely healthy about the internal workings of motor vehicles. He has been spurred on by the myths surrounding water-powered cars, a notion first cooked up in Dallas in 1935 that has powered conspiracy theories and investment frauds ever since. Laessing insists I climb in among the boxes and dials that half-fill the front passenger seat of his humble VW Golf. We’re in Liverpool, where his Water Gas Car is being exhibited in No Such Thing as Gravity, an art show that curator Rob La Frenais says reveals the shape of science by mapping “where the relation between data and knowledge is uncertain”. There’s mischief here: Agnes Meyer-Brandis’s 2010 video Studies in Applied Falling makes a seamless and hard-to-spot nonsense of astronaut David Scott’s famous experiment, in which he dropped a hammer and a feather together in the airless environment of the moon. Nevertheless, La Frenais, who used to curate for the London-based art-science organisation Arts Catalyst, is adamant that his show is not about pseudoscience: “It is about those areas where science is still a developing body of knowledge,” he explains. “It lets people ask naive questions about science and not feel embarrassed.” Laessing’s car is a case in point. No one, however well-informed, really knows whether water-gas cars have a future. Laessing’s on-board technology isn’t going to set the markets alight, but it does work, harvesting hydrogen fuel from water through solar-powered electrolysis. Tania Candiani’s lovingly recreated 17th-century flying machine also works – up to a point. At least, she has ridden it through the hull of a jumbo jet in free fall, and lived to film the tale. What was, centuries ago, a serious technical effort becomes, in light of subsequent knowledge, a touching and amusing entertainment. Nearby, an installation called Heirloom stands this formula on its head. Artist Gina Czarnecki and John Hunt at the University of Liverpool’s Institute of Ageing and Chronic Disease have produced an extraordinary living artwork that promises one day to become a useful technology. Living portraits of Gina’s two daughters are being grown on glass casts from cells collected from inside their mouths. Over time, the cells will grow to the thickness of tissue paper. The surgical possibilities for custom-shaped grafts are considerable, if still far off. A correctly curved graft means a more natural fit for the client, with less scarring and less disfigurement. Meanwhile, as we wait for the technology to improve, Czarnecki’s haunting portraits raise natural (though perhaps too obvious) questions about biological ownership and identity. Sometimes, scientific advances throw up questions that only art can answer. Two artists in the show explore near-death experiences. Sarah Sparkes is interested in the psychology of the phenomenon, recreating a classic experiment in generating uncanny sensations. Push a lever, and a rod pokes you in the back. Fair enough. Now push the lever again, and the rod pokes you in the back a split-second later. An irresistible suspicion arises that you are communicating with a hidden presence. Helen Pynor, by contrast, explores the way in which advances in resuscitation medicine have increased the frequency of near-death experiences. This has led her to make artworks that challenge the tricky notion of a “moment of death”. Two pig hearts from an abattoir, kept alive by an artificially maintained flow of oxygenated blood, dominated her 2013 installation The Body is a Big Place. Her work displayed at FACT, The End is a Distant Memory, was inspired by a casual conversation with regeneration biologist Jochen Rink of the Max Planck Institute of Molecular Cell Biology and Genetics. During this exchange, Rink remarked that individual cells long outlive whole bodies — and that supermarket chicken would surely still contain healthy cells. Pynor’s photographic and videographic installation runs with this notion, tracing the processes that turn a live chicken into food. Plucked chickens are dignified through portraiture, while successive images of a chicken being plucked are subtly choreographed to suggest that the animal’s life is being rewound. Once fully plucked, it resembles a fetus in an egg. Pynor dignifies and personalises the meat on our plate without hysteria, and sends a shiver of memento mori down the back of all but the most insensitive visitor. It is the emotional highlight of a show that, though driven by the high purpose of getting non-scientists thinking scientifically, will probably be more remembered for its cleverness and its wit. No Such Thing as Gravity is on show at FACT arts centre, Liverpool, UK, from now to 5 February 2017

West M.A.,University of Liverpool | West M.A.,Institute of Ageing and Chronic Disease | West M.A.,National Health Research Institute | Parry M.G.,University of Liverpool | And 6 more authors.
British Journal of Surgery | Year: 2014

