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CEN Case Reports May 2014A 32-year-old Japanese woman presented with hypertension, nephrotic syndrome, microhematuria, and severe hypocomplementemia. Her serum creatinine concentration increased...
A 32-year-old Japanese woman presented with hypertension, nephrotic syndrome, microhematuria, and severe hypocomplementemia. Her serum creatinine concentration increased from 1.46 mg/dL (129.0 μmol/L) to 3.46 mg/dL (305.8 μmol/L) over 1 month. Renal biopsy revealed Congo red-negative nodular glomerulosclerosis accompanied by mesangial proliferation. There was extensive staining of immunoglobulin (Ig) G in the glomerular and tubular basement membranes and expanded mesangial regions. Staining was negative for IgA, IgM, and kappa and lambda light chains and positive for the gamma 1 IgG subclass. Staining for constant domains of the gamma heavy chains showed a deletion of the first constant domain (CH1). Electron microscopy revealed electron-dense deposits in the glomerular and tubular basement membranes and mesangium. These findings indicated gamma 1-heavy chain deposition disease (HCDD). Serum and urine immunoelectrophoresis revealed an IgG kappa monoclonal band, whereas bone marrow biopsy revealed monoclonal plasmacytosis with positive staining for kappa chains. HCDD associated with kappa light chain is extremely rare. We report the first case of HCDD with IgG kappa detected in the serum, urine, and bone marrow.
PubMed: 28509245
DOI: 10.1007/s13730-013-0083-0 -
Nature Communications Apr 2018Alternative cleavage and polyadenylation (ApA) is known to alter untranslated region (3'UTR) length but can also recognize intronic polyadenylation (IpA) signals to...
Alternative cleavage and polyadenylation (ApA) is known to alter untranslated region (3'UTR) length but can also recognize intronic polyadenylation (IpA) signals to generate transcripts that lose part or all of the coding region. We analyzed 46 3'-seq and RNA-seq profiles from normal human tissues, primary immune cells, and multiple myeloma (MM) samples and created an atlas of 4927 high-confidence IpA events represented in these cell types. IpA isoforms are widely expressed in immune cells, differentially used during B-cell development or in different cellular environments, and can generate truncated proteins lacking C-terminal functional domains. This can mimic ectodomain shedding through loss of transmembrane domains or alter the binding specificity of proteins with DNA-binding or protein-protein interaction domains. MM cells display a striking loss of IpA isoforms expressed in plasma cells, associated with shorter progression-free survival and impacting key genes in MM biology and response to lenalidomide.
Topics: 3' Untranslated Regions; Angiogenesis Inhibitors; Case-Control Studies; Gene Expression; Gene Library; Gene Ontology; Heavy Chain Disease; Humans; Immunoglobulin mu-Chains; Introns; Lenalidomide; Multiple Myeloma; Plasma Cells; Polyadenylation; Primary Cell Culture; Progression-Free Survival; Transcriptome
PubMed: 29712909
DOI: 10.1038/s41467-018-04112-z -
Acta Pharmaceutica Sinica. B Jun 2020Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead... (Review)
Review
Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase 1 (LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.
PubMed: 32837872
DOI: 10.1016/j.apsb.2020.06.007 -
Internal Medicine (Tokyo, Japan) 2010Heavy chain deposition disease (HCDD) is characterized by glomerular and tubular deposition of non-amyloidotic monoclonal heavy chains without associated light chains.... (Review)
Review
Heavy chain deposition disease (HCDD) is characterized by glomerular and tubular deposition of non-amyloidotic monoclonal heavy chains without associated light chains. We describe a case of gamma1-HCDD who presented with nephrotic syndrome, microhematuria, and hypocomplementemia. Renal biopsy showed lobular and nodular glomerulosclerosis along with IgG and C3 deposition. Electron microscopy revealed electron-dense deposits on the glomerular and tubular basement membranes and mesangium. Congo red staining was negative. Staining was positive for IgG1 on glomerular and tubular basement membranes but negative for IgG2-4, kappa and lambda light chains. Staining for the constant heavy chain domains showed the deletion of the first constant heavy chain domain. Thus, we diagnosed gamma1-HCDD. She was considered to be early-stage HCDD because proteinuria and hematuria were not observed before the nephrotic syndrome onset. Melphalan and prednisolone (MP) therapy reduced proteinuria as well as improved renal function and complement levels. Although renal prognosis of HCDD is poor, aggressive chemotherapy with MP may be effective in early-stage HCDD patients.
Topics: Aged; Drug Therapy, Combination; Female; Heavy Chain Disease; Humans; Immunoglobulin gamma-Chains; Melphalan; Prednisolone
PubMed: 20647658
DOI: 10.2169/internalmedicine.49.3499 -
British Medical Journal Nov 1968
Topics: Heavy Chain Disease; Humans; Immunoglobulin G; Male; Middle Aged
PubMed: 5687601
DOI: No ID Found -
The Journal of Clinical Investigation Apr 1969A new heavy chain disease protein ((gamma)HCD-JM) has been characterized by antigenic and structural criteria. The protein belongs to the IgG3-subclass and is closely...
A new heavy chain disease protein ((gamma)HCD-JM) has been characterized by antigenic and structural criteria. The protein belongs to the IgG3-subclass and is closely related to Fc-fragment of G3-immunoglobulins. The predominant N-terminal amino acid of this protein is glutamic acid in the uncyclized form, and that of another (gamma)HCD is glycine. Studies of the N-terminal peptides indicate that the N-terminal portion of the (gamma)3-heavy polypeptide chain is absent from the (gamma)HCD-JM. These findings rule out a process of normal heavy chain initiation and a large deletion of the Fd region as being responsible for these two heavy chain disease proteins. The (gamma)HCD-JM is a secretory product of cells from bone marrow as shown by studies of in vitro incorporation of amino acids-(14)C. Bone marrow and lymph node have a population of lymphoplasmacytic cells which by immunofluorescence contain (gamma)-heavy chain antigens in the absence of light chain antigens.
Topics: Amino Acids; Blood Proteins; Bone Marrow; Bone Marrow Cells; Carbon Isotopes; Fluorescent Antibody Technique; Heavy Chain Disease; Humans; Immunoelectrophoresis; Ultracentrifugation; gamma-Globulins
PubMed: 4180120
DOI: 10.1172/JCI106036 -
British Journal of Haematology Oct 2018
Topics: Diagnostic Imaging; Heavy Chain Disease; Humans; IgA Deficiency; Immunoglobulin A; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Immunoglobulin kappa-Chains; Multiple Myeloma
PubMed: 29808912
DOI: 10.1111/bjh.15420 -
Blood Jun 2011Heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by the production of monoclonal, incomplete, immunoglobulin (Ig) heavy chains (HCs) without... (Review)
Review
Heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by the production of monoclonal, incomplete, immunoglobulin (Ig) heavy chains (HCs) without associated light chains (LCs). These abnormal HCs are produced as a consequence of HC gene alterations in the neoplastic B cells. HC gene alterations will also impact on surface HC, which is part of the B-cell receptor (BCR), a crucial player in lymphocyte activation by antigen. The selective advantage conferred to mutant cells by abnormal BCR without an antigen-binding domain may be explained by activation of ligand-independent signaling, in analogy to what has been shown for mutated oncogenic growth factor receptors. Here we review data obtained from mouse models showing abnormal, constitutive activity of HCD-BCR, and we discuss the possible mechanism involved, namely, aberrant spontaneous self-aggregation. This self-aggregation might occur as a consequence of escape from the chaperone immunoglobulin binding protein (BiP) and from the anti-aggregation effect of LC association. The concept of misfolding-induced signaling elaborated here may extend to other pathologies termed conformational diseases.
Topics: Animals; Disease Models, Animal; Genes, Neoplasm; Heavy Chain Disease; Humans; Mice; Molecular Chaperones; Mutation; Receptors, Antigen, B-Cell; Signal Transduction
PubMed: 21508409
DOI: 10.1182/blood-2011-02-336164 -
Journal of Clinical Pathology.... 1975
Review
Topics: Amino Acid Sequence; Heavy Chain Disease; Humans; Immunoglobulin gamma-Chains; Immunoglobulin mu-Chains; Multiple Myeloma; Myeloma Proteins
PubMed: 830056
DOI: 10.1136/jcp.s1-6.1.65 -
Biochimie Apr 2015The deposition of misfolded peptides and proteins in the form of amyloid fibrils is the hallmark of nearly fifty medical disorders, including Alzheimer's disease,... (Review)
Review
The deposition of misfolded peptides and proteins in the form of amyloid fibrils is the hallmark of nearly fifty medical disorders, including Alzheimer's disease, Parkinson's disease, prion diseases and type II diabetes. These disorders, referred to as amyloidoses, generally become apparent late in life. Their psycho-sociological and economic incidence in western societies will be therefore considerable in the coming decades due to the ageing of the population. Neither preventing nor curative treatments are available yet. These disorders constitute therefore a medical challenge of great importance. Thus, an extensive research is being carried out to understand, at the molecular level, (i) how amyloidogenic proteins misfold and convert from their soluble form into amyloid fibrils, and (ii) how these aggregates or some of their oligomeric precursor species are toxic. The formation of amyloid fibrils proceeds through a complex nucleation/polymerisation mechanism with the formation of various species, including small oligomers. In this review, we focus on how VHHs or nanobodies, the antigen-binding domains of camelid heavy-chain antibodies, are being increasingly used to characterise each of the species formed on the pathway of fibril formation in terms of structure, stability, kinetics of formation and toxicity. We first introduce the characteristic features of nanobodies compared to those of conventional antibody fragments. Thereafter, we discuss how nanobodies, due to their unique properties, are used as probes to dissect the molecular mechanisms of misfolding and aggregation of six proteins associated with diseases, i.e. human lysozyme, β2-microglobulin, α-synuclein, prion, polyadenylate binding protein nuclear 1 and amyloid β-peptide. A brief general presentation of each disease and the associated peptide/protein is also provided. In addition, we discuss how nanobodies could be used as early diagnostic tools and as novel strategies to treat diseases associated with protein misfolding and aggregation.
Topics: Animals; Camelids, New World; Humans; Immunoglobulin Heavy Chains; Protein Aggregation, Pathological; Proteostasis Deficiencies; Single-Domain Antibodies
PubMed: 25656912
DOI: 10.1016/j.biochi.2015.01.012