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The incidence of bile duct cancer (cholangiocarcinoma) is increasing year on year throughout the world. More than 2,500 people will be diagnosed with this cancer in the UK in the next year and for most this will be a lethal diagnosis. Fewer than 5% will survive for 12 months – an appalling statistic which hasn’t changed in decades.   In light of this, UK’s leading charity dedicated to bile duct cancer, AMMF, will bring together scientists, researchers, medics and patients from across the globe at its third Conference and Information Day dedicated exclusively to bile duct cancer, on 11 May, 2017 at the Radisson Blu Hotel, Stansted Airport, Essex.   Amongst AMMF-funded researchers who will be presenting updates on their work at this year’s AMMF Conference, will be Professor Stuart Forbes from the MRC Centre for Regenerative Medicine, explaining his research into the signals Wnt and Notch which are thought to drive the growth of cholangiocarcinoma. In addition, Dr Luke Boulter from Edinburgh’s Institute of Genetics & Molecular Medicine will be discussing his very promising work, “Discovering driver mutations in cholangiocarcinoma using forward genetics”.   The work of both these teams, if successful, could bring closer some ‘game changing’ treatment targets for cholangiocarcinoma.   This year’s Conference also sees Professor Narong Khuntikeo from Khon Kaen University, Thailand presenting the work of the CASCAP (Cholangiocarcinoma Screening and Care Program) team in north east Thailand, which has the world’s highest incidence of cholangiocarcinoma. Professor Khuntikeo is vice-president of the Cholangiocarcinoma Foundation of Thailand and recipient of The Royal College of Surgeons of Thailand Outstanding Surgeon Honours Award 2016.   Conference to highlight latest surgical treatments and targeted therapies for bile duct cancer   Other topics to be addressed at this year’s Conference will include the latest surgical developments in the treatment of bile duct cancer, updates on clinical trials, and the status of targeted therapies for cholangiocarcinoma.   Helen Morement, founder and CEO of the AMMF explains, “Although bile duct cancer is the second most common primary liver cancer in the world, with an increasing incidence globally, and despite its appalling survival rates due to late diagnosis and few treatment options, it remains poorly understood and under researched. The Conference is a key platform for an international panel of experts to share news and information about clinical studies and latest research. The findings bring the prospect of early diagnosis and more effective treatments one step closer.”   Helen continues, “We are especially delighted that Professor Richard Syms from Imperial College London, who is also working collaboratively with the team at Khon Kaen University on an AMMF-funded internal imaging project, will be presenting the positive early results of this work at the Conference.”   Bile duct cancer is a rare cancer that occurs in the bile duct in or outside the liver. With few noticeable and often misunderstood symptoms, this disease is frequently diagnosed too late for surgery, the only potentially curative treatment. Without treatment fewer than 5% of patients will survive beyond 12 months. Cases of bile duct cancer have risen steeply and steadily across the world over the past decades. According to the recent NCIN/Cancer52 report, 2,161 people died in 2013 from this disease in England alone.   About AMMF AMMF (The Alan Morement Memorial Fund) was founded and registered as a charity with the Charity Commission in 2002 (registered charity no 1091915). AMMF is the UK’s only cholangiocarcinoma charity, dedicated to tackling this devastating cancer on all fronts: providing information and support, campaigning to raise awareness, and encouraging and supporting research.   In recent years an enormous and extremely worrying worldwide increase in cholangiocarcinoma’s incidence has been noted. Latest figures show there were 2,161 deaths caused by cholangiocarcinoma in 2013 in England alone (NCIN/Cancer52 report). The incidence appears to be increasing across all age groups, including younger people, and the cause of this ongoing increase is unknown. Much more research is desperately needed.   AMMF is dedicated to bringing about improvement for the cholangiocarcinoma patient, working closely throughout the UK with patients, families, carers, clinicians, healthcare professionals, researchers, politicians and policy makers. For more information visit: www.ammf.org.uk (registered charity no.1091915).   About the Conference & Information Day AMMF is not making a charge for attendance at the conference; it is open to all who have an interest in cholangiocarcinoma. However, if delegates would like to help to offset costs, a suggested donation of £25 per head can be made to the AMMF 2017 Conference Justgiving Page by clicking here: https://www.justgiving.com/fundraising/AMMF-Charity2   About the MRC Centre for Regenerative Medicine at the University of Edinburgh The MRC Centre for Regenerative Medicine (CRM) is a research institute based at the University of Edinburgh. Scientists and clinicians study stem cells, disease and tissue repair to advance human health. For more information please visit: http://www.crm.ed.ac.uk/   About the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh (IGMM). The MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh (IGMM), formed in 2007, is a strategic partnership of the: • MRC Human Genetics Unit (MRC HGU) • Cancer Research UK Edinburgh Centre (CRUK EC) • Centre for Genomic and Experimental Medicine (CGEM).   The IGMM constitutes one of the largest aggregates of human molecular genetics and biology research capacity in the UK with over 70 Principal Investigators and 500 staff and PhD students. By pooling the resources and complementary skills of the constituent centres, IGMM brings together the scientific expertise, technology and support services needed to maximise scientific discovery.   The Institute enables rapid translation of basic scientific discoveries into new treatments, clinical guidelines and innovative products that have significant impact on the society in the UK and Worldwide.   For more information please visit: http://www.ed.ac.uk/igmm/about   About CASCAP (Cholangiocarcinoma Screening and Care Program), Thailand CASCAP stands for the Cholangiocarcinoma Screening and Care Program. The aim of CASCAP is to accelerate the transition of CCA from being a neglected disease to being on the public health national agenda. Its specific focus is to develop and make available a high quality database of compiled information about CCA in the region, to determine the optimal screening program for early diagnosis to maximize the success of surgical treatment, and to increasing both the quality of life and long-term survival of patients. For more information please visit http://www.cascap.info/main/index.php/about-us/about-cascap.html National Cancer Intelligence Network (NCIN) and Cancer52 For more information please visit: http://www.ncin.org.uk/publications/rare_and_less_common_cancers For media inquiries and interviews, please contact: ESTHER PORTA, 3CommPR LONDON, United Kingdom 07870439158 esther@3commpr.co.uk The post Why latest work from top UK cancer researchers could hold potential for future ‘game-changing’ treatments for rare bile duct cancer, cholangiocarcinoma appeared first on PR Fire.


