ABSTRACT
BACKGROUND: ALPK3 encodes α-kinase 3, a muscle-specific protein of unknown function. ALPK3 loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood. METHODS: We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues. RESULTS: Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function. CONCLUSIONS: ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.
Subject(s)
Cardiomyopathies , Induced Pluripotent Stem Cells , Muscle Proteins , Protein Kinases , Adult , Animals , Child , Humans , Mice , Cardiomyopathies/genetics , Cardiomyopathies/metabolism , Connectin/metabolism , Induced Pluripotent Stem Cells/metabolism , Muscle Proteins/genetics , Myocytes, Cardiac/metabolism , Sarcomeres/metabolism , Protein Kinases/geneticsABSTRACT
Both genetic and environmental factors contribute to the development of dilated cardiomyopathy. Among the genes involved, TTN mutations, including truncated variants, explain 25% of DCM cases. We performed genetic counseling and analysis on a 57-year-old woman diagnosed with severe DCM and presenting relevant acquired risk factors for DCM (hypertension, diabetes, smoking habit, and/or previous alcohol and cocaine abuse) and with a family history of both DCM and sudden cardiac death. The left ventricular systolic function, as assessed by standard echocardiography, was 20%. The genetic analysis performed using TruSight Cardio panel, including 174 genes related to cardiac genetic diseases, revealed a novel nonsense TTN variant (TTN:c.103591A > T, p.Lys34531*), falling within the M-band region of the titin protein. This region is known for its important role in maintaining the structure of the sarcomere and in promoting sarcomerogenesis. The identified variant was classified as likely pathogenic based on ACMG criteria. The current results support the need of genetic analysis in the presence of a family history, even when relevant acquired risk factors for DCM may have contributed to the severity of the disease.
ABSTRACT
Transversal structural elements in cross-striated muscles, such as the M-band or the Z-disc, anchor and mechanically stabilize the contractile apparatus and its minimal unit-the sarcomere. The ability of proteins to target and interact with these structural sarcomeric elements is an inevitable necessity for the correct assembly and functionality of the myofibrillar apparatus. Specifically, the M-band is a well-recognized mechanical and signaling hub dealing with active forces during contraction, while impairment of its function leads to disease and death. Research on the M-band architecture is focusing on the assembly and interactions of the three major filamentous proteins in the region, mainly the three myomesin proteins including their embryonic heart (EH) isoform, titin and obscurin. These proteins form the basic filamentous network of the M-band, interacting with each other as also with additional proteins in the region that are involved in signaling, energetic or mechanosensitive processes. While myomesin-1, titin and obscurin are found in every muscle, the expression levels of myomesin-2 (also known as M-protein) and myomesin-3 are tissue specific: myomesin-2 is mainly expressed in the cardiac and fast skeletal muscles, while myomesin-3 is mainly expressed in intermediate muscles and specific regions of the cardiac muscle. Furthermore, EH-myomesin apart from its role during embryonic stages, is present in adults with specific cardiac diseases. The current work in structural, molecular, and cellular biology as well as in animal models, provides important details about the assembly of myomesin-1, obscurin and titin, the information however about the myomesin-2 and -3, such as their interactions, localization and structural details remain very limited. Remarkably, an increasing number of reports is linking all three myomesin proteins and particularly myomesin-2 to serious cardiovascular diseases suggesting that this protein family could be more important than originally thought. In this review we will focus on the myomesin protein family, the myomesin interactions and structural differences between isoforms and we will provide the most recent evidence why the structurally and biophysically unexplored myomesin-2 and myomesin-3 are emerging as hot targets for understanding muscle function and disease.
