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Berlin Brandenburg

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  • 1
    Language: English
    In: Blood, 01 March 2018, Vol.131(9), pp.974-981
    Description: To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1β (IL-1β) production, although interest in the contribution of genetic factors has been fueled by detection of somatic mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic , , , or mutations, apart from 1 patient with a germ line p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients.
    Keywords: Germ-Line Mutation ; Schnitzler Syndrome ; Interleukin 1 Receptor Antagonist Protein -- Administration & Dosage
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 2
    Language: English
    In: Blood, 01 May 2014, Vol.123(18), pp.2899-900
    Keywords: Amyloidosis -- Complications ; Factor X -- Therapeutic Use ; Factor X Deficiency -- Complications ; Immunoglobulin Light Chains -- Metabolism
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 3
    Language: English
    In: Blood, 01 November 2004, Vol.104(9), pp.2991; author reply 2992-4
    Description: In contrast to the view proposed by Dr Mehta in the commentary[1][1] accompanying the case-control study of peripheral blood stem cell transplantation (PBSCT) versus conventional therapy for AL (primary) amyloidosis reported by Dispenzieri et al,[2][2] we believe that the role of high-dose therapy
    Keywords: Amyloidosis -- Therapy ; Research Design -- Standards
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 4
    Language: English
    In: Blood, 27 May 2010, Vol.115(21), pp.4313; author reply 4314-5
    Description: To the editor: Having had the opportunity to follow up 71 patients with hereditary fibrinogen A α-chain amyloidosis (AFib) at the United Kingdom National Amyloidosis Centre,[1][1] our perspective on this disease differs substantially in several important respects from that of Dr Stangou and
    Keywords: Liver Transplantation ; Amyloidosis, Familial -- Genetics ; Fibrinogen -- Genetics
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 5
    In: EMBO Molecular Medicine, October 2015, Vol.7(10), pp.1337-1349
    Description: The mechanisms underlying transthyretin‐related amyloidosis remain unclear. The abundance of the 49–127 transthyretin fragment in deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non‐amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano‐enzymatic mechanism mediates transthyretin amyloid fibrillogenesis . This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis‐mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied. Selective proteolysis of generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac amyloidosis, and offers new therapeutic targets for treating the disease. Shear forces are required to prime proteolysis of wild‐type and other variant TTRs and to release the amyloidogenic fragment. These forces are present in the heart, offering an explanation for tissue specificity in cardiac TTR amyloidosis. TTR stabilizers, currently used to treat amyloidosis, can inhibit this mechanism; however, their efficacy differs for each variant. Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.
    Keywords: Amyloid ; Mechano‐Enzymatic Cleavage ; Transthyretin
    ISSN: 1757-4676
    E-ISSN: 1757-4684
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  • 6
    Language: English
    In: Blood, 06 November 2014, Vol.124(19), pp.3025-7
    Keywords: Amyloid -- Metabolism ; Amyloidosis -- Metabolism ; Heart Diseases -- Metabolism ; Myocardium -- Metabolism
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 7
    Language: English
    In: Blood, 01 March 2007, Vol.109(5), pp.1971-4
    Description: Hereditary systemic amyloidosis caused by fibrinogen Aalpha-chain gene mutations is an autosomal dominant condition with variable penetrance, usually of late onset, and typically presents with nephropathy leading to renal failure. Amyloid deposits often develop rapidly in transplanted kidneys, and concomitant orthotopic liver transplantation has lately been performed in several patients with the hope of halting amyloid deposition. Fibrinogen is produced in vitro by hepatocytes but also by other human cell types, and although the liver is the source of plasma fibrinogen in vivo in rats, this is not known in humans. Transplantation of livers expressing wild-type fibrinogen into patients with variant fibrinogen amyloidosis provides a unique opportunity to establish the source of human plasma fibrinogen. We therefore characterized plasma fibrinogen Aalpha-chain allotypes by electrospray ionization mass spectrometry mapping of tryptic digests before and after liver transplantation. Before liver transplantation, fibrinogen amyloidosis patients with the Glu526Val Aalpha-chain variant had approximately equal proportions of peptide with the wild-type sequence TFPGFFSPMLGEFVSETESR, and with the amyloidogenic variant sequence TFPGFFSPMLGEFVSVTESR, as expected for individuals heterozygous for the mutation. After transplantation, only the wild-type sequence was detected, and the liver is thus the source of at least 98% of the circulation fibrinogen.
