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  • Hawkins, P.N.  (237)
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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 October 2013, Vol.110(40), pp.16115-20
    Description: Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.
    Keywords: 3rs ; Disease Model ; Amyloid -- Metabolism ; Amyloidosis -- Physiopathology ; Inflammation -- Complications ; Serum Amyloid A Protein -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Article
    Article
    BMJ Publishing Group Ltd and British Cardiovascular Society
    Language: English
    In: Heart, 11 November 2012, Vol.98(21), p.1546
    Description: Cardiac amyloidosis of transthyretin fibril protein (ATTR) type is an infiltrative cardiomyopathy characterised by ventricular wall thickening and diastolic heart failure. Increased access to cardiovascular magnetic resonance imaging has led to a marked increase in referrals to our centre of Caucasian patients with wild-type ATTR (senile systemic) amyloidosis and Afro-Caribbean patients with the hereditary ATTR V122I type. Both subtypes present predominantly as isolated cardiomyopathy. The differential diagnosis includes cardiac amyloid light-chain (AL) amyloidosis, which has a poorer prognosis and can be amenable to chemotherapy. We review here the clinical features of cardiac ATTR amyloidosis and describe the diagnostic tests to determine ATTR type. Correct diagnosis is ever more crucial given that several novel therapies for ATTR amyloidosis are on the near horizon.
    Keywords: Cardiac Amyloidosis ; Cardiovascular Mri ; Cardiomyopathy ; Valvular Disease ; Cardiac Function ; Cardiac Remodelling ; Interventional Cardiology ; Non-Coronary Intervention ; Percutaneous Valve Therapy ; Heart Failure ; Systolic Heart Failure ; Diastolic Dysfunction ; Myocardial Disease ; Cardiomyopathy Restrictive
    ISSN: 1355-6037
    ISSN: 13556037
    E-ISSN: 1468-201X
    E-ISSN: 1468201X
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  • 3
    Language: English
    In: The Lancet, 25 June 2016, Vol.387(10038), pp.2641-2654
    Description: Tissue deposition of protein fibrils causes a group of rare diseases called systemic amyloidoses. This Seminar focuses on changes in their epidemiology, the current approach to diagnosis, and advances in treatment. Systemic light chain (AL) amyloidosis is the most common of these conditions, but wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly being diagnosed. Typing of amyloid fibrils, a critical determinant of therapy, has improved with the wide availability of laser capture and mass spectrometry from fixed histological tissue sections. Specific and accurate evaluation of cardiac amyloidosis is now possible using cardiac magnetic resonance imaging and cardiac repurposing of bone scintigraphy tracers. Survival in AL amyloidosis has improved markedly as novel chemotherapy agents have become available, but challenges remain in advanced disease. Early diagnosis, a key to better outcomes, still remains elusive. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilisers and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise to transform outcomes in systemic amyloidoses.
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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  • 4
    Language: English
    In: Arthritis and rheumatism, February 2011, Vol.63(2), pp.314-24
    Keywords: Autoimmune Diseases -- Immunology ; Autoimmunity -- Immunology ; Immunity, Innate -- Immunology ; Interleukin-1beta -- Immunology
    E-ISSN: 1529-0131
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  • 5
    In: Kidney International, 2014
    Description: Amyloidosis results from protein misfolding, and ongoing amyloid deposition can ultimately lead to organ failure and death. Historically, this is a group of diseases with limited treatment options and frequently poor prognosis. However, there are now 'targeted' therapeutics emerging in the form of stabilizers of the precursor protein, inhibitors of fibrillogenesis, fibril disruptors, and blockers of protein translation, transcription, and immunotherapy. We review many of these approaches that are currently being assessed in clinical trials.
