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David C Seldin - One of the best experts on this subject based on the ideXlab platform.

  • Risk factors for venous thromboembolism in immunoglobulin light chain Amyloidosis ARTICLE
    2020
    Co-Authors: Katherine M Bever, Lauren Stern, Andrea Havasi, David C Seldin, John L. Berk, Vaishali Sanchorawala, Luke I Masha, Fangui Sun, Mark J Sloan
    Abstract:

    P atients with immunoglobulin light chain Amyloidosis are at risk for both thrombotic and bleeding complications. While the hemostatic defects have been extensively studied, less is known about thrombotic complications in this disease. This retrospective study examined the frequency of venous thromboembolism in 929 patients with immunoglobulin light chain Amyloidosis presenting to a single referral center, correlated risk of venous thromboembolism with clinical and laboratory factors, and examined complications of anticoagulation in this population. Sixty-five patients (7%) were documented as having at least one venous thromboembolic event. Eighty percent of these patients had events within one year prior to or following diagnosis. Lower serum albumin was associated with increased risk of VTE, with a hazard ratio of 4.30 (CI 1.60-11.55; P=0.0038) for serum albumin less than 3 g/dL compared to serum albumin greater than 4 g/dL. Severe bleeding complications were observed in 5 out of 57 patients with venous thromboembolism undergoing treatment with anticoagulation. Prospective investigation should be undertaken to better risk stratify these patients and to determine the optimal strategies for prophylaxis against and management of venous thromboembolism. Risk factors for venous thromboembolism in immunoglobulin light chain amyloidosi

  • a new lysozyme tyr54asn mutation causing Amyloidosis in a family of swedish ancestry with gastrointestinal symptoms
    Amyloid, 2012
    Co-Authors: Saulius Girnius, David C Seldin, Martha Skinner, Carl Ohara, Tatiana Prokaeva, Brian Spencer, Catherine Bartholomew, Lawreen H Connors
    Abstract:

    Familial amyloidoses are a group of inherited disorders that cause deposition of misfolded amyloidogenic proteins in various tissues, resulting in organ dysfunction. Point mutations in the coding region of seven different genes are known to cause clinically significant systemic amyloid disease. We describe a new mutation in exon 2 of the lysozyme gene associated with Amyloidosis (ALys) in a 61-year-old woman with a 7-year history of non-bloody, watery diarrhea, and weight loss. Biopsies of the duodenum and stomach were positive for amyloid deposits in the lamina propria and blood vessels. Direct DNA sequencing of the lysozyme gene revealed a single base nucleotide transversion from T to A at the first position of codon 54, resulting in replacement of Tyr by Asn in the mature lysozyme protein (pTyr54Asn). Immunoblot analysis of amyloid fibrils extracted from a fat tissue sample confirmed lysozyme as the amyloid protein. Clinically, the phenotype associated with this lysozyme mutation featured chronic abdom...

  • doxycycline reduces fibril formation in a transgenic mouse model of al Amyloidosis
    Blood, 2011
    Co-Authors: Jennifer E Ward, Carl Ohara, Lawreen H Connors, Ronglih Liao, Gianluca Toraldo, Pam Soohoo, Jian Guan, Ravi Jasuja, Vickery Trinkausrandall, David C Seldin
    Abstract:

    Systemic AL Amyloidosis results from the aggregation of an amyloidogenic immunoglobulin (Ig) light chain (LC) usually produced by a plasma cell clone in the bone marrow. AL is the most rapidly fatal of the systemic amyloidoses, as amyloid fibrils can rapidly accumulate in tissues including the heart, kidneys, autonomic or peripheral nervous systems, gastrointestinal tract, and liver. Chemotherapy is used to eradicate the cellular source of the amyloidogenic precursor. Currently, there are no therapies that target the process of LC aggregation, fibril formation, or organ damage. We developed transgenic mice expressing an amyloidogenic λ6 LC using the cytomegalovirus (CMV) promoter to circumvent the disruption of B cell development by premature expression of recombined LC. The CMV-λ6 transgenic mice develop neurologic dysfunction and Congophilic amyloid deposits in the stomach. Amyloid deposition was inhibited in vivo by the antibiotic doxycycline. In vitro studies demonstrated that doxycycline directly disrupted the formation of recombinant LC fibrils. Furthermore, treatment of ex vivo LC amyloid fibrils with doxycycline reduced the number of intact fibrils and led to the formation of large disordered aggregates. The CMV-λ6 transgenic model replicates the process of AL Amyloidosis and is useful for testing the antifibril potential of orally available agents.