Background This study investigated the relationship between objectively measured physical fitness variables derived by cardiopulmonary exercise testing (CPET) and in-hospital morbidity after rectal cancer surgery. Methods Patients scheduled for rectal cancer surgery underwent preoperative CPET (reported blind to patient characteristics) with recording of morbidity (recorded blind to CPET variables). Non-parametric receiver operating characteristic (ROC) curves and logistic regression were used to assess the relationship between CPET variables and postoperative morbidity. Results Of 105 patients assessed, 95 (72 men) were included; ten patients had no surgery and were excluded (3 by choice, 7 owing to unresectable metastasis). Sixty-eight patients had received neoadjuvant treatment. ROC curve analysis of oxygen uptake (VËo2) at estimated lactate threshold (θ^L) and peak VËo2 gave an area under the ROC curve of 0·87 (95 per cent confidence interval 0·78 to 0·95; P < 0·001) and 0·85 (0·77 to 0·93; P < 0·001) respectively, indicating that they can help discriminate patients at risk of postoperative morbidity. The optimal cut-off points identified were 10·6 and 18·6 ml per kg per min for VËo2 at θ^L and peak respectively. Conclusion CPET can help predict morbidity after rectal cancer surgery. Practical, useful and worthwhile © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

PubMed | Shinshu University and Institute of Ageing and Chronic Disease
Type: Journal Article | Journal: Royal Society open science | Year: 2016

During walking, variability in step parameters allows the body to adapt to changes in substrate or unexpected perturbations that may occur as the feet interface with the environment. Despite a rich literature describing biomechanical variability in step parameters, there are as yet no studies that consider variability at the body-environment interface. Here, we used pedobarographic statistical parametric mapping (pSPM) and two standard measures of variability, mean square error (m.s.e.) and the coefficient of variation (CV), to assess the magnitude and spatial variability in plantar pressure across a range of controlled walking speeds. Results by reduced major axis, and pSPM regression, revealed no consistent linear relationship between m.s.e. and speed or m.s.e. and Froude number. A positive linear relationship, however, was found between CV and walking speed and CV and Froude number. The spatial distribution of variability was highly disparate when assessed by m.s.e. and CV: relatively high variability was consistently confined to the medial and lateral forefoot when measured by m.s.e., while the forefoot and heel show high variability when measured by CV. In absolute terms, variability by CV was universally low (less than 2.5%). From these results, we determined that variability as assessed by m.s.e. is independent of speed, but dependent on speed when assessed by CV.

News Article | October 26, 2016
Site: www.eurekalert.org

New research from the University of Liverpool highlights problems impacting on the cognitive development of children in sub-Saharan Africa. Cognitive function includes a wide range of processes including perception, memory, attention and behavioural control, with some of these processes not being fully developed until early adulthood. Over a period of two-and-a-half years researchers from the University's Institute of Ageing and Chronic Disease, led by Dr Paul Knox, studied the longitudinal development of children in the city of Blantyre, Malawi, who had suffered from cerebral malaria (one of the severest forms of malaria) and compared them to local children who had not. Malaria presents a substantial global health challenge, with an estimated annual incidence of approximately two million cases and over 600,000 deaths per year. Most deaths occur in children under five years of age, particularly in sub-Saharan Africa. To assess the children, a particular type of eye movement test, the anti-saccade test, was used. The participant fixates on a small, central, dot; a second dot is then presented to either left or right of centre. The participant has to make a saccadic eye movement away from the target dot. For example, if the target is on the left, the participant looks to the right. The proportion of errors (occasions on which the dot is looked at) is closely related to key aspects of cognitive function, allowing performance to be tracked over time, and compared between groups. While the performance of children who had suffered from cerebral malaria in the past was expected to be worse than children who had not, results revealed that both the performance and development of children who had survived cerebral malaria without epilepsy or other severe complications, was indistinguishable to that of controls. However, the results also showed that all of the children from Blantyre performed much worse than expected, based on other published data. Dr Paul Knox, said: "Our research suggests that factors beyond cerebral malaria are affecting cognitive development in this population as a whole. Real progress is being made in tackling malaria. But this study is a reminder that we need to know more about factors such as nutrition, other diseases, and even environmental factors like cooking smoke, that impact on child development." The research was carried out in the Queen Elisabeth Central Hospital in Blantyre, Malawi, as part of the Malawi-Liverpool Wellcome Trust Clinical Research Programme. MLW is an internationally leading health research institution led by Malawian & International Scientists, pursuing scientific excellence and improving the health of people in sub-Saharan Africa. The study, entitled 'Longitudinal Visuomotor Development in a Malaria Endemic Area: Cerebral Malaria and Beyond', has been published in the PLOS ONE journal. The full study can be found here http://journals.