Subject(s)
Heart Diseases , Muscle Proteins , Animals , Connectin/analysis , Connectin/genetics , Connectin/metabolism , Muscle Proteins/genetics , Muscle, Skeletal/metabolism , Sarcomeres/chemistry , Sarcomeres/metabolismABSTRACT
Spinal muscular atrophy (SMA) is caused by a deletion or mutation of the survival motor neuron 1 (SMN1) gene. Reduced SMN levels lead to motor neuron degeneration and muscular atrophy. SMN protein localizes to the cytoplasm and Cajal bodies. Moreover, in myofibrils from Drosophila and mice, SMN is a sarcomeric protein localized to the Z-disc. Although SMN participates in multiple functions, including the biogenesis of spliceosomal small nuclear ribonucleoproteins, its role in the sarcomere is unclear. Here, we analyzed the sarcomeric organization of SMN in human control and type I SMA skeletal myofibers. In control sarcomeres, we demonstrate that human SMN is localized to the titin-positive M-band and actin-positive I-band, and to SMN-positive granules that flanked the Z-discs. Co-immunoprecipitation assays revealed that SMN interacts with the sarcomeric protein actin, α-actinin, titin, and profilin2. In the type I SMA muscle, SMN levels were reduced, and atrophic (denervated) and hypertrophic (nondenervated) myofibers coexisted. The hypertrophied myofibers, which are potential primary targets of SMN deficiency, exhibited sites of focal or segmental alterations of the actin cytoskeleton, where the SMN immunostaining pattern was altered. Moreover, SMN was relocalized to the Z-disc in overcontracted minisarcomeres from hypertrophic myofibers. We propose that SMN could have an integrating role in the molecular components of the sarcomere. Consequently, low SMN levels might impact the normal sarcomeric architecture, resulting in the disruption of myofibrils found in SMA muscle. This primary effect might be independent of the neurogenic myopathy produced by denervation and contribute to pathophysiology of the SMA myopathy.
Subject(s)
Muscle, Skeletal/metabolism , Muscular Atrophy, Spinal/metabolism , Myofibrils/metabolism , Sarcomeres/metabolism , HumansABSTRACT
Muscular contraction is a fundamental phenomenon in all animals; without it life as we know it would be impossible. The basic mechanism in muscle, including heart muscle, involves the interaction of the protein filaments myosin and actin. Motility in all cells is also partly based on similar interactions of actin filaments with non-muscle myosins. Early studies of muscle contraction have informed later studies of these cellular actin-myosin systems. In muscles, projections on the myosin filaments, the so-called myosin heads or cross-bridges, interact with the nearby actin filaments and, in a mechanism powered by ATP-hydrolysis, they move the actin filaments past them in a kind of cyclic rowing action to produce the macroscopic muscular movements of which we are all aware. In this special issue the papers and reviews address different aspects of the actin-myosin interaction in muscle as studied by a plethora of complementary techniques. The present overview provides a brief and elementary introduction to muscle structure and function and the techniques used to study it. It goes on to give more detailed descriptions of what is known about muscle components and the cross-bridge cycle using structural biology techniques, particularly protein crystallography, electron microscopy and X-ray diffraction. It then has a quick look at muscle mechanics and it summarises what can be learnt about how muscle works based on the other studies covered in the different papers in the special issue. A picture emerges of the main molecular steps involved in the force-producing process; steps that are also likely to be seen in non-muscle myosin interactions with cellular actin filaments. Finally, the remarkable advances made in studying the effects of mutations in the contractile assembly in causing specific muscle diseases, particularly those in heart muscle, are outlined and discussed.
Subject(s)
Actins/metabolism , Muscles/physiology , Myosins/metabolism , Actins/chemistry , Animals , Humans , Models, Biological , Muscle Contraction , Muscle, Striated/physiology , Muscle, Striated/ultrastructure , Muscles/ultrastructure , Myosins/chemistry , Protein Binding , Sarcomeres/metabolism , Structure-Activity RelationshipABSTRACT
Titin (TTN) has multifunctional roles in sarcomere assembly, mechanosignaling transduction, and muscle stiffness. TTN splicing generates variable protein sizes with different functions. Therefore, understanding TTN splicing is important to develop a novel treatment for TTN-based diseases. The I-band TTN splicing regulated by RNA binding motif 20 (RBM20) has been extensively studied. However, the Z- and M-band splicing and regulation remain poorly understood. Herein, we aimed to define the Z- and M-band splicing in striated muscles and determined whether RBM20 regulates the Z- and M-band splicing. We discovered four new Z-band TTN splicing variants, and one of them dominates in mouse, rat, sheep, and human hearts. But only one form can be detected in frog and chicken hearts. In skeletal muscles, three new Z repeats (Zr) were detected, and Zr4 to 6 exclusion dominates in the fast muscles, whereas Zr4 skipping dominates in the slow muscle. No developmental changes were detected in the Z-band. In the M-band, two new variants were discovered with alternative 3' splice site in exon363 (Mex5) and alternative 5' splice site in intron 362. However, only the sheep heart expresses two new variants rather than other species. Skeletal muscles express three M-band variants with altered ratios of Mex5 inclusion to Mex5 exclusion. Finally, we revealed that RBM20 does not regulate the Z- and M-band splicing in the heart, but does in skeletal muscles. Taken together, we characterized the Z- and M-band splicing and provided the first evidence of the role of RBM20 in the Z- and M-band TTN splicing.