    Keywords: Fibrinogen -- Biosynthesis ; Liver -- Metabolism
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 8
    Language: English
    In: Blood, 15 January 2007, Vol.109(2), pp.457-64
    Description: High-dose melphalan with stem-cell transplantation is believed to be the most effective treatment for systemic light-chain (AL) amyloidosis, but many patients are ineligible because of the extent of their disease, and treatment-related mortality (TRM) remains substantial. We report the use of a risk-adapted oral regimen of cyclophosphamide, thalidomide, and dexamethasone (CTD) or attenuated CTD (CTDa) in 75 patients with advanced AL amyloidosis, including 44 patients with clonal relapse after prior therapy. Fifty-one (68%) patients received CTD and 24 (32%) received CTDa. A hematologic response occurred in 48 (74%) of 65 evaluable patients, including complete responses in 14 (21%) and partial responses in 34 (53%) cases. Median estimated overall survival (OS) from commencement of treatment was 41 months, and from diagnosis median was not reached with a median follow-up of 22 months. Three-year estimated OS was 100% and 82% among complete and partial hematologic responders, respectively. Toxicity necessitating cessation of therapy occurred in 8% and was at least grade 2 in 52% of patients. TRM was 4%. The clonal response rates to CTD reported here are higher than any previously reported nontransplantation regimen in AL amyloidosis, and risk adaptation allows its use in poorer risk patients. CTD merits prospective randomized study.
    Keywords: Amyloidosis -- Drug Therapy ; Cyclophosphamide -- Therapeutic Use ; Dexamethasone -- Therapeutic Use ; Immunoglobulin Light Chains -- Immunology ; Thalidomide -- Therapeutic Use
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 9
    Language: English
    In: Blood, 24 December 2015, Vol.126(26), pp.2805-10
    Description: Light chain deposition disease (LCDD) is characterized by the deposition of monotypic immunoglobulin light chains in the kidney, resulting in renal dysfunction. Fifty-three patients with biopsy-proven LCDD were prospectively followed at the UK National Amyloidosis Center. Median age at diagnosis was 56 years, and patients were followed for a median of 6.2 years (range, 1.1-14.0 years). Median renal survival from diagnosis by Kaplan-Meier analysis was 5.4 years, and median estimated patient survival was 14.0 years; 64% of patients were alive at censor. Sixty-two percent of patients required dialysis, and median survival from commencement of dialysis was 5.2 years. There was a strong association between hematologic response to chemotherapy and renal outcome, with a mean improvement in glomerular filtration rate (GFR) of 6.1 mL/min/year among those achieving a complete or very good partial hematologic response (VGPR) with chemotherapy, most of whom remained dialysis independent, compared with a mean GFR loss of 6.5 mL/min/year among those achieving only a partial or no hematologic response (P 〈 .009), most of whom developed end-stage renal disease (ESRD; P = .005). Seven patients received a renal transplant, and among those whose underlying clonal disorder was in sustained remission, there was no recurrence of LCDD up to 9.7 years later. This study highlights the need to diagnose and treat LCDD early and to target at least a hematologic VGPR with chemotherapy, even among patients with advanced renal dysfunction, to delay progression to ESRD and prevent recurrence of LCDD in the renal allografts of those who subsequently receive a kidney transplant.
    Keywords: Immunoglobulin Light Chains ; Kidney Failure, Chronic -- Etiology ; Paraproteinemias -- Pathology
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 10
    Language: English
    In: American journal of clinical pathology, July 2016, Vol.146(1), pp.78-85
    Description: Measurement of serum free light chains (FLCs) is critical in diagnosis, prognosis, and monitoring treatment responses in light chain (AL) amyloidosis. We compare the Freelite assay (polyclonal antibodies to hidden light chain epitopes), which is the current gold standard, with a new assay: a mixture of monoclonal antibodies to light chain epitopes (N Latex). We collected 240 serum samples from 94 consecutive patients with newly diagnosed AL amyloidosis (at least three serial serum samples during the first 6 months) analyzed at the National Amyloidosis Centre, London, from January 2011 to April 2012. Concordance in detecting abnormal light chain components and hematologic response was assessed at 2, 4, and 6 months. The κ and λ clonal light chain involvement was 21% and 79%, respectively, with an abnormal κ/λ ratio or detectable protein in 78.7%. Median κ, λ, and difference in involved and uninvolved FLCs by Freelite and N Latex assays were 17.3 vs 16 mg/L (R(2 ) = 0.91), 48.8 vs 52.6 mg/L (R(2) = 0.52), and 43.2 vs 39.1 mg/L, respectively. Discordant κ/λ ratios at presentation were as follows: 10 of 90 abnormal by Freelite/normal by N Latex and 11 of 90 abnormal by N Latex/normal by Freelite. Both FLC assays show good correlation in detecting the abnormal light chain subtype with discordance in absolute values and thus are not interchangeable.
    Keywords: Freelite ; Light Chain Amyloidosis ; Light Chain Assays ; N Latex ; Prognostic Utility ; Amyloidosis -- Diagnosis ; Immunoassay -- Methods ; Immunoglobulin Light Chains -- Blood
    ISSN: 00029173
    E-ISSN: 1943-7722
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