Francesca Lavatelli

Francesca Lavatelli
  • MD, PhD
  • Researcher at University of Pavia

About

152
Publications
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4,352
Citations
Current institution
University of Pavia
Current position
  • Researcher

Publications

Publications (152)
Article
Full-text available
Immunoglobulin light chain (LC) amyloidosis (AL) is one of the most common types of systemic amyloidosis but there is no reliable in vivo model for better understanding this disease. Here, we develop a transgenic mouse model producing a human AL LC. We show that the soluble full length LC is not toxic but a single injection of pre-formed amyloid fi...
Preprint
Full-text available
AL amyloidosis is one of the most common types of systemic amyloidosis, caused by the deposition in tissues of fibrillar aggregates of abnormal immunoglobulin (Ig) light chain (LC), leading to organ dysfunction. The most frequent and severe forms affect the kidneys and heart, the latter being associated with a poor prognosis. Despite extensive effo...
Article
AA-amyloidosis is frequent in shelter cats, and chronic kidney disease is the foremost cause of death. The aims were to describe kidney laboratory and microscopic findings in shelter cats with AA-amyloidosis. Cats were included if kidney specimens were collected post-mortem and laboratory data were available within 6 months before death. Renal lesi...
Article
Full-text available
AL amyloidosis is a life-threatening disease caused by deposition of immunoglobulin light chains. While the mechanisms underlying light chains amyloidogenesis in vivo remain unclear, several studies have highlighted the role that tissue environment and structural amyloidogenicity of individual light chains have in the disease pathogenesis. AL natur...
Article
Full-text available
The mechanism that converts native human transthyretin into amyloid fibrils in vivo is still a debated and controversial issue. Commonly, non‐physiological conditions of pH, temperature, or organic solvents are used in in vitro models of fibrillogenesis of globular proteins. Transthyretin amyloid formation can be achieved under physiological condit...
Article
Full-text available
Background Amyloid A (AA) amyloidosis is a protein misfolding disease arising from serum amyloid A (SAA). Systemic AA amyloidosis recently was shown to have a high prevalence in shelter cats in Italy and was associated with azotemia and proteinuria. Objectives Investigate urine protein profiles and diagnostic biomarkers in cats with renal AA amylo...
Article
Full-text available
2 ‐microglobulin (β 2 ‐m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild‐type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N β 2 ‐m, which favor protein depo...
Article
Full-text available
Systemic AA-amyloidosis is a protein-misfolding disease characterized by fibril deposition of serum amyloid-A protein (SAA) in several organs in humans and many animal species. Fibril deposits originate from abnormally high serum levels of SAA during chronic inflammation. A high prevalence of AA-amyloidosis has been reported in captive cheetahs and...
Article
Full-text available
AL amyloidosis is caused by the misfolding of immunoglobulin light chains leading to an impaired function of tissues and organs in which they accumulate. Due to the paucity of -omics profiles from undissected samples, few studies have addressed amyloid-related damage system wide. To fill this gap, we evaluated proteome changes in the abdominal subc...
Article
Full-text available
AA amyloidosis is a systemic disease characterized by deposition of misfolded serum amyloid A protein (SAA) into cross-β amyloid in multiple organs in humans and animals. AA amyloidosis occurs at high SAA serum levels during chronic inflammation. Prion-like transmission was reported as possible cause of extreme AA amyloidosis prevalence in captive...
Article
Full-text available
Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among...
Preprint
Full-text available
Systemic AA-amyloidosis is a protein-misfolding disease that is characterized by fibril deposition of serum amyloid-A protein (SAA) in several organs in humans and many animal species. Fibril deposits originate from abnormally high serum levels of SAA during chronic inflammation. In domestic short-hair cats, AA-amyloidosis has only been anecdotally...
Preprint
Full-text available
AA amyloidosis is a systemic disease characterized by deposition of misfolded serum amyloid A protein (SAA) into cross-β amyloid in multiple organs in humans and animals. AA amyloidosis occurs at high SAA serum levels during chronic inflammation. The disease can be transmitted horizontally, likely facilitated by prion-like mechanism, in captive ani...