    Keywords: Molecular Targeted Therapy ; Amyloidosis -- Drug Therapy ; Prealbumin -- Metabolism;
    ISSN: 0085-2538
    E-ISSN: 15231755
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 January 2014, Vol.111(4), pp.1539-44
    Description: The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for the causative mutation. Together with a minor quantity of full-length wild-type and variant TTR, the main component of the ex vivo fibrils was the residue 49-127 fragment of the TTR variant, the portion of the TTR sequence that previously has been reported to be the principal constituent of type A, cardiac amyloid fibrils formed from wild-type TTR and other TTR variants [Bergstrom J, et al. (2005) J Pathol 206(2):224-232]. This specific truncation of Ser52Pro TTR was generated readily in vitro by limited proteolysis. In physiological conditions and under agitation the residue 49-127 proteolytic fragment rapidly and completely self-aggregates into typical amyloid fibrils. The remarkable susceptibility to such cleavage is likely caused by localized destabilization of the β-turn linking strands C and D caused by loss of the wild-type hydrogen-bonding network between the side chains of residues Ser52, Glu54, Ser50, and a water molecule, as revealed by the high-resolution crystallographic structure of Ser52Pro TTR. We thus provide a structural basis for the recently hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly, but neither protected the variant from proteolysis. However, binding of RBP, but not thyroxine, inhibited subsequent fibrillogenesis.
    Keywords: Misfolding ; Protein Aggregation ; Amyloid -- Metabolism ; Prealbumin -- Metabolism ; Proline -- Metabolism ; Serine -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 7
    Language: English
    In: Journal of the American College of Cardiology, 09 October 2018, Vol.72(15), pp.1881-1881
    Keywords: Medicine
    ISSN: 0735-1097
    E-ISSN: 1558-3597
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  • 8
    Language: English
    In: Nature, 04 November 2010, Vol.468(7320), pp.93-7
    Description: Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one in a thousand deaths in developed countries. Localized amyloid can also have serious consequences; for example, cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present. There is therefore a major unmet need for therapy that safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor proteins can arrest amyloid accumulation. Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar plasma glycoprotein, serum amyloid P component (SAP). Here we show that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP-antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-d-proline compound CPHPC, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.
    Keywords: Amyloid -- Drug Effects ; Amyloidosis -- Prevention & Control ; Antibodies -- Immunology ; Serum Amyloid P-Component -- Antagonists & Inhibitors
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 9
    Language: English
    In: Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians, March 2011, Vol.42(1), pp.149-52
    Description: Amyloidosis has been described in a wide range of domestic and wild species and man. A 10-yr-old male Eastern (Mountain) Bongo (Tragelaphus eurycerus isaaci) was submitted for postmortem examination after a period of 24-hr malaise. Gross examination found evidence of biventricular cardiac hypertrophy, congestive heart failure, and focal pulmonary abscessation. Histologic changes in the heart were consistent with hypertrophic change. Amyloid deposits were found within the liver, kidney medulla, heart, adrenal cortex, and pituitary gland and were confirmed as reactive systemic amyloid (AA) by immunohistochemistry. The pulmonary abscessation was thought to be the stimulus for excessive serum amyloid associated protein production leading to the reactive systemic amyloidosis. Colloidal goiter was also identified as an incidental finding.
    Keywords: Amyloidosis -- Veterinary
    ISSN: 1042-7260
    E-ISSN: 19372825
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  • 10
    In: The New England Journal of Medicine, 2012, Vol.366(24), pp.2276-2283
    Description: We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β 2 -microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β 2 -microglobulin, the affected members of this kindred had normal renal function and normal circulating β 2 -microglobulin values. The Asp76Asn β 2 -microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β 2 -microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β 2 -microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding. A kindred with familial amyloidosis was found to have bowel and autonomic dysfunction and the sicca syndrome from an aspartate-to-asparagine alteration at amino acid 76 of β2-microglobulin. Unexpectedly, this alteration promoted fibrillogenesis and tissue deposition. Summary We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β2-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β2-microglobulin, the affected members of this kindred had normal renal function and normal circulating β2-microglobulin values. The Asp76Asn β2-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β2-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β . . .
    Keywords: Amyloidosis, Familial -- Genetics ; Beta 2-Microglobulin -- Genetics;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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