Subject(s)
Connectin/metabolism , Muscle, Skeletal/metabolism , Myocardium/metabolism , RNA-Binding Proteins/metabolism , Alternative Splicing , Animals , Connectin/genetics , Humans , Mice , Protein Kinases/genetics , Protein Kinases/metabolism , RNA Splice Sites , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Sarcomeres/metabolism , Sheep/genetics , Sheep/metabolismABSTRACT
Cells that constitute fully differentiated tissues are characterised by an architecture that makes them perfectly suited for the job they have to do. This is especially obvious for cardiomyocytes, which have an extremely regular shape and display a paracrystalline arrangement of their cytoplasmic components. This article will focus on the two major cytoskeletal multiprotein complexes that are found in cardiomyocytes, the myofibrils, which are responsible for contraction and the intercalated disc, which mediates mechanical and electrochemical contact between individual cardiomyocytes. Recent studies have revealed that these two sites are also crucial in sensing excessive mechanical strain. Signalling processes will be triggered that## lead to changes in gene expression and eventually lead to an altered cardiac cytoarchitecture in the diseased heart, which results in a compromised function. Thus, understanding these changes and the signals that lead to them is crucial to design treatment strategies that can attenuate these processes. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
Subject(s)
Cell Communication , Heart/anatomy & histology , Heart/physiology , Mechanotransduction, Cellular , Myocardium/cytology , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Myofibrils/metabolism , Animals , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/physiopathology , Gene Expression Regulation , Humans , Membrane Potentials , Myocardial Contraction , Stress, MechanicalABSTRACT
Highly ordered organisation of striated muscle is the prerequisite for the fast and unidirectional development of force and motion during heart and skeletal muscle contraction. A group of proteins, summarised as the sarcomeric cytoskeleton, is essential for the ordered assembly of actin and myosin filaments into sarcomeres, by combining architectural, mechanical and signalling functions. This review discusses recent cell biological, biophysical and structural insight into the regulated assembly of sarcomeric cytoskeleton proteins and their roles in dissipating mechanical forces in order to maintain sarcomere integrity during passive extension and active contraction. α-Actinin crosslinks in the Z-disk show a pivot-and-rod structure that anchors both titin and actin filaments. In contrast, the myosin crosslinks formed by myomesin in the M-band are of a ball-and-spring type and may be crucial in providing stable yet elastic connections during active contractions, especially eccentric exercise.
Subject(s)
Cytoskeleton/metabolism , Motion , Sarcomeres/metabolism , Animals , Humans , Models, Biological , Muscle Proteins/metabolismABSTRACT
The first descriptions of muscle spindles with intrafusal fibres containing striated myofibrils and nervous elements were given approximately 150â years ago. It took, however, another 100â years to establish the presence of two types of intrafusal muscle fibres: nuclear bag and nuclear chain fibres. The present paper highlights primarily the contribution of Robert Banks in fibre typing of intrafusal fibres: the confirmation of the principle of two types of nuclear bag fibres in mammalian spindles and the variation in occurrence of a dense M-band along the fibres. Furthermore, this paper summarizes how studies from the Umeå University group (Laboratory of Muscle Biology in the Department of Integrative Medical Biology) on fibre typing and the structure and composition of M-bands have contributed to the current understanding of muscle spindle complexity in adult humans as well as to muscle spindle development and effects of ageing. The variable molecular composition of the intrafusal sarcomeres with respect to myosin heavy chains and M-band proteins gives new perspectives on the role of the intrafusal myofibrils as stretch-activated sensors influencing tension/stiffness and signalling to nuclei.