Article
Full-text available
The globular to fibrillar transition of proteins represents a key pathogenic event in the development of amyloid diseases. Although systemic amyloidoses share the common characteristic of amyloid deposition in the extracellular matrix, they are clinically heterogeneous as the affected organs may vary. The observation that precursors of amyloid fibr...
Article
Full-text available
The deposition of amyloid light chains (LCs) in target sites translates into tissue damage and organ dysfunction. Clinical and experimental advances have cast new light on the pathophysiology of damage in AL amyloidosis. The currently accepted view is that, besides the alterations caused by fibrillar deposits in the extracellular space, direct prot...
Article
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Diagnosis of cryoproteinemia: important collaboration between the laboratory and clinicians for the proper management of a rare disease. Cryoglobulinemia is a rare pathologic condition that can be difficult to diagnose both clinically and in the laboratory, which is why close collaboration between the clinic and laboratory is essential. The laborat...
Article
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A reliable diagnosis of amyloidosis is usually based on a tissue biopsy. With increasing options for specific treatments of the different amyloid diseases, an exact and valid diagnosis including determination of the biochemical fibril nature is imperative. Biopsy sites as well as amyloid typing principles vary and this paper describes methods emplo...
Article
Introduction In patients affected by monoclonal gammopathies, tumoral B cells or plasma cells secrete a monoclonal antibody (termed M protein), which can be used to track the presence of the tumor itself. Moreover, the M protein can directly cause potentially life-threatening organ damage, which is dictated by the specific, patient's unique clonal...
Article
Full-text available
Light‐chain (AL) amyloidosis is characterized by deposition of immunoglobulin light chains (LC) as fibrils in target organs. Alongside the full‐length protein, abundant LC fragments are always present in AL deposits. Herein, by combining gel‐based and mass spectrometry analyses, we identified and compared the fragmentation sites of amyloid LCs from...
Article
Full-text available
Amyloidoses are characterized by aggregation of proteins into highly ordered amyloid fibrils, which deposit in the extracellular space of tissues, leading to organ dysfunction. In AL (amyloid light chain) amyloidosis, the most common form in Western countries, the amyloidogenic precursor is a misfolding-prone immunoglobulin light chain (LC), which,...
Article
Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer’s and Parkinson’s diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk facto...
Article
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Amyloidosis is a relatively rare human disease caused by the deposition of abnormal protein fibres in the extracellular space of various tissues, impairing their normal function. Proteomic analysis of patients’ biopsies, developed by Dogan and colleagues at the Mayo Clinic, has become crucial for clinical diagnosis and for identifying the amyloid t...
Article
Full-text available
Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N-...
Article
Full-text available
In AL amyloidosis complete response (aCR) is defined as negative serum and urine immunofixation with normalized free light chain ratio (FLCR). However, achievement of low levels of involved FLC (iFLC) or difference between iFLC and uninvolved FLC (dFLC) are also relevant endpoints for treatment. We divided 434 consecutive patients with AL amyloidos...
Article
Background: The aim of the present prospective study (ClinicalTrials.gov Identifier: NCT02111538) was to assess the prognostic value of phase angle (PhA), derived from bioimpedance vectorial analysis (BIVA), in patients affected by systemic amyloid light-chain (AL) amyloidosis. Methods: One hundred-twenty seven consecutive newly diagnosed, treatmen...
Article
Full-text available
In light chain amyloidosis (AL), fibrillar deposition of monoclonal immunoglobulin light chains (LCs) in vital organs, such as heart, is associated with their severe dysfunction. In addition to the cellular damage caused by fibril deposition, direct toxicity of soluble prefibrillar amyloidogenic proteins has been reported, in particular for cardiot...
Article
Full-text available
Background Light chain amyloidosis (LC-AL) is the most common systemic AL. It is caused by the overproduction and the aggregation of toxic and monoclonal immunoglobulin LCs in target organs. Among all the organs injured by the pathology, the heart is the most affected one. In particular, the ventricular compliance is reduced, resulting in a symptom...
Article
Full-text available
Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid f...
Article
Cardiac dysfunction is the most frequent cause of morbidity and mortality in amyloid light chain (AL) amyloidosis caused by a clonal immunoglobulin light chain (LC). Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis, which has limited our understand...
Article
Deposition of misfolded proteins as extracellular amyloid aggregates is the pathological hallmark of systemic amyloidoses. Subcutaneous fat acquired by fine needle aspiration is the preferred screening tissue in suspected patients. In this study we employed Fourier transform infrared (FTIR) spectroscopy in attenuated total reflection (ATR) to inves...
Article
In patients with light chain (AL) amyloidosis, reduction of amyloidogenic circulating free light chain (FLC) concentration translates in improvement of organ dysfunction and is associated with an increase in overall survival. Validated criteria for hematologic response to therapy are based on FLC quantification. However, patients with a difference...
Preprint
Full-text available
Systemic light chain (AL) amyloidosis is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Angstroem resolution cryo-electron microscopy (cryo-EM) map and structural...
Article
Detection and typing of amyloid deposits in tissues are two crucial steps in the management of systemic amyloidoses. The presence of amyloid deposits is routinely evaluated through Congo red staining, whereas proteomics is now a mainstay for in the identification of the deposited proteins. In this issue of Proteomics, Winter and colleagues describe...
Article
The detection and quantification of amyloidogenic light-chains (LC) is necessary for diagnosis and evaluation of response in AL amyloidosis. A 69 years old woman was initially diagnosed, in another center, with AL-λ amyloidosis with renal and soft tissue involvement in December 2001. After 4 cycles of therapy with melphalan and dexamethasone serum...
Article
Full-text available
Light chain amyloidosis (AL), the most common systemic amyloidosis, is caused by the overproduction and the aggregation of monoclonal immunoglobulin light chains (LC) in target organs. Due to genetic rearrangement and somatic hypermutation, virtually, each AL patient presents a different amyloidogenic LC. Because of such complexity, the fine molecu...
Article
Full-text available
AL amyloidosis is characterized by widespread deposition of immunoglobulin light chains (LCs) as amyloid fibrils. Cardiac involvement is frequent and leads to life-threatening cardiomyopathy. Besides the tissue alteration caused by fibrils, clinical and experimental evidence indicates that cardiac damage is also caused by proteotoxicity of prefibri...
Article
Background: The measurement of circulating free light chain (FLC) is essential in the diagnosis, prognostic stratification and evaluation of response to therapy in light chain (AL) amyloidosis. For more than 10 years, this has been done with an immunonephelometric assay based on polyclonal antibodies (Freelite), and cutoffs for staging and respons...
Article
Introduction: More than ten distinct forms of amyloidoses that can involve the heart have been described, classified according to which protein originates the deposits. Cardiac amyloid infiltration translates into progressive and often life-threatening cardiomyopathy, but disease severity, prognosis and treatment drastically differ according to the...
Article
Full-text available
Light chain (AL) amyloidosis, caused by deposition of amyloidogenic immunoglobulin light chains (LCs), is the most common systemic form in industrialized countries. Still open questions, and premises for developing targeted therapies, concern the mechanisms of amyloid formation in vivo and the bases of organ targeting and dysfunction. Investigating...
Article
Background: The measurement of circulating free light chains (FLC) is of utmost importance in immunoglobulin light chain (AL) amyloidosis, being a fundamental part of the diagnostic workup, prognostic stratification and assessment of response to therapy. Renal failure is a common feature of AL amyloidosis and can considerably affect the concentrat...
Article
Full-text available
Systemic amyloidoses are caused by misfolding-prone proteins that polymerize in tissues, causing organ dysfunction. Since proteins are etiological agents of these diseases, proteomics was soon recognized as a privileged instrument for their investigation. Mass spectrometry-based proteomics has acquired a fundamental role in management of systemic a...
Article
Patients with AL amyloidosis often have small monoclonal components (MCs) difficult to quantify by densitometry. IgA are the most problematic, due to anodic migration and possible masking under proteins migrating in β zone. We evaluated the usefulness of the Hevylite assay (Binding Site, Birmingham UK), at diagnosis and during follow-up, in a patie...
Article
In immunoglobulin (Ig) light-chain (LC) (AL) amyloidosis, AL deposition translates into lifethreatening cardiomyopathy. Clinical and experimental evidence indicates that soluble cardiotoxic LCs are themselves harmful for cells, by which they are internalized. Hypothesizing that interaction of soluble cardiotoxic LCs with cellular proteins contribut...
Article
Full-text available
Accurate diagnosis of systemic amyloidosis is necessary for both assessing the prognosis and to delineate the appropriate treatment. It is based on histological evidence of amyloid deposits and characterization of the amyloidogenic protein. We prospectively evaluated the diagnostic performance of immuno-electron microscopy (IEM) of abdominal fat as...
Chapter
Upon demonstration of the presence of amyloid deposits in tissues, disease typing is necessary for establishing a correct diagnosis, planning a therapeutic strategy, defining the prognosis, and programming genetic counseling. Recent years have witnessed the introduction in the clinical setting of a new resource for the characterization of tissue am...
Article
Abnormalities in protein folding are involved in many localized and systemic diseases, all of which are characterized by insoluble amyloid formation and deposition. In immunoglobulin light chain (LC) amyloidosis, the most frequent systemic form of amyloidosis, the amyloid involvement of the heart dictates the prognosis and the elucidation of the me...
Article
Oral melphalan and dexamethasone (MDex) is a standard treatment for patients with AL amyloidosis who are not eligible for stem cell transplantation at many referral centers. However, following encouraging reports on the activity of bortezomib combined with alkylators and dexamethasone, these combinations are being moved to frontline therapy. We com...
Article
Abstract Systemic amyloid diseases are characterized by widespread protein deposition as amyloid fibrils. Precise diagnostic framing is the prerequisite for a correct management of patients. This complex process is achieved through a series of steps, which include detection of the tissue amyloid deposits, identification of the amyloid type, demonst...
Article
Full-text available
Key Points C elegans specifically recognizes cardiotoxic LCs as toxicants. This is an innovative model for studying the heart-specific toxicity of amyloidogenic LCs and developing new therapeutic strategies.
Article
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The combination of oral melphalan and dexamethasone is considered standard therapy for patients with light-chain amyloidosis ineligible for autologous stem cell transplantation. However, previous trials reported different rates of response and survival, mainly because of the different proportion of high-risk patients. In the present study, includin...
Article
In systemic amyloidosis, accumulation of misfolded proteins as extracellular amyloid fibrils in tissues causes severe organ dysfunction, but the molecular events of tissue damage related to amyloid deposition are still largely unknown. Through the use of MudPIT proteomic approach, comprehensive protein profiles of human amyloid-affected adipose tis...
Article
Full-text available
Monoclonal immunoglobulin light chains are normally synthesized in excess compared to the heavy chain partners and can be detected in serum and urine ("free" LC). Occasionally free LC are per se cause of organ toxicity, as in free LC-related disorders. In AL amyloidosis, the most common of these conditions, free LC with peculiar biophysical propert...
Article
Full-text available
Background: Nutrition status was shown to be a prognostic factor in patients with immunoglobulin light-chain amyloidosis (AL). However, malnutrition was associated with cardiac involvement, thus suggesting potential interactions. This study aim was to clarify the association among nutrition status, cardiac stage, and mortality in AL. Methods: On...
Article
Immunoglobulin light chain (LC) amyloidosis (AL) results from overproduction of circulating amyloidogenic LC proteins and subsequent amyloid fibril deposition in organs. Mortality in AL amyloidosis patients is highly associated with a rapidly progressive AL cardiomyopathy, marked by profound impairment of diastolic and systolic cardiac function and...
Article
Full-text available
Purpose: Congestive heart failure (CHF) represents the major cause of mortality among patients suffering primary amyloidosis (AL-A). The physiopathology and molecular mechanisms underlying this severe form of CHF remain elusive. Deposition of amyloid fibers seems to be the main cause but it has been recently shown that light chains (LC) isolated fr...
Article
Abstract The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A)...
Article
Amyloidoses are characterized by deposition of misfolded proteins as beta-pleated sheet fibrils in organs. Despite the similar morphologic appearance of fibrils, at least 28 different proteins have been identified as causative agents of amyloidosis in humans, 14 of which responsible for systemic forms. Correct identification of the amyloidogenic pr...
Article
AL amyloid cardiomyopathy is characterized by the deposition of amyloid fibers from monoclonal immunoglobulin light chain proteins (AL-LC) in the heart. We and others have shown that AL-LC directly results in cardiac toxicity; however, the mechanisms underlying this toxicity remain to be determined. Morphological examinations of hearts from patient...
Article
3913 The possibility of measuring the circulating free light chains (FLC) improved our ability to detect the amyloidogenic clone, allowed refined risk stratification in combination with cardiac biomarkers, and provided a formidable tool for assessing response to treatment in AL amyloidosis. Recently, a novel method for FLC quantitation based on mon...
Article
Immune-modulatory drugs are active in immunoglobulin light-chain amyloidosis and the addition of alkylating agents can potentiate their action. In this phase II prospective trial we treated with cyclophosphamide, lenalidomide and dexamethasone 21 patients who were refractory (13, 62%) or relapsed (8, 38%) after prior treatment including melphalan i...
Article
In Transthyretin amyloidosis (ATTR), tissue deposition of transthyretin fibrils translates into a significant subversion of the tissues proteome. We used multidimensional protein identification technology for profiling the proteome of subcutaneous adipose tissue in patients with ATTR, in comparison with controls and patients with other types of amy...
Article
In AL amyloidosis prognosis depends on the severity of heart dysfunction which is best assessed by natriuretic peptides (BNP and NT-proBNP). However, their clearance relies on glomerular filtration rate (GFR) and their concentration increases with renal failure. We evaluated the diagnostic and prognostic performance of NT-proBNP and BNP in 248 pati...
Article
Amyloidoses are characterized by the presence of extracellular amyloid deposits, constituted by fibrillar aggregates of misfolded proteins. Despite the similar morphologic appearance of fibrils, at least 28 different proteins have been detected as causative agents of human amyloidoses, 14 of which associated with systemic forms. Unequivocal typing...
Article
3977 Results from retrospective case series and from clinical trials indicate that bortezomib is highly effective in AL amyloidosis. In particular, early reports on associations with melphalan and dexamethasone (BMDex) and cyclophosphamide and dexamethasone (CyBorD) showed hematologic response rates of approximately 90%, with an unprecedented propo...
Article
Full-text available
Cardiac biomarkers play a major role in the identification of patients at risk of early death in AL amyloidosis, and a staging system based on amino-terminal pro-natriuretic peptide type-B (NT-proBNP) and troponins (cTn) is used for prognostic stratification. Adrenomedullin is produced by several tissues including the heart, and portends a poor pro...
Conference Paper
Full-text available
Aim. 99mTc Aprotinin has been employed as a suitable amyloid seeker with particular regard to cardiac involvement, however the use of a peptide could overcome the potential risk of virus and prion contamination of extractive aprotinin and potential ADR of recombinant allowing faster kinetics in vivo. Materials & Methods. The native Aprotinin molecu...
Article
Full-text available
Considering the important advances in treating specific types of systemic amyloidoses, unequivocal typing of amyloid deposits is now essential. Subcutaneous abdominal fat aspiration is the easiest, most common diagnostic procedure. We developed a novel, automated approach, based on Multidimensional Protein Identification Technology, for typing amyl...
Article
Full-text available
Nutritional status is an independent prognostic factor in immunoglobulin light-chain amyloidosis (AL), but its influence on quality of life (QoL) is unknown. The aim of this cross-sectional study was to investigate the association between nutritional status and QoL in AL patients at diagnosis. One hundred and fifty consecutive patients with biopsy-...
Article
Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry (MS)-based proteomics is useful for characterizing amyloid deposits. We used this approach to analyze transthyretin (TTR) in fat from patients with ATTR amyloidosis associated with various mutations. Extracted proteins were separated by 2D-PAGE. Spots uniquely presen...
Article
Mass spectrometry (MS)-based proteomics can directly identify amyloid deposits. We describe successful proteomic amyloid typing in fat aspirates in which immunoelectron microscopy (IEM) had not provided conclusive results. Samples with amyloid fibrils not labeled by the antibodies used in IEM were referred for 2D-PAGE-based comparative proteomics....
Article
In cardiac (light chain) AL amyloidosis, a decrease in circulating free light chains (FLCs) higher than 50% is associated with reduced N-terminal natriuretic peptide type B (NT-proBNP) serum concentration, improvement of heart failure symptoms, and prolonged survival. To assess the functional correlates of these changes, echocardiographic indices o...

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