  • Amyloidosis pathogenesis and new therapeutic options
    Journal of Clinical Oncology, 2011
    Co-Authors: Giampaolo Merlini, David C Seldin, Morie A Gertz
    Abstract:

    The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. The most common type, immunoglobulin light chain Amyloidosis (AL), is caused by clonal plasma cells that produce misfolded light chains. The purpose of this review is to provide up-to-date information on diagnosis and treatment options for AL Amyloidosis. Early, accurate diagnosis is the key to effective therapy, and unequivocal identification of the amyloidogenic protein may require advanced technologies and expertise. Prognosis is dominated by the extent of cardiac involvement, and cardiac staging directs the choice of therapy. Treatment for AL Amyloidosis is highly individualized, determined on the basis of age, organ dysfunction, and regimen toxicities, and should be guided by biomarkers of hematologic and cardiac response. Alkylator-based chemotherapy is effective in almost two thirds of patients. Novel agents are also active, and trials are ongoing to establish their optimal use. Treatment algorithms will continue to be refined through controlled trials. Advances in basic research have led to the identification of new drug targets and therapeutic approaches, which will be integrated with chemotherapy in the future.

  • evidence for a functional role of the molecular chaperone clusterin in amyloidotic cardiomyopathy
    American Journal of Pathology, 2011
    Co-Authors: Michael J Greene, David C Seldin, Rupesh S Patel, Lawreen H Connors
    Abstract:

    Molecular chaperones, including the extracellular protein clusterin (CLU), play a significant role in maintaining proteostasis; they have a unique capacity to bind and stabilize non-native protein conformations, prevent aggregation, and keep proteins in a soluble folding-competent state. In this study, we investigated amyloid-infiltrated cardiac tissue for the presence of CLU and measured serum levels of CLU in patients with and without amyloidotic cardiomyopathy (CMP). Cardiac tissues containing amyloid deposits composed of either transthyretin (TTR) or Ig light chain from nine patients with amyloidotic CMP were examined for the presence of CLU using immunohistochemical techniques. CLU staining coincided with the extracellular myocardial amyloid deposits in tissues from patients with familial TTR, senile systemic, and Ig light chain Amyloidosis. The association of CLU with cardiac amyloid deposits was confirmed by immunogold electron microscopy. Serum concentrations of CLU were measured in familial TTR, senile systemic, and Ig light chain Amyloidosis patient groups and compared with both age-matched healthy controls and with patients with CMP unrelated to amyloid disease. Subset analysis of disease cohorts, based on cardiac involvement, indicated that decreased serum CLU concentrations were associated with amyloidotic CMP. Taken together, these results suggest that CLU may play a pathogenetic role in TTR and Ig light chain amyloidoses and amyloidotic CMP.

Giampaolo Merlini - One of the best experts on this subject based on the ideXlab platform.

  • al Amyloidosis from molecular mechanisms to targeted therapies
    Hematology, 2017
    Co-Authors: Giampaolo Merlini
    Abstract:

    Systemic Amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vital organs. The most common systemic Amyloidosis, light-chain (AL) Amyloidosis, is caused by misfolded light chains produced by a small, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a challenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vital. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overall survival, making AL Amyloidosis the most successful model of all amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL Amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.

  • kidney involvement in light chain Amyloidosis
    Journal of Onco-Nephrology, 2017
    Co-Authors: Paolo Milani, Giampaolo Merlini, Giovanni Palladini
    Abstract:

    Systemic amyloidoses are complex diseases caused by the misfolding of autologous protein. Immunoglobulin light chain (AL) Amyloidosis is caused by usually small plasma cell clone synthesizing light chains undergoing conformational changes that lead to their aggregation and deposition in tissues. Although the presence of heart involvement is the most important prognostic determinant, the kidney is involved in 70% of patients. Renal involvement results in significant morbidity, and renal failure limits the therapeutic options. The clinical presentation of kidney involvement is characterized by nephrotic syndrome and progressive renal failure. Diagnosis relies on the identification and accurate typing of amyloid deposits at the abdominal fat pad aspirate or with renal biopsy. Refined diagnostic and staging systems based on biomarkers have helped in assessing prognoses and evaluating responses to therapy, which has considerably improved the management of these conditions. In addition, the availability of nove...