Gunther C.,TU Dresden | Kind B.,TU Dresden | Reijns M.A.M.,University of Edinburgh | Berndt N.,TU Dresden | And 46 more authors.
Journal of Clinical Investigation | Year: 2015

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.


Yen J.,Wellcome Trust Sanger Institute | White R.M.,Sloan Kettering Cancer Center | Wedge D.C.,Wellcome Trust Sanger Institute | Van Loo P.,Wellcome Trust Sanger Institute | And 38 more authors.
Genome Biology | Year: 2013

Background: Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. Results: To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAFV600E or NRASQ61K driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAFV600E and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway.Conclusion: This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation. © 2013 Yen et al.; licensee BioMed Central Ltd.


Lindstrom N.O.,Roslin Institute | Lindstrom N.O.,MRC Institute of Genetics and Molecular Medicine | Lawrence M.L.,University of Edinburgh | Burn S.F.,Columbia University | And 12 more authors.
eLife | Year: 2015

The different segments of the nephron and glomerulus in the kidney balance the processes of water homeostasis, solute recovery, blood filtration, and metabolite excretion. When segment function is disrupted, a range of pathological features are presented. Little is known about nephron patterning during embryogenesis. In this study, we demonstrate that the early nephron is patterned by a gradient in β-catenin activity along the axis of the nephron tubule. By modifying β-catenin activity, we force cells within nephrons to differentiate according to the imposed β-catenin activity level, thereby causing spatial shifts in nephron segments. The β-catenin signalling gradient interacts with the BMP pathway which, through PTEN/PI3K/AKT signalling, antagonises β-catenin activity and promotes segment identities associated with low β-catenin activity. β-catenin activity and PI3K signalling also integrate with Notch signalling to control segmentation: modulating β-catenin activity or PI3K rescues segment identities normally lost by inhibition of Notch. Our data therefore identifies a molecular network for nephron patterning. © Lindström et al.


Patton E.E.,MRC Institute of Genetics and Molecular Medicine
Journal of Pathology | Year: 2012

Non-cancerous immune cells can significantly contribute to tumour progression and metastases. Neutrophils associated with tumours can both promote and inhibit tumour progression, but less is known about how non-associated immune cells contribute to cancer biology. In a recent issue of the Journal of Pathology, He and colleagues use non-invasive, high-resolution imaging of the whole living animal to provide a compelling glimpse at how physiological migration of neutrophils can prepare a metastatic niche and how their activities can be altered by the unintended consequences of targeted therapeutics. © 2012 Pathological Society of Great Britain and Ireland.