Subject(s)
Muscle Spindles/anatomy & histology , Aging , Animals , Connectin/physiology , Connectin/ultrastructure , Cytoskeleton , Elasticity/physiology , Humans , Muscle Development/physiology , Muscle Spindles/physiology , Myofibrils/physiology , Myosin Heavy Chains/physiologyABSTRACT
The filament lattice in relaxed striated muscle is thought to be stabilized by electrostatic forces between charged filaments; electrostatic theories based on known filament charge densities do predict that the lattice spacing drops slightly with sarcomere length when actin and myosin filaments overlap. However, at sarcomere lengths with no overlap, electrostatic forces are reduced to a very low level and electrostatic models predict that the lattice collapses to a much smaller spacing. This collapse is not observed, which suggests that the A-band and I-band lattices are stabilized mechanically by the M-band and Z-line. To determine which mechanisms operate, consider a model where charged-filament interactions are supplemented by elastic titin filaments and radially elastic M-bands and Z-lines. To make progress, this model is simplified by assuming that the areas of A-band and Z-line unit cells are equal. Published data for the length-dependence of the lattice spacing, in and out of overlap, can be fitted to a mechanical model with known titin elasticity and very weak M-band or Z-line stiffness (≈0.15 pN/nm per unit cell), which implies that electrostatic interactions cannot be ignored. A better fit is obtained when electrostatic interactions are restored. Electrostatic interactions also explain why the lattice spacing of relaxed muscle is a decreasing function of temperature.
Subject(s)
Models, Biological , Muscle Fibers, Skeletal/physiology , Muscle Relaxation/physiology , Static Electricity , Animals , HumansABSTRACT
Multiple myeloma is a disease of the plasma cells of the bone marrow, resulting in the proliferation and release of the monoclonal protein, which further causes end-organ damage. We report an unusual presentation of multiple myeloma, thereby insisting on the need for the treating physician to be aware of the various presentations that can be encountered in regular practice. It is often difficult to diagnose, and the diagnosis is usually made at a late stage of the disease. Even though uncurable, with recent advances, a proper regimen, newer chemotherapeutic agents, and stem cell transplantation, the disease can be brought into remission.
ABSTRACT
Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. It commonly presents with bone pain, anemia, renal failure, and hypercalcemia. Pleural effusion in MM usually has multiple causes, but it is rare for the effusion to be due to myelomatous deposition of the pleura. Here, we present a rare case in which the patient presented to the outpatient department with a dry cough, breathlessness, and generalized weakness. The patient was diagnosed with MM with myelomatous pleural effusion (MPE), highlighting the importance of considering MM as a differential diagnosis in patients with atypical presentations. MPE indicates a poor prognosis, and early consideration of MPE can lead to an earlier diagnosis and a more effective treatment of MM.
ABSTRACT
Cardiomyocytes that are derived from human-induced pluripotent stem cells (iPSC-CM) are an exciting tool to investigate cardiomyopathy disease mechanisms at the cellular level as well as to screen for potential side effects of novel drugs. However, currently their benefit is limited due to their fairly immature differentiation status under conventional culture conditions. This review is mainly aimed at researchers outside of the iPSC-CM field and will describe potential pitfalls and which features at the level of the myofibrils would be desired to make them a more representative model system. We will also discuss different strategies that may help to achieve these.
ABSTRACT
Fluorescence in situ hybridization (FISH) to metaphase chromosomes, in conjunction with SNP array, array CGH, or whole genome sequencing, can help determine the organization of abnormal genomes after chromothripsis and other types of complex genome rearrangement. DNA microarrays can identify the changes in copy number, but they do not give information on the organization of the abnormal chromosomes, balanced rearrangements, or abnormalities of the centromeres and other regions comprised of highly repetitive DNA. Many of these details can be determined by the strategic use of metaphase FISH. FISH is a single-cell technique, so it can identify low-frequency chromosome abnormalities, and it can determine which chromosome abnormalities occur in the same or different clonal populations. These are important considerations in cancer. Metaphase chromosomes are intact, so information about abnormalities of the chromosome homologues is preserved. Here we describe strategies for working out the organization of highly rearranged genomes by combining SNP array data with various metaphase FISH methods. This approach can also be used to address some of the uncertainties arising from whole genome or mate-pair sequencing data.