  • amyloid fibril proteins and Amyloidosis chemical identification and clinical classification international society of Amyloidosis 2016 nomenclature guidelines
    Amyloid, 2016
    Co-Authors: Jean D Sipe, Jeffrey N Buxbaum, Merrill D Benson, Giampaolo Merlini, Shuichi Ikeda, Maria Joao Saraiva, Per Westermark
    Abstract:

    AbstractThe Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XVth Symposium of the Society, 3 July–7 July 2016, Uppsala, Sweden, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. An amyloid fibril must exhibit affinity for Congo red and with green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. While congophilia and birefringence remain the gold standard for demonstration of amyloid deposits, new staining and imaging techniques are proving useful. To be included in the nomenclature list, in addition to congophilia and birefringence, the chemical identity of the protein must be unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant changes in the amyloid fibril protein. Each distinct form...

  • Current treatment of AL Amyloidosis
    2015
    Co-Authors: Giovanni Palladini, Giampaolo Merlini
    Abstract:

    Immunoglobulin light chain systemic Amyloidosis(AL) is a progressive disease caused by monoclonallight chains with specific mutations that confer a unique propensity to misfold from their native structure to less stable, partially folded intermediates that self-aggregate into oligomers and then into the highly-ordered cross β-sheet structure which defines amyloid fibrils.1 At least 11 additional proteins, synthesized by different organs (liver, intestine, etc) can cause systemic amyloidoses which can be difficult to distinguish from AL Amyloidosis on a clinical basis. These proteins form amyloid deposits that share the common tinctorial, green birefringence under polarized light after staining with Congo red, and ultrastructural features, rigid, non-branching fibril with a distinct diameter of 7.5 to 10 nm (Figure 1). The unequivocal identification of the protein forming the amyloid fibril is essential for the choice o

  • systemic light chain Amyloidosis an update for treating physicians
    Blood, 2013
    Co-Authors: Giampaolo Merlini, Ashutosh D Wechalekar, Giovanni Palladini
    Abstract:

    In immunoglobulin light chain Amyloidosis a small, indolent plasma cell clone synthesizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of "red-flags" before advanced cardiomyopathy ensues, is essential for improving outcomes. Differentiation from other systemic amyloidoses may require advanced technologies. Prognosis depends on the extent of cardiac involvement, and cardiac biomarkers guide the choice of therapy. The protean clinical presentation requires individualized treatment. Close monitoring of clonal and organ response guides therapy changes and duration. Conventional or high-dose alkylator-based chemotherapy is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylators achieve high response rates, although controlled studies are needed. Risk-adapted stem cell transplant and consolidation with novel agents may be considered in selected patients. Immune-modulatory drugs are good options for refractory/relapsed patients. Novel agents and therapeutic targets are expected to be exploited, in an integrated, more effective and less toxic treatment strategy.

Sari Atula - One of the best experts on this subject based on the ideXlab platform.

  • finnish gelsolin Amyloidosis causes significant disease burden but does not affect survival fin gar phase ii study
    Orphanet Journal of Rare Diseases, 2020
    Co-Authors: Eevakaisa Schmidt, Tuuli Mustonen, Sari Kiuruenari, Tero Kivela, Sari Atula
    Abstract:

    Hereditary gelsolin (AGel) Amyloidosis is an autosomal dominantly inherited systemic Amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel Amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice Amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70–74 years, for which it was 0.96. AGel Amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel Amyloidosis does not shorten the life span of the patients at least for the first 75 years.

Rodney H Falk - One of the best experts on this subject based on the ideXlab platform.

  • al light chain cardiac Amyloidosis a review of diagnosis and therapy
    Journal of the American College of Cardiology, 2016
    Co-Authors: Rodney H Falk, Kevin M Alexander, Ronglih Liao, Sharmila Dorbala
    Abstract:

    Abstract The amyloidoses are a group of protein-folding disorders in which ≥1 organ is infiltrated by proteinaceous deposits known as amyloid. The deposits are derived from 1 of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart (cardiac Amyloidosis) carries the worst prognosis of any involved organ, and light-chain (AL) Amyloidosis is the most serious form of the disease. The last decade has seen considerable progress in understanding the amyloidoses. In this review, current and novel approaches to the diagnosis and treatment of cardiac Amyloidosis are discussed, with particular reference to AL Amyloidosis in the heart.

  • cardiac Amyloidosis in african americans comparison of clinical and laboratory features of transthyretin v122i Amyloidosis and immunoglobulin light chain Amyloidosis
    American Heart Journal, 2009
    Co-Authors: Lawreen H Connors, Carl Ohara, Tatiana Prokaeva, Amareth Lim, Roger Theberge, Rodney H Falk, Gheorghe Doros, Alan M Berg, Catherine E Costello, David C Seldin
    Abstract:

    Background Transthyretin (TTR) mutations known to cause cardiac Amyloidosis include V122I, found almost exclusively in African Americans at a prevalence of 3-3.9%. This retrospective study describes TTR V122I-associated cardiac amyloid disease (ATTR) in a major amyloid referral clinic population. Methods Self-identified African Americans with Amyloidosis (n = 156) were screened for TTR V122I by serum isoelectric focusing; mutant TTR was confirmed by DNA sequencing or mass spectrometry. Cardiac findings in ATTR V122I and immunoglobulin light chain (AL) amyloidoses were compared. Results TTR V122I was identified in 36/156 (23.1%) of evaluated patients and included 5 homozygotes; the allele frequency was 0.013. One compound heterozygote (F44L/V122I) and 4 patients who had AL and the mutant TTR allele were characterized. In patients negative for V122I, AL was the most frequent diagnosis (86/120). Cardiomyopathy was present in 100% of patients with ATTR and 84% of patients with AL (P = .01). In patients with dominant cardiac involvement, better survival occurred in ATTR (n = 30) compared to AL (n = 31), (27 vs 5 months, P Conclusions ATTR V122I and AL are equally prevalent as the cause of cardiomyopathy in African Americans referred for a diagnosis of Amyloidosis. Available therapy for AL underscores the need for early and accurate determination of amyloid type.

Sari Kiuruenari - One of the best experts on this subject based on the ideXlab platform.

  • finnish gelsolin Amyloidosis causes significant disease burden but does not affect survival fin gar phase ii study
    Orphanet Journal of Rare Diseases, 2020
    Co-Authors: Eevakaisa Schmidt, Tuuli Mustonen, Sari Kiuruenari, Tero Kivela, Sari Atula
    Abstract:

    Hereditary gelsolin (AGel) Amyloidosis is an autosomal dominantly inherited systemic Amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel Amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice Amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70–74 years, for which it was 0.96. AGel Amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel Amyloidosis does not shorten the life span of the patients at least for the first 75 years.

  • investigation of age their receptor and nf kappab activation and apoptosis in patients with attr and gelsolin Amyloidosis
    Histology and Histopathology, 2010
    Co-Authors: Intissar Anan, Konen Obayashi, Sari Kiuruenari, Poul Jorgen Ranlov, Yukio Ando
    Abstract:

    Background: Transthyretin (TTR) and gelsolin amyloidoses represent two types of hereditary Amyloidosis in which point mutations in the respective protein lead to conformational changes of the protein with subsequent amyloid fibril formation. Material and methods: Tissues from Finnish gelsolin amyloid patients, Danish, Japanese and Swedish ATTR patients were immunostained for AGE, RAGE, NF-?B, PARP, and caspases 3 and 8. Results: Amyloid was heavily deposited in myocard, kidney and gastrointestinal tract of all patients. Immunoreactive areas to AGE and RAGE were detected in the heart, kidney, rectum, gut and appendix. AGE and RAGE were well co-localised with amyloid deposits. In five out of 14 patients neither NF-?B activation nor induction of apoptosis marked by positive immunostaining for NF-?B, PARP, or caspases 3 and 8 was found, and markers of apoptosis were detected in some samples without accompanying NF-?B activation. Conclusion: Our results suggest that both AGE and RAGE may have a common role in evolution of TTR and gelsolin-related amyloidoses. Apart from AGE-RAGE interactions both amyloid proteins may directly bind to RAGE and result in cellular perturbations; but in view of this study cytotoxic effects other than those triggered by activation of NF-?B or apoptosis should be considered