News Article | December 2, 2016
Newcastle scientists and medics have developed a promising new test to identify patients with a rare liver disease who will not respond to standard treatment, allowing earlier intervention with alternatives. Primary Biliary Cholangitis (PBC which was previously known as Primary Biliary Cirrhosis) is a long-term, auto-immune condition which causes injury to bile ducts within the liver, causing fatigue, itchy skin, poor memory and concentration. It can lead to liver fibrosis, cirrhosis and liver failure. Of patients with the condition, 70% respond to treatment, however for the remaining 30% the tablets - Ursodeoxycholic acid - do not work and this is not known until after a year of treatment. The new test has identified a gene signature related to the immune response in the liver tissue of patients with high risk disease, including the senescence marker p21WAF1/Cip. Using the NanoString nCounter digital expression platform, standard liver biopsies taken at diagnosis can be directly and rapidly screened for this gene signature. The team are looking to work with industry to develop this as a companion diagnostic test which alongside a new treatment would determine its applicability to a specific patient. Publishing the work in e-biomedicine, lead author Dr Lucy Walker from the Institute of Cellular Medicine at Newcastle University said: "This NanoString test would be easy to introduce into a clinical setting as it needs no separate samples. "Our initial results show the technique provides a reliable indicator of a patient's likelihood of failing to respond to the standard treatment. "This means medical teams could intervene earlier with alternative treatments, increasing the chances of success and perhaps staving off the need for a liver transplant." In patients with PBC, the body thinks that the bile ducts within the liver are foreign objects and tries to destroy the lining to these ducts. These bile ducts are designed to allow the flow of bile from the liver, so damage of these ducts leads to poor drainage of bile acids. The bile acids then leak from the bile ducts, damaging surrounding liver cells, which then causes inflammation and scarring in the liver. PBC is relatively rare affecting up to 1 in 3-4,000 people and of those 9 out of 10 are women. While there is a genetic element to PBC, it is thought to be within the auto-immune family of conditions and experts do not yet know what causes PBC or what can cure it. In the early stages of the disease, PBC often doesn't cause any symptoms and many people are only diagnosed during tests carried out for another reason. Developed at the NanoString facility within the Faculty of Medical Sciences at Newcastle University, the test raises questions about PBC as lead author, Dr Lucy Walker, explains: "As we have identified a separate gene expression for those with high-risk PBC, it raises the possibility that PBC may actually be two separate conditions with very similar symptoms. This is something we will be examining further in future, larger studies." This study only examined samples from a small group of patients (13) and a further study into a larger group to validate the results will begin shortly. The work was funded by the Medical Research Council. Dave Jones, Professor of Liver Immunology and co-author on the paper said: "Currently patients with high-risk PBC may be offered immunotherapies, however, these have mixed results and it may be that often the aggressive nature of the condition in high-risk patients means that even as the treatment starts the condition has created too much damage in the liver. "A test which could identify those who would benefit from treatment and provide earlier intervention may increase the possibilities of success." This test has emerged from the unique collaboration of healthcare expertise and research excellence at the CRESTA clinics (Clinics for Research and Service in Themed Assessment) which are led and managed by the Newcastle Hospitals and bring in expertise from Newcastle University and are supported by the NIHR Newcastle Biomedical Research Centre. The CRESTA clinic provides enhanced care for patients with PBC through a 'one-stop' multidisciplinary visit to better serve the needs of a diverse patient population, ranging from young working mums to older patients with complex needs. The clinic is also geared for recruitment of such patients for participation in early phase trials - Newcastle is one of the world's leading centres for trials of new therapy in PBC. This is part of the Newcastle Academic Health Partners, a collaboration involving Newcastle Upon Tyne Hospitals NHS Foundation Trust, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University. This partnership harnesses world-class expertise to ensure patients benefit sooner from new treatments, diagnostics and prevention strategies. People who have symptoms of PBC (Primary Biliary Cholangitis previously known as Primary Biliary Cirrhosis) may experience:
Gomez R.,Institute of Cellular Medicine |
Villalvilla A.,Autonomous University of Madrid |
Largo R.,Autonomous University of Madrid |
Gualillo O.,University of Santiago de Compostela |
Herrero-Beaumont G.,Autonomous University of Madrid
Nature Reviews Rheumatology | Year: 2015
Osteoarthritis (OA), the most common rheumatic disease, is characterized by joint-space narrowing due to progressive cartilage degradation and alterations in subchondral bone and the synovial membrane. These articular disturbances can have severe consequences, including pain, disability and loss of joint architectural integrity. Although the aetiology of OA is not understood, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by damage-associated molecules are thought to be involved. In this Review, we examine the relationship between Toll-like receptor 4 (TLR4) and OA in cartilage as well as in other OA-affected tissues, such as subchondral bone and synovium. We also discuss the different TLR4 agonists associated with OA and their effects in joint tissues. Finally, we describe existing and novel strategies that might be used to develop TLR4-specific disease-modifying OA drugs (DMOADs). © 2015 Macmillan Publishers Limited.