MacDonald N.P.,University of Glasgow | Zhu F.,RMIT University | Hall C.J.,University of Auckland | Reboud J.,University of Glasgow | And 4 more authors.
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2016

3D printing has emerged as a rapid and cost-efficient manufacturing technique to enable the fabrication of bespoke, complex prototypes. If the technology is to have a significant impact in biomedical applications, such as drug discovery and molecular diagnostics, the devices produced must be biologically compatible to enable their use with established reference assays and protocols. In this work we demonstrate that we can adapt the Fish Embryo Test (FET) as a new method to quantify the toxicity of 3D printed microfluidic devices. We assessed the biocompatibility of four commercially available 3D printing polymers (VisiJetCrystal EX200, Watershed 11122XC, Fototec SLA 7150 Clear and ABSplus P-430), through the observation of key developmental markers in the developing zebrafish embryos. Results show all of the photopolymers to be highly toxic to the embryos, resulting in fatality, although we do demonstrate that post-printing treatment of Fototec 7150 makes it suitable for zebrafish culture within the FET. © 2016 The Royal Society of Chemistry.


Williamson I.,MRC Institute of Genetics and Molecular Medicine | Lettic L.A.,MRC Institute of Genetics and Molecular Medicine | Hill R.E.,MRC Institute of Genetics and Molecular Medicine | Bickmore W.A.,MRC Institute of Genetics and Molecular Medicine
Development (Cambridge) | Year: 2016

Limb-specific Shh expression is regulated by the (∼1 Mb distant) ZRS enhancer. In the mouse, limb bud-restricted spatiotemporal Shh expression occurs from ∼E10 to E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation of Shh in expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies of Shh/ZRS colocalisation only in the Shh-expressing regions of the limb bud, in a conformation consistent with enhancer-promoter loop formation. However, in all tissues and at all developmental stages analysed, Shh-ZRS spatial distances were still consistently shorter than those to a neural enhancer located between Shh and ZRS in the genome. 5C identified a topologically associating domain (TAD) over the Shh/ZRS genomic region and enriched interactions between Shh and ZRS throughout E11.5 embryos. Shh/ZRS colocalisation, therefore, correlates with the spatiotemporal domain of limb bud-specific Shh expression, but close Shh and ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigate the expression of Shh. © 2016, Company of Biologists Ltd. All rights reserved.


PubMed | MRC Institute of Genetics and Molecular Medicine
Type: Journal Article | Journal: Development (Cambridge, England) | Year: 2016

Limb-specific Shh expression is regulated by the (1Mb distant) ZRS enhancer. In the mouse, limb bud-restricted spatiotemporal Shh expression occurs from E10 to E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation of Shh in expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies of Shh/ZRS colocalisation only in the Shh-expressing regions of the limb bud, in a conformation consistent with enhancer-promoter loop formation. However, in all tissues and at all developmental stages analysed, Shh-ZRS spatial distances were still consistently shorter than those to a neural enhancer located between Shh and ZRS in the genome. 5C identified a topologically associating domain (TAD) over the Shh/ZRS genomic region and enriched interactions between Shh and ZRS throughout E11.5 embryos. Shh/ZRS colocalisation, therefore, correlates with the spatiotemporal domain of limb bud-specific Shh expression, but close Shh and ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigate the expression of Shh.


PubMed | University of Auckland, RMIT University, University of Glasgow and MRC Institute of Genetics and Molecular Medicine
Type: Journal Article | Journal: Lab on a chip | Year: 2016

3D printing has emerged as a rapid and cost-efficient manufacturing technique to enable the fabrication of bespoke, complex prototypes. If the technology is to have a significant impact in biomedical applications, such as drug discovery and molecular diagnostics, the devices produced must be biologically compatible to enable their use with established reference assays and protocols. In this work we demonstrate that we can adapt the Fish Embryo Test (FET) as a new method to quantify the toxicity of 3D printed microfluidic devices. We assessed the biocompatibility of four commercially available 3D printing polymers (VisiJetCrystal EX200, Watershed 11122XC, Fototec SLA 7150 Clear and ABSplus P-430), through the observation of key developmental markers in the developing zebrafish embryos. Results show all of the photopolymers to be highly toxic to the embryos, resulting in fatality, although we do demonstrate that post-printing treatment of Fototec 7150 makes it suitable for zebrafish culture within the FET.


PubMed | MRC Institute of Genetics and Molecular Medicine
Type: Comment | Journal: The Journal of pathology | Year: 2012

Non-cancerous immune cells can significantly contribute to tumour progression and metastases. Neutrophils associated with tumours can both promote and inhibit tumour progression, but less is known about how non-associated immune cells contribute to cancer biology. In a recent issue of the Journal of Pathology, He and colleagues use non-invasive, high-resolution imaging of the whole living animal to provide a compelling glimpse at how physiological migration of neutrophils can prepare a metastatic niche and how their activities can be altered by the unintended consequences of targeted therapeutics.

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