Subject(s)
Chromothripsis , In Situ Hybridization, Fluorescence , Oligonucleotide Array Sequence Analysis , Chromosome Banding , Humans , Karyotype , Polymorphism, Single NucleotideABSTRACT
The sarcomeric cytoskeleton is a network of modular proteins that integrate mechanical and signaling roles. Obscurin, or its homolog obscurin-like-1, bridges the giant ruler titin and the myosin crosslinker myomesin at the M-band. Yet, the molecular mechanisms underlying the physical obscurin(-like-1):myomesin connection, important for mechanical integrity of the M-band, remained elusive. Here, using a combination of structural, cellular, and single-molecule force spectroscopy techniques, we decode the architectural and functional determinants defining the obscurin(-like-1):myomesin complex. The crystal structure reveals a trans-complementation mechanism whereby an incomplete immunoglobulin-like domain assimilates an isoform-specific myomesin interdomain sequence. Crucially, this unconventional architecture provides mechanical stability up to forces of â¼135 pN. A cellular competition assay in neonatal rat cardiomyocytes validates the complex and provides the rationale for the isoform specificity of the interaction. Altogether, our results reveal a novel binding strategy in sarcomere assembly, which might have implications on muscle nanomechanics and overall M-band organization.
Subject(s)
Connectin/chemistry , Connectin/metabolism , Cytoskeletal Proteins/chemistry , Cytoskeletal Proteins/metabolism , Rho Guanine Nucleotide Exchange Factors/chemistry , Rho Guanine Nucleotide Exchange Factors/metabolism , Animals , Binding Sites , Cells, Cultured , Crystallography, X-Ray , Cytoskeleton/metabolism , Humans , Immunoglobulins/metabolism , Models, Molecular , Muscle, Skeletal/metabolism , Myocytes, Cardiac/metabolism , Protein Binding , Protein Domains , Protein Serine-Threonine Kinases , Rats , Sarcomeres/metabolismABSTRACT
BACKGROUND: Monoclonal gammopathies occurs in patients with malignant diseases of plasma cells and lymphocytes and in few benign conditions. The objective of this study was to assess the precision, accuracy and confirmation of monoclonal gammopathies on serum protein electrophoresis (SPE) and the clinical relevance of detection and characterization of M component. METHODS: All samples received for serum electrophoresis in the last 3 years were analysed for data on M band positivity and correlating it with clinical profile of the patients. Immunofixation (IFE), Immunoelectrophoresis (IEP) and IgG, IgM estimation were carried out in few cases. The follow up of cases was done by serial monitoring of SPE and ß2 microglobulin levels. RESULTS: 1155 samples were received during the 3 years period. 282 (24.4%) samples were positive for M component on SPE. Of these, 239 (84.8%) patients had M spike in λ region and 43 patients had M spike in ß region. The mean load of the M protein band in the λ region was 37.8% and in ß region was 35.8%. IgG with κ chain was seen in 40%, IgG with λ chain was seen in 50%, 5% patients each had IgM with κ and IgA with λ light chain. 246 samples (96.5%) had high levels of ß2 microglobulin. Of the 116 cases of multiple myeloma, IgG levels was more commonly raised (5%) as compared to IgA (6.9%) and IgM (5.2%). CONCLUSION: It is recommended that SPE should be performed in patients having unexplained weakness, anaemia, back pain, osteoporosis, osteolytic lesions, fractures, renal insufficiency or recurrent infections.
ABSTRACT
Hypertrophic cardiomyopathy is characterised by a histological phenotype of myocyte disarray, but heart tissue samples from patients with dilated cardiomyopathy (DCM) often look comparatively similar to those from healthy individuals apart from conspicuous regions of fibrosis and necrosis. We have previously investigated subcellular alterations in the cytoarchitecture of mouse models of dilated cardiomyopathy and found that both the organisation and composition of the intercalated disc, i.e. the specialised type of cell-cell contact in the heart, is altered. There is also is a change in the composition of the M-band of the sarcomere due to an expression shift towards the more extensible embryonic heart (EH)-myomesin isoform. Analysis of human samples from the Sydney Human Heart Tissue Bank have revealed similar structural findings and also provided evidence for a dramatic change in overall cardiomyocyte size control, which has also been seen in the mouse. Together these changes in cytoarchitecture probably contribute to the decreased functional output that is seen in DCM.