Jackson M.J.,Institute of Cellular Medicine |
Ivaz S.L.,University College London
Current Opinion in Urology | Year: 2015
Purpose of review: This article walks through some of the ideas behind patient-reported outcome measurement and quality of life research against the backdrop of urethral stricture disease and conditions of the lower urinary tract more generally, why measurement matters at all, future areas for research and development and potential opportunities for misuse and manipulation. Recent findings: It is the authors' opinion that only one published study has substantially advanced our understanding of the way men with urethral stricture disease manage this condition in the real world, and, in turn, the outcomes those men seek when they consent to surgery and its associated risks. There is, however, almost certainly greater acceptance now by reconstructive urologists of the utility of patient-reported outcome measures in audit; surgical performance evaluation; clinical research; and fair, logical and transparent healthcare resource allocation at a population level. This is evidenced by the recent proliferation of studies incorporating patient-reported outcomes, which appear today to be on parity at least with those that surgeons historically gave priority to. Summary: The next frontier in urethral stricture disease outcomes research is a better understanding of the impact of this condition on men's daily lives. That level of insight is likely to be gained through a mixture of qualitative and quantitative research methods applied to collaborative research ventures with men with the condition who, as those that have the most to gain and lose, must be majority stakeholders in this process. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Chakraborty J.B.,Institute of Cellular Medicine |
Mann D.A.,Institute of Cellular Medicine
Journal of Hepatology | Year: 2010
NF-κB is a dimeric transcription factor that has emerged as an important regulator of liver homeostasis and is mechanistically implicated in a variety of liver pathologies including hepatitis, steatosis, fibrosis, and hepatocellular carcinoma. The question remains as to whether NF-κB can really be exploited for the development of therapeutics for these pathologies in the diseased human liver. This review casts a critical eye on the experimental evidence gathered to date and in particular questions the rationale for the current focus on components of the upstream IKK complex as therapeutic targets. We make the argument that translation of NF-κB biology to new therapies is more likely to emerge from a re-focus of basic research back to the NF-κB/Rel subunit functions and the complexities of their post-translational modifications and context-dependent co-regulator interactions. © 2009 European Association for the Study of the Liver.
Anstee Q.M.,Institute of Cellular Medicine |
Day C.P.,Institute of Cellular Medicine
Nature Reviews Gastroenterology and Hepatology | Year: 2013
NAFLD is a disease spectrum ranging from simple steatosis, through steatohepatitis to fibrosis and, ultimately, cirrhosis. This condition is characterized by considerable interpatient variability in terms of severity and rate of progression: although a substantial proportion of the population is at risk of progressive disease, only a minority experience associated morbidity. As such, NAFLD is best considered a complex disease trait resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers. Much ongoing research is focused on identifying the genetic factors that contribute to NAFLD pathogenesis. This Review describes the current status of the field, discussing specific genetic and epigenetic modifiers, including the mechanisms through which genes identified by genome-wide association studies, including PNPLA3, influence disease progression. © 2013 Macmillan Publishers Limited. All rights reserved.
Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via gremlin protein
O'Reilly S.,Institute of Cellular Medicine |
Ciechomska M.,Institute of Cellular Medicine |
Cant R.,Institute of Cellular Medicine |
Van Laar J.M.,Institute of Cellular Medicine
Journal of Biological Chemistry | Year: 2014
Fibrosis is a common and intractable condition associated with various pathologies. It is characterized by accumulation of an excessive amount of extracellular matrix molecules that primarily include collagen type I. IL-6 is a profibrotic cytokine that is elevated in the prototypic fibrotic autoimmune condition systemic sclerosis and is known to induce collagen I expression, but the mechanism(s) behind this induction are currently unknown. Using healthy dermal fibroblasts in vitro, we analyzed the signaling pathways that underscore the IL-6-mediated induction of collagen. We show that IL-6 trans signaling is important and that the effect is dependent on STAT3; however, the effect is indirect and mediated through enhanced TGF-β signaling and the classic downstream cellular mediator Smad3. This is due to induction of the bone morphogenetic protein (BMP) antagonist Gremlin-1, and we show that Gremlin-1 is profibrotic and is mediated through canonical TGF-β signaling. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
O'Reilly S.,Institute of Cellular Medicine
Clinical science (London, England : 1979) | Year: 2014
The innate immune system is a critical part of the response to pathogens and overall immunity. Compared with the adaptive immune response, these innate responses are not antigen-specific and recognize patterns in bacteria, viruses and fungi. Chief among these are TLRs (Toll-like receptors). TLRs are PRRs (pattern recognition receptors) that are germ-line-encoded and are also able to recognize endogenous molecules that are released upon cell damage or stress and have been demonstrated to have a key role in numerous autoimmune diseases, including RA (rheumatoid arthritis) and SSc (systemic sclerosis). SSc is an autoimmune disorder in which vascular injury occurs and there is a chronic low-grade inflammation followed by excessive ECM (extracellular matrix) deposition and ultimately fibrosis. The fibrosis ultimately leads to organ dysfunction and death. The preceding vascular damage and activation of the innate immune system leads to mobilization of the innate lymphoid cells and the up-regulation of multiple genes and pro-fibrotic cytokines. These locally released cytokines activate resident fibroblasts to differentiate into myofibroblasts. The aim of the present review is to explore the role of the innate immune system in SSc and TLRs and how these interact with stromal cells to produce fibrosis. Targeting the innate immune system or specific components of the TLR signalling cascade may be a novel therapeutic option in what is an incurable disease.