News Article | April 25, 2016
Site: www.biosciencetechnology.com

Researchers from the University of Liverpool have identified a specific gene that plays a key role in an inherited eye disorder. The discovery solves a 20 year-old puzzle for a family in Liverpool who all developed epithelial recurrent erosion dystrophy (ERED), a genetic corneal dystrophy disorder that causes abnormality of the outer layer of the eye. Corneal dystrophies may not cause symptoms in some individuals; in others they may cause significant vision impairment. These disorders are caused by many different genes some of which are known but many have yet to be identified. The Liverpool family, Ridland and Kadiri, first met Professor Colin Willoughby, from the University's Institute of Ageing and Chronic Disease (IACD), when he was a junior doctor and corneal fellow at St. Paul's Eye Unit in 1996. They had a type of corneal dystrophy, as yet unidentified, which caused spontaneous, recurrent, painful scratches on the cornea from early life. In discussion with New Zealand-based Opthalmologist, Dr. Andrea Vincent, Professor Willoughby learnt that there were similar families in New Zealand and Australia. Working together they sought to characterize the gene responsible for this particular disorder by using genomics. Professor Willoughby, said: "Technological advances in the clinic and laboratory have allowed us a greater appreciation of the observable physical or biochemical characteristics of an organism and the genetic diversity of corneal dystrophies. "As a result of this study we are now able to offer a genetic diagnosis of the disease before the actual symptoms of the disease have appeared. We can also give advice to parents concerning the risks associated with this disorder in a child." Epithelial recurrent erosion dystrophy (ERED) is a rare form of superficial corneal dystrophy which affects the clear window on the front of the eye. Patients develop recurrent, painful scratches on the cornea damaging its outermost layer and healing with a scar. These erosions which usually commence in childhood are painful and lead to intense light sensitivity and reduced vision. Laser treatment can help alleviate the symptoms and although this does not cure the disease it does slow it down. No treatments are available to correct the genetic defect at the present time. Lecturer in Cell and Molecular Biology at the University's Department of Eye and Vision Science (IACD), Dr Kevin Hamill, said: "The protein identified in this study is called collagen 17 and it has a pivotal role in the skin. And, from this study, the eye. Understanding the function of these types of proteins have broader implications for wound healing in the body and scarring in the eye. "This work shows the power of genomics and success of the unique research environment here at the Institute of Ageing and Chronic Disease for studying the genetics and biology of eye disease."

McDonagh B.,Institute of Ageing and Chronic Disease | Sakellariou G.K.,Institute of Ageing and Chronic Disease | Smith N.T.,Institute of Ageing and Chronic Disease | Brownridge P.,University of Liverpool | Jackson M.J.,Institute of Ageing and Chronic Disease
Journal of Proteome Research | Year: 2014

The molecular mechanisms underlying skeletal muscle aging and associated sarcopenia have been linked to an altered oxidative status of redox-sensitive proteins. Reactive oxygen and reactive nitrogen species (ROS/RNS) generated by contracting skeletal muscle are necessary for optimal protein function, signaling, and adaptation. To investigate the redox proteome of aging gastrocnemius muscles from adult and old male mice, we developed a label-free quantitative proteomic approach that includes a differential cysteine labeling step. The approach allows simultaneous identification of up-and downregulated proteins between samples in addition to the identification and relative quantification of the reversible oxidation state of susceptible redox cysteine residues. Results from muscles of adult and old mice indicate significant changes in the content of chaperone, glucose metabolism, and cytoskeletal regulatory proteins, including Protein DJ-1, cAMP-dependent protein kinase type II, 78 kDa glucose regulated protein, and a reduction in the number of redox-responsive proteins identified in muscle of old mice. Results demonstrate skeletal muscle aging causes a reduction in redox-sensitive proteins involved in the generation of precursor metabolites and energy metabolism, indicating a loss in the flexibility of the redox energy response. Data is available via ProteomeXchange with identifier PXD001054. © 2014 American Chemical Society.