ABSTRACT
M10 is the most C-terminal immunoglobulin (Ig) domain of the giant protein titin and a frequent target of disease-linked mutations. Currently, it is the only known muscle Ig domain able to interact with two alternative ligands-obscurin and obscurin-like-1 (Obsl1)-in different sarcomeric subregions. Obscurin and Obsl1 use their homologous N-terminal Ig domain (O1 in obscurin and OL1 in Obsl1) to bind M10 in a mutually exclusive manner. We present here the X-ray structure of the human titin:obscurin M10:O1 complex extending our previous work on the M10:OL1 interaction. Similar to M10:OL1, the M10:O1 complex displays a chevron-shaped antiparallel Ig-Ig architecture held together by a conserved molecular interface, which we validated by isothermal titration calorimetry and sorting experiments in neonatal rat cardiomyocytes. O1, although structurally related to OL1 and M10, both members of the intermediate set (I-set) Ig family, presents an intriguing switch of its ßA' strand. This leads to structural differences between the complexes, particularly for the "open side" of the chevron-shaped assembly. A bioinformatics analysis reveals that the ßA'-switch observed for O1 is rare and that it is involved in mediating protein-protein interactions. Molecular dynamics simulations also suggest that this topological alteration substantially increases local flexibility compared to the conventional I-set Ig domains. The O1/OL1 Ig domains are candidate discriminatory structural modules potentially directing the binding of specific additional partners at the M-band. Cellular sorting experiments in neonatal rat cardiomyocytes are consistent with the view that the titin:obscurin/Obsl1 complexes might be a platform for higher-order interactions.
Subject(s)
Connectin/ultrastructure , Myocytes, Cardiac/metabolism , Rho Guanine Nucleotide Exchange Factors/ultrastructure , Amino Acid Sequence , Animals , Calorimetry , Connectin/chemistry , Crystallography, X-Ray , Cytoskeletal Proteins/chemistry , Humans , Models, Molecular , Molecular Dynamics Simulation , Molecular Sequence Data , Multiprotein Complexes/ultrastructure , Protein Serine-Threonine Kinases , Protein Structure, Tertiary , Rats , Rho Guanine Nucleotide Exchange Factors/chemistryABSTRACT
Pleural effusion in case of multiple myeloma is usually multifactorial but effusion due to myelomatous deposition of pleura is extremely uncommon. We are reporting a unique case of unsuspected multiple myeloma presenting as left sided massive pleural effusion due to myelomatous deposit in pleura and a rare M-band in the alpha-2 region in serum protein electrophoresis. A 61 year lady presented with cough, weakness and progressive shortness of breath. Examination revealed mild pallor and left sided massive pleural effusion that re-accumulated despite treatment. PAP stained smear of pleural fluid showed a large number of plasma cells and pleural biopsy revealed infiltration of plasma cells. Fiber-optic bronchoscopy was inconclusive. Blood examination revealed high value of alpha-2 globulin. Serum electrophoresis showed M band in alpha-2 region and urine electrophoresis showed faint monoclonal light chain pattern. X-ray skull showed multiple punched out osteolytic lesions. Bone marrow examination revealed hypercellular marrow with atypical plasma cells including binucleate forms in large number (above 55% of nucleated cell population).
ABSTRACT
Objective To develop and evaluate the digital discrimination system for pancreatic ultrasound endoscopy images. Methods EUS images of 153 pancreatic cancer and 63 non-cancer cases were selected. According to the multi-fractal feature vectors based on the M-band wavelet transform, we acquired the fractal features with lower dimension with the feature screening algorithm. With the optimal feature combination, cases were classified into pancreatic cancer group and non-pancreatic cancer group automatically.Then the sensitivity, specificity and accuracy of this method were calculated, and compared with those of traditional 9 dimension fractal feature vectors. Results Three kinds of multi-fractal dimensions were introduced to the framework of M-band wavelet transform according to the EUS images to form fractal vectors of 18 dimension. With the selection by sequence forward search (SFS) algorithm, 7 dimension of feature vectors were chosen and were combined with bi-order multi-fractal dimension to a better feature combination. The Bayes, support vector machine (SVM) and ModestAdaBoost classifiers were introduced to evaluate the classification efficiency, resulting in a classification accuracy of 97.98% and short running time of 0. 49 s with lower feature dimension. Conclusion These data suggest the feasibility, accuracy, noninvasiveness and efficacy of classification of EUS images to differentiate pancreatic cancer from normal tissue based on the Mband wavelet transform algorithm. It is a new and valuable research area in diagnosis of pancreatic cancer.