Ciechomska M.,Institute of Cellular Medicine
Expert reviews in molecular medicine | Year: 2013
Accumulative evidence demonstrates the crucial role of evolutionary conserved Toll-like receptors (TLRs) in identifying microbial or viral compounds. TLRs are also able to recognise endogenous molecules which are released upon cell damage or stress and have been shown to play a key role in numerous autoimmune diseases including systemic sclerosis (SSc). A classic feature of SSc, is vascular injury manifested as Raynaud's phenomenon and ischaemia of the skin, resulting in the release of endogenous TLR ligands during inflammation and local tissue damage. These locally released TLR ligands bind TLRs possibly complexed to autoantibodies, and initiate intracellular signalling pathways and may be one of the mechanisms that initiate and drive autoimmunity and subsequent fibrosis. Activation of the immune system results in interferon (IFN) sensitive gene transcription. There is also an IFN gene signature in SSc peripheral blood. TLRs may represent the link between immune activation, common in SSc, and tissue fibrosis. Therefore, a better understanding of the mechanisms of TLR-mediated pathogenesis and therapies targeting individual TLRs, may provide a more specific approach of treating multi-systemic autoimmune diseases. This review aims to integrate the current knowledge of TLR function in the autoimmune disorders with particular emphasis on SSc. We suggest the TLR system as a new therapeutic target.
O'Reilly S.,Institute of Cellular Medicine
Clinical Science | Year: 2015
Damage-associated molecular patterns (DAMPs) are chemically heterogeneous endogenous host molecules rapidly released from damaged or dying cells that incite a sterile inflammatory response mediated via pattern recognition receptors (PRRs). The sources of DAMPs are dead or dying cells or the extracellular matrix and can signal through the PRRs, the Toll-like receptors or cytosolic Nod-like receptors, culminating in nuclear factor κB (NF-κB) activation and pro-inflammatory cytokine secretion. Together, these molecules are involved in sterile inflammation and many are associated with rheumatic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythromatosus, psoriatic arthritis and systemic sclerosis. These diseases are associated with inflammation and many danger signals are found in sites of sterile inflammation and mediate inflammation. The present review examines the role of DAMPs in rheumatic conditions and suggests avenues for their therapeutic modulation. © 2015 Biochemical Society.
Tyndall A.,University of Basel |
Van Laar J.M.,Institute of Cellular Medicine
Best Practice and Research: Clinical Rheumatology | Year: 2010
Autologous haematopoietic stem cell transplantation in patients with rheumatoid arthritis (RA) resulted in a positive short-term outcome clinically with low treatment-related toxicity. However, early conditioning regimens were of low immunoablative intensity and most patients relapsed. Mechanistic studies suggest that residual lesional effector cells may have been responsible for the relapses. The introduction of biopharmaceuticals has, for the moment, reduced the need for further experimental studies. Juvenile idiopathic arthritis patients, mostly of the systemic subgroup, have shown nearly 33% durable drug-free remission, but with significant toxicity, including fatal macrophage-activation syndrome early in the programme. Later modifications to the protocol have reduced this toxicity. Mesenchymal stem cells (MSCs), derived from several sources including bone marrow and adipose tissue, are being tested as tissue-regenerative and immunomodulating agents in many autoimmune diseases and animal models of inflammatory arthritis have been positive. MSCs and other stromal cells derived from actively inflamed synovium and peripheral blood of RA patients do not always demonstrate a full range of differentiation potential compared with healthy MSCs, although their immunomodulalatory capacity is unimpaired. © 2010 Elsevier Ltd. All rights reserved.