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Medicine Dec 2019Pleomorphic adenoma is the most common salivary gland neoplasm with a variety of histologic appearances. Due to this diversity, precise preoperative diagnosis through... (Observational Study)
Observational Study
Pleomorphic adenoma is the most common salivary gland neoplasm with a variety of histologic appearances. Due to this diversity, precise preoperative diagnosis through fine needle aspiration cytology is difficult.This study sought to identify the differentially expressed genes in pleomorphic adenoma to aid precise diagnosis and clarify the mechanism of tumorigenesis.Suppressive subtractive hybridization was performed on pleomorphic adenoma tissues and the corresponding normal salivary gland tissues to screen of the differential expression of genes in pleomorphic adenoma.Four known genes (microfibrillar associated protein 4 [MFAP4], dystonin [DST], solute carrier family 35 [SLC35], and potassium channel tetramerization domain containing 15 [KCTD15]) were differentially expressed in the tumors compared with the genes in normal tissues. The expression profiles were further confirmed in 15 pleomorphic adenoma and corresponding normal salivary gland tissues by quantitative real-time reverse transcription-polymerase chain reaction.MFAP4, DST, SLC35, and KCTD15 gene expression could be potential biomarkers of pleomorphic adenoma for precise diagnosis.
Topics: Adenoma, Pleomorphic; Adolescent; Adult; Female; Gene Expression Profiling; Humans; Male; Middle Aged; Salivary Gland Neoplasms; Young Adult
PubMed: 31861025
DOI: 10.1097/MD.0000000000018468 -
Frontiers in Immunology 2019Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal... (Clinical Trial)
Clinical Trial
Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants. The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients ( = 180) and age- and sex-matched healthy controls ( = 188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP ( = 89) and control cohort ( = 104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (50%; 3 in 6 BP with haplogroup T). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.16051A>G, and m.16162A>G in the D-loop region of the mtDNA, and m.11914G>A in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 gene (), were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data ( = 0.0017, = 0.0129, = 0.0076, and = 0.0132, respectively, Peto's test). More specifically, the three SNPs in the D-loop region were negatively, and the SNP in the gene was positively associated with BP. Our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.
Topics: Aged; Aged, 80 and over; Autoantibodies; Autoantigens; DNA, Mitochondrial; Dystonin; Female; Genome, Mitochondrial; High-Throughput Nucleotide Sequencing; Humans; