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Gossage L.,University of Cambridge | Murtaza M.,University of Cambridge | Slatter A.F.,Babraham Research Campus | Lichtenstein C.P.,Babraham Research Campus | And 11 more authors.
Genes Chromosomes and Cancer | Year: 2014

VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P=0.023), advanced clinical stage (P=0.042) and a trend towards shorter recurrence free survival (P=0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted. © 2013 Wiley Periodicals, Inc.


Jensen L.E.,Babraham Institute | Bultynck G.,Catholic University of Leuven | Luyten T.,Catholic University of Leuven | Amijee H.,Babraham Research Campus | And 3 more authors.
Frontiers in Molecular Neuroscience | Year: 2013

Dysregulation of Ca2+ homeostasis is considered to contribute to the toxic action of the Alzheimer's disease (AD)-associated amyloid-β-peptide (Aβ). Ca2+ fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca2+ fluxes induced by Aβ42. Here, we investigated the contribution of Ca2+ release from the endoplasmic reticulum (ER) to the effects of Aβ42 upon Ca2+ homeostasis and the mechanism by which Aβ42 elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of Aβ42 induced an elevation in intracellular Ca2+. The Aβ42-stimulated Ca2+ signals persisted in the absence of extracellular Ca2+ indicating a significant contribution of Ca2+ release from the ER Ca2+ store to the generation of these signals. Moreover, inositol 1,4,5-trisphosphate (InsP3) signaling contributed to Aβ42-stimulated Ca2+ release. The Ca2+ mobilizing effect of Aβ42 was also observed when applied to permeabilized cells deficient in InsP3 receptors, revealing an additional direct effect of Aβ42 upon the ER, and a mechanism for induction of toxicity by intracellular Aβ42. © 2013 Jensen, Bultynck, Luyten, Amijee, Bootman and Roderick.


Home > Press > Kymouse success in steps to developing HIV vaccine: Kymab, the Scripps Research Institute and International AIDS Vaccine Initiative collaboration improves discovery and testing of promising HIV vaccine strategies Abstract: A new approach to developing a human vaccine against HIV has been developed by researchers at Kymab, a UK therapeutic antibody platform Company, The Scripps Research Institute (TSRI) of San Diego, California, and the International AIDS Vaccine Initiative (IAVI). HIV is one of the most intransigent targets for vaccine development, and no effective vaccine has been developed in thirty years of global research. The research, which tested the first step in an approach to develop effective vaccines against the range of HIV variants existing worldwide, is published in Science on Thursday 8 September, 2016, and was supported by funding from the International AIDS Vaccine Initiative and the US National Institutes of Health. The results show that Kymouse, which is a mouse that has been modified to mimic human antibody responses, is an effective platform for discovering and testing possible vaccines and suggest ways in which testing of vaccine candidates can be improved. "We increasingly recognize that traditional vaccine strategies will not be successful against all viruses, especially not HIV," says Dennis Burton, chair of the TSRI Department of Immunology and Microbial Science and scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center (NAC) at TSRI and the National Institutes of Health (NIH) Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). "Together with the Kymab team, we have taken a novel approach in which have induced human antibodies in Kymouse that are at the beginning of the pathway to protective antibodies and which is a huge boost to our mission to develop an HIV vaccine." The work is based on the observation that a fraction of people who become infected by HIV develop broadly neutralizing antibodies against diverse HIV strains. Such antibodies would be ideal to protect against or possibly treat HIV infection - if a vaccine could be made to elicit them. However, these antibodies originate from a limited number of precursor antibody-producing cells in the body and acquire their unusual and protective properties only during a long course of infection. Moreover, although these cells have been activated when immunizing certain biased animal models, this is the first time it has been achieved through immunization of an immune system, as in the Kymouse, that resembles the human. The researchers injected Kymouse strains with a nanoparticle formed of 60 copies of a small protein that mimics HIV and was designed to bind and stimulate the specific precursor cells for one class of broadly neutralizing antibody. They expected to find just one such precursor cell (among tens of millions of such cells) in each immunized mouse. The research team then looked to see whether or not the mice had mounted an antibody response to this injection. Given the combined challenges of a complex immunogen structure and the rarity of the right antibodies, an effective response against the HIV immunogen was elicited remarkably efficiently. "Our phenomenal results with the teams at TSRI and IAVI came from work at the boundaries of protein engineering, immunology and vaccine technology," explains Professor Allan Bradley, Chief Technical Officer at Kymab and Director Emeritus of the Wellcome Trust Sanger Institute, who developed the Kymouse platform. "Using Kymouse, we show how an advanced vaccine candidate can search out the one cell among tens of million antibody-producing cells and make it proliferate. "Kymouse can deliver antibody responses that we need to build effective HIV vaccines." The team validated their antibody response by sequencing genes from more than 10,000 cell samples, and showed that genes from responding mice had the expected sequence for precursors to broadly neutralizing antibodies against the HIV target. "It is a big step forward in this branch of HIV vaccine development," says William Schief, TSRI Professor and Director of Vaccine Design for the IAVI Neutralizing Antibody Center at TSRI, in whose lab the vaccine nanoparticle was developed. "We have the first proof of principle that this HIV vaccine strategy and our vaccine candidate can work in a human immune system and trigger the first step in the pathway to developing broadly neutralizing and protective antibodies against the virus. "It is the very sort of response we'd want to see as we test components of a future vaccine." HIV has proved an extremely difficult challenge in vaccine development. The new research shows that Kymouse can produce antibodies of the type that could evolve to confer protection, suggests ways in which the immunization regime can be improved and indicates that Kymab's technologies will support and accelerate the search for other, rarer and perhaps even more effective antibodies. "About 35 million people have died of HIV/AIDS and 36 million are currently infected. Although a vaccine is the most likely way to stem this loss, no successful vaccine has been found in more than thirty years of HIV research," says Professor Paul Kellam, Vice President of Infectious Diseases and Vaccines at Kymab. "This is a pressing need and these results show that our Kymouse technologies can serve a vital part in the search for effective vaccines that help to protect against this most challenging disease." "This dramatic proof of concept gives us hope we can find better broadly effective vaccines for HIV and, indeed, for other infections, using the human immune system to help guide us along the best path." Participating Centers Kymab Ltd, Babraham Research Campus, Cambridge, UK Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA About Don Powell Associates LTD About Kymab Kymab is a leading biopharmaceutical company focused on the discovery and development of fully human monoclonal antibody drugs using its proprietary Kymouse™ antibody platform. Kymouse™ has been designed to maximize the diversity of human antibodies produced in response to immunization with antigens. Selecting from a broad diversity of fully human antibodies assures the highest probability of finding that rare drug candidate with best-in-class characteristics. The Kymouse™ naturally matures these molecules to highly potent drugs obviating the need for further time-consuming modifications. Kymab is using the platform for its internal drug discovery programs and in partnership with pharmaceutical companies. Kymab commenced operations in 2010 and has raised over US$120m of equity financing which includes $90m Series B financing. It has an experienced management team with a successful track record in drug discovery and development and has numerous therapeutic antibody programs in immune-oncology, auto-immunity; hematology, infectious disease and other areas. www.kymab.com About The Scripps Research Institute The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu. About International Aids Vaccine Initiative (IAVI) The International AIDS Vaccine Initiative (IAVI) is a global not-for-profit organization whose mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996 and operational in 25 countries, IAVI and its network of collaborators research and develop vaccine candidates. IAVI was founded with the generous support of the Alfred P. Sloan Foundation, The Rockefeller Foundation, The Starr Foundation, and Until There's A Cure Foundation. Other major supporters include the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, The John D. Evans Foundation, The New York Community Trust, the James B. Pendleton Charitable Trust; the Governments of Canada, Denmark, India, Ireland, Japan, The Netherlands, Norway, Spain, Sweden, the United Kingdom, and the United States, the Basque Autonomous Government (Spain), the European Union as well as the National Institute of Allergy and Infectious Diseases and The City of New York, Economic Development Corporation; multilateral organizations such as The World Bank and The OPEC Fund for International Development; corporate donors including BD (Becton, Dickinson & Co.), Bristol-Myers Squibb, Continental Airlines, Google Inc., Pfizer Inc, and Thermo Fisher Scientific Inc.; leading AIDS charities such as Broadway Cares/Equity Fights AIDS; and many generous individuals from around the world. For more information, see www.iavi.org. Contacts: For Kymab Don Powell Don Powell Associates Ltd +44 (0)778 6858220 +44 (0)1223 515436 Mary Clark, Supriya Mathur and Hollie Vile Hume Brophy +44 (0)207 862 6390 For TSRI Madeline McCurry-Schmidt Science Writer The Scripps Research Institute Tel: 858-784-9254 Office of Communications The Scripps Research Institute Tel: +1 858-784-2666 Fax: +1 858-784-8118 For IAVI Arne Näveke Executive Director Advocacy, Policy, Communications International AIDS Vaccine Initiative (IAVI) +1.212.847.1055 (office) +1.646.623.47.85 (mobile) If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


Marr J.H.,Babraham Research Campus
Monthly Notices of the Royal Astronomical Society | Year: 2015

The lognormal distribution represents the probability of finding randomly distributed particles in a micro canonical ensemble with high entropy. To a first approximation, a modified form of this distribution with a truncated termination may represent an isolated galactic disc, and this disc density distributionmodelwas therefore run to give the best fit to the observational rotation curves for 37 representative galaxies. The resultant curves closely matched the observational data for a wide range of velocity profiles and galaxy types with rising, flat or descending curves in agreement with Verheijen's classification of 'R', 'F' and 'D' type curves, and the corresponding theoretical total disc masses could be fitted to a baryonic Tully-Fisher relation. Nine of the galaxies were matched to galaxies with previously published masses, suggesting a mean excess dynamic disc mass of dex 0.61 ± 0.26 over the baryonic masses. Although questionable with regard to other measurements of the shape of disc galaxy gravitational potentials, thismodel can accommodate a scenario in which the gravitational mass distribution, as measured via the rotation curve, is confined to a thin plane without requiring a dark matter halo or the use of modified Newtonian dynamics. © 2015 The Author Published by Oxford University Press on behalf of the Royal Astronomical Society.


Marr J.H.,Babraham Research Campus
Monthly Notices of the Royal Astronomical Society | Year: 2015

By postulating that the majority of the mass and angular momentum of a disc galaxy is confined to the disc with a lognormal surface density distribution, and that galactic discs are substantially, if not fully, self-gravitating, it may be shown that the resultant rotation curves (RCs) display a good overall fit to observational data for a wide range of galaxy types. With this hypothesis, the total angular momentum J, and total energy |E| of 38 disc galaxies was computed and plotted against the derived disc masses, with best fit slopes for J of 1.683±0.018 and |E| of 1.643±0.038, and a universal disc spin parameter λ=0.423±0.014. Using the disc parameters Vmax and Rmax as surrogates for the virial velocity and radius, a virial mass estimator Mdisc ∝ RmaxV 2 max was generated, with a log-log slope of 1.024 ± 0.014 for the 38 galaxies, and a proportionality constant λ* = 1.47 ± 0.20 × 105 M⊙kpc-1 km-2 s2. This relationship has less scatter than M ∝ (Vrot)α, and may provide an alternative to the Tully-Fisher relation in determining virial disc masses. © 2015 The Authors.


Breckpot J.,University Hospital Leuven | Thienpont B.,Babraham Research Campus | Arens Y.,Maastricht University | Tranchevent L.C.,Catholic University of Leuven | And 4 more authors.
Cytogenetic and Genome Research | Year: 2011

Array comparative genomic hybridization (aCGH) has led to an increased detection of causal chromosomal imbalances in individuals with congenital heart defects (CHD). The introduction of aCGH as a diagnostic tool in a clinical cardiogenetic setting entails numerous challenges. Based on our own experience as well as those of others described in the literature, we outline the state of the art and attempt to answer a number of outstanding questions such as the detection frequency of causal imbalances in different patient populations, the added value of higher-resolution arrays, and the existence of predictive factors in syndromic cases. We introduce a step-by-step approach for clinical interpretation of copy number variants (CNV) detected in CHD, which is primarily based on gene content and overlap with known chromosomal syndromes, rather than on CNV inheritance and size. Based on this algorithm, we have reclassified the detected aberrations in aCGH studies for their causality for syndromic and non-syndromic CHD. From this literature overview, supplemented with own investigations in a cohort of 46 sporadic patients with severe non-syndromic CHD, it seems clear that the frequency of causal CNVs in non-syndromic CHD populations is lower than that in syndromic CNV populations (3.6 vs. 19%). Moreover, causal CNVs in non-syndromic CHD mostly involve imbalances with a moderate effect size and reduced penetrance, whereas the majority of causal imbalances in syndromic CHD consistently affects human development and significantly reduces reproductive fitness. Copyright © 2011 S. Karger AG, Basel.


Clark J.,Babraham Research Campus | Kay R.R.,University of Cambridge | Kielkowska A.,Babraham Research Campus | Niewczas I.,Babraham Research Campus | And 5 more authors.
EMBO Journal | Year: 2014

Inositol phospholipids are critical regulators of membrane biology throughout eukaryotes. The general principle by which they perform these roles is conserved across species and involves binding of differentially phosphorylated inositol head groups to specific protein domains. This interaction serves to both recruit and regulate the activity of several different classes of protein which act on membrane surfaces. In mammalian cells, these phosphorylated inositol head groups are predominantly borne by a C38:4 diacylglycerol backbone. We show here that the inositol phospholipids of Dictyostelium are different, being highly enriched in an unusual C34:1e lipid backbone, 1-hexadecyl-2-(11Z-octadecenoyl)-sn-glycero- 3-phospho-(1'-myo-inositol), in which the sn-1 position contains an ether-linked C16:0 chain; they are thus plasmanylinositols. These plasmanylinositols respond acutely to stimulation of cells with chemoattractants, and their levels are regulated by PIPKs, PI3Ks and PTEN. In mammals and now in Dictyostelium, the hydrocarbon chains of inositol phospholipids are a highly selected subset of those available to other phospholipids, suggesting that different molecular selectors are at play in these organisms but serve a common, evolutionarily conserved purpose. © 2014 The Authors.


Euler M.,University of Gottingen | Wang Y.,Shanghai Ocean University | Nentwich O.,Babraham Research Campus | Piepenburg O.,Babraham Research Campus | And 2 more authors.
Journal of Clinical Virology | Year: 2012

Background: Detection of nucleic acids of Rift Valley fever virus (RVFV) has been shown to be useful in field diagnostics. Objectives: To develop an isothermal 'recombinase polymerase amplification (RPA)' assay on an ESEquant tubescanner device. Study design: RPA was adapted for RNA amplification by first developing a two-step and then a one-step-RT-RPA protocol. Several RT enzymes were tested and the best sensitivity was achieved using Transcriptor (Roche). Finally an RT-RPA pellet containing a recombinant MuLV was tested in RVFV one-step-RT-RPA. Results: The one-step-RT-RPA assay showed a sensitivity of 19 molecules detected as determined by probit analysis of eight runs using a RVFV S-segment based quantitative RNA standard and detected 20 different RVFV strains. The assays showed no cross detection of the human genome and several agents of a typical biothreat panel. It performed almost as good as the assay using glycerol buffer based Transcriptor albeit at a cost of 1-log10 step in sensitivity. The presented combination of one-step-RT-RPA and portable fluorescence reading device could be a useful tool for field or point of care diagnostics. © 2012 Elsevier B.V.


Breckpot J.,University Hospitals Leuven | Thienpont B.,University Hospitals Leuven | Thienpont B.,Babraham Research Campus | Gewillig M.,University Hospitals Leuven | And 3 more authors.
Molecular Syndromology | Year: 2011

Studies addressing the role of somatic copy number variation (CNV) in the genesis of congenital heart defects (CHDs) are scarce, as cardiac tissue is difficult to obtain, especially in non-affected individuals. We explored the occurrence of copy number differences in monozygotic (MZ) twins discordant for the presence of a CHD, as an illustrative model for chromosomal mosaicism in CHDs. Array comparative genomic hybridization was performed on peripheral blood-derived DNA obtained from 6 discordant MZ twin pairs and on sex-matched reference samples. To identify CNV differences between both twin members as well as potential CNVs in both twins contributing to the phenotype, DNA from each twin was hybridized against its co-twin, and against a normal control. Three copy number differences in 1 out of 6 MZ twin pairs were detected, confirming the occurrence of somatic CNV events in MZ twins. Further investigation by copy number and (epi)genome sequencing analyses in MZ twins, discordant for the presence of CHDs, is required to improve our knowledge on how postzygotic genetic, environmental and stochastic factors can affect human heart development. © 2012 S. Karger AG, Basel.


Callingham M.,Babraham Research Campus | Blum F.,Babraham Research Campus | Pave G.,Babraham Research Campus
Organic Letters | Year: 2015

A novel, high-yielding, one-step synthesis of 2-chloroquinazolin-4-ols and analogous bicycles from 2-aminoamides using thiophosgene is described. The scope of the reaction includes aminothioamides, amino acids, and fused heterocycle derivatives, furnishing quinazolines, oxazinones, and substituted fused pyrimidine bicycles, respectively. On the basis of observed results with substituted analogues, a mechanism for this transformation is thought to occur via an isothiocyanate intermediate followed by an unexpected chemoselective reaction of thiophosgene on the thiol intermediate. © 2015 American Chemical Society.

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