Noble P.,University of Liverpool | Singer E.R.,Institute of Ageing and Chronic Disease | Jeffery N.S.,Institute of Ageing and Chronic Disease | Jeffery N.S.,University of Liverpool
Journal of Anatomy | Year: 2016

Sagittal fractures of the first phalanx are a common, potentially catastrophic injury in racehorses. These fractures are often linked to an acute, one time, biomechanical event; however, recent evidence implies that chronic exposure to stress can lead to the accumulation of bony changes that affect the structural integrity of the bone and increase the likelihood of fracture. The aim of the study was to compare variations of two common metrics of bone adaptation – subchondral bone density and thickness across the proximal articular surface of the first phalanx in Thoroughbred horses that (1) raced but never experienced a first phalanx fracture (Raced Control); (2) raced and had experienced fracture of the contralateral first phalanx (Contralateral to Fracture); (3) had never raced or experienced a first phalanx fracture (Unraced Control). A total of 22 first phalangeal bones were sampled post-mortem and imaged using micro-computed tomography calibrated for mineral density measures. Measurements of volumetric subchondral bone mineral density and thickness were taken from images at five sites from medial to lateral, in three coronal planes (25, 50 and 75% dorsal-palmar). At each of the 15 sites, measurements were repeated and averaged across 10 adjacent micro-computed tomography slices of bone, spanning 0.75 mm. The magnitude and variance of these measurements were compared between sites and between cohorts with non-parametric statistical tests. Across the proximal osteochondral surface of the first phalanx, the pattern of subchondral bone volumetric bone mineral density and thickness varied with each coronal section studied. The subchondral bone thickness was greater for the central and dorsal coronal sections, compared with the palmar section. For the race-fit groups (Raced Control and Contralateral to Fracture), the highest volumetric bone mineral density was in the central sagittal groove. The volumetric bone mineral density was significantly greater in the sagittal groove in the central coronal section in the raced than the unraced group. The Contralateral to Fracture group demonstrated significantly greater variance of volumetric bone mineral density compared with the Raced Control and Unraced Control (P < 0.0001), with no difference in variance noted between the Raced Control and Unraced Control groups. There was a small (R rank = 0.3) but significant correlation between subchondral bone volumetric bone mineral density and thickness in the Contralateral to Fracture group (P = 0.005). The findings demonstrate that differences exist in subchondral bone volumetric bone mineral density and thickness across the proximal osteochondral surface of the equine first phalanx in horses with different training histories. The findings also demonstrate that the subchondral bone of the sagittal groove of the equine first phalanx adapts to race-training in the race-fit groups (Raced Control and Contralateral to Fracture) with an increase in volumetric bone mineral density relative to unraced controls. Within the race-trained groups, the Contralateral to Fracture bones had a greater variance of volumetric bone mineral density, suggesting that stress-induced bone adaptation had become more erratic, potentially contributing to the aetiology of sagittal fractures of the first phalanx in the Thoroughbred racehorse. © 2016 Anatomical Society

Cachinho S.C.P.,Institute of Ageing and Chronic Disease | Pu F.,Institute of Ageing and Chronic Disease | Hunt J.A.,Institute of Ageing and Chronic Disease
Journal of Biomedical Materials Research - Part A | Year: 2013

The failure of implanted medical devices can be associated with changes in the production of cytokines by cells of the immune system. Cytokines released by peripheral blood mononuclear cells upon contact with metal particles were quantified to understand their role in implantation intergration and their importance as messengers in the recruitment of T-lymphocytes at the implantation site. Opsonization was utilised to understand the influence of serum proteins on particle-induced cytokine production and release. Different metal compositions were used in the particulate format, Titanium (Ti), Titanium alloy (Ti6Al4V), and Stainless Steel 316L (SS), and were cultured in vitro with a mixed population of monocytes/macrophages and lymphocytes. The cells were also exposed to an exogenous stimulant mixture of phytohemagglutinin-P and interferon-gamma (IFN-c) and opsonized particles with human serum. Interleukins, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IFN-γ, and tumor necrosis factor-alpha (TNF-α) were investigated using enzyme-linked immunosorbent assay as they are an indicator of the inflammation evoked by particulate metals. It has been experimentally evidenced that metal particles induced higher amounts of IL-6 and IL-1 but very low amounts of TNF-α. T-lymphocyte activation was evaluated by the quantification of IL-2 and IFN-γ levels. The results showed that nonopsonized and opsonized metal particles did not induce the release of increased levels of IL-2 and IFN-γ. © 2013 WILEY PERIODICALS, INC.

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