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Rapisarda A.,Frederick National Laboratory for Cancer Research | Melillo G.,Bristol Myers Squibb
Nature Reviews Clinical Oncology | Year: 2012

Cancer cells rely on angiogenesis to fulfil their need for oxygen and nutrients; hence, agents targeting angiogenic pathways and mediators have been investigated as potential cancer drugs. Although this strategy has demonstrated delayed tumour progression-leading to progression-free survival and overall survival benefits compared with standard therapy-in some patients, the results are more modest than predicted. A significant number of patients either do not respond to antiangiogenic agents or fairly rapidly develop resistance to them, which raises questions about how resistance develops and how it can be overcome. Furthermore, whether cancers, once they develop resistance, become more invasive or lead to metastatic disease remains unclear. Several mechanisms of resistance have been recently proposed and emerging evidence indicates that, under certain experimental conditions, antiangiogenic agents increase intratumour hypoxia by promoting vessel pruning and inhibiting neoangiogenesis. Indeed, several studies have highlighted the possibility that inhibitors of VEGF (and its receptors) can promote an invasive metastatic switch, in part by creating an increasingly hypoxic tumour microenvironment. As a potential remedy, a number of therapeutic approaches have been investigated that target the hypoxic tumour compartment to improve the clinical outcome of antiangiogenic therapy. © 2012 Macmillan Publishers Limited. All rights reserved. Source


McLaren P.J.,Ecole Polytechnique Federale de Lausanne | Carrington M.,Frederick National Laboratory for Cancer Research | Carrington M.,Massachusetts Institute of Technology
Nature Immunology | Year: 2015

The outcome after infection with the human immunodeficiency virus type 1 (HIV-1) is a complex phenotype determined by interactions among the pathogen, the human host and the surrounding environment. An impact of host genetic variation on HIV-1 susceptibility was identified early in the pandemic, with a major role attributed to the genes encoding class I human leukocyte antigens (HLA) and the chemokine receptor CCR5. Studies using genome-wide data sets have underscored the strength of these associations relative to variants located throughout the rest of the genome. However, the extent to which additional polymorphisms influence HIV-1 disease progression, and how much of the variability in outcome can be attributed to host genetics, remain largely unclear. Here we discuss findings concerning the functional impact of associated variants, outline methods for quantifying the host genetic component and examine how available genome-wide data sets may be leveraged to discover gene variants that affect the outcome of HIV-1 infection. Source


O'Carroll I.P.,Frederick National Laboratory for Cancer Research
Virus research | Year: 2013

The Gag polyprotein is the building block of retroviral particles and its expression is sufficient for assembly in cells. In HIV-1, nucleic acid (NA) is required for recombinant Gag molecules to assemble in a defined system in vitro. Experiments performed by Barklis and co-workers suggested that NA contributes to assembly by promoting Gag oligomerization. Gag is composed of four main domains: the matrix (MA), capsid (CA), nucleocapsid (NC), and p6 domains. We have recently shown that the SP1 linker, which lies between the CA and NC domains, assumes a helical structure at high, but not low, concentrations. We suggested that Gag oligomerization mediates assembly via an SP1-dependent conformational switch that exposes new interfaces for assembly. Although NA is required for assembly in vitro, deletion of NC, the main RNA-binding domain, does not eliminate particle formation in vivo; these particles lack NA. We hypothesized that alternative pathways that lead to Gag oligomerization or an increase in local Gag concentration, namely Gag-membrane or inter-protein interactions, rescue assembly in the absence of NC-RNA binding. We constructed mutants in which either Gag-membrane binding, the Gag dimer interface, or NC-RNA binding are disrupted. None of these mutants disables assembly. However, combined mutations in any two of these three classes render Gag completely unable to form virus-like particles. Thus, it seems, Gag utilizes at least three types of interactions to form oligomers and any two out of the three are sufficient for assembly. Published by Elsevier B.V. Source


Dimitrov D.S.,Frederick National Laboratory for Cancer Research
Methods in Molecular Biology | Year: 2012

Protein-based therapeutics are highly successful in clinic and currently enjoy unprecedented recognition of their potential. More than 100 genuine and similar number of modified therapeutic proteins are approved for clinical use in the European Union and the USA with 2010 sales of US$108 bln; monoclonal antibodies (mAbs) accounted for almost half (48%) of the sales. Based on their pharmacological activity, they can be divided into five groups: (a) replacing a protein that is deficient or abnormal; (b) augmenting an existing pathway; (c) providing a novel function or activity; (d) interfering with a molecule or organism; and (e) delivering other compounds or proteins, such as a radionuclide, cytotoxic drug, or effector proteins. Therapeutic proteins can also be grouped based on their molecular types that include antibody-based drugs, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytics. They can also be classified based on their molecular mechanism of activity as (a) binding non-covalently to target, e.g., mAbs; (b) affecting covalent bonds, e.g., enzymes; and (c) exerting activity without specific interactions, e.g., serum albumin. Most protein therapeutics currently on the market are recombinant and hundreds of them are in clinical trials for therapy of cancers, immune disorders, infections, and other diseases. New engineered proteins, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs, and proteins with optimized pharmacokinetics, are currently under development. However, in the last several decades, there are no conceptually new methodological developments comparable, e.g., to genetic engineering leading to the development of recombinant therapeutic proteins. It appears that a paradigm change in methodologies and understanding of mechanisms is needed to overcome major challenges, including resistance to therapy, access to targets, complexity of biological systems, and individual variations. © 2012 Springer Science+Business Media, LLC. Source


Estes J.D.,Frederick National Laboratory for Cancer Research
Immunological Reviews | Year: 2013

Acquired immunodeficiency syndrome (AIDS) is principally a disease of lymphoid tissues (LTs), due to the fact that the main target cell of human immunodeficiency virus (HIV) is the CD4+ T lymphocyte that primarily resides within organs of the immune system. The impact of HIV infection on secondary LTs, in particular lymph nodes, is critical to delineate, as these immune organs are the principal sites for initiating and facilitating immune responses and are critical for lymphocyte homeostatic maintenance and survival. The underlying structural elements of LTs, fibroblastic reticular cell (FRC) network, not only form the architectural framework for these organs, but also play in integral role in the production and storage of cytokines needed for T-cell survival. There is an interdependent relationship between the FRC stromal network and CD4+ T lymphocytes for their survival and maintenance that is progressively disrupted during HIV disease. HIV infection results in profound pathological changes to LTs induced by persistent chronic immune activation and inflammation that leads to progressive collagen deposition and fibrosis disrupting and damaging the important FRC network. In this review, I focus on the process, mechanisms, and the implications of pathological damage to important secondary LTs, combining what we have learned from HIV-infected individuals as well as the invaluable knowledge gained from studies in non-human primate simian immunodeficiency virus infection models. © 2013 John Wiley & Sons A/S 254 1 July 2013 10.1111/imr.12070 Invited Review Invited Reviews Published 2013. This article is a U.S. Government work and is in the public domain in the USA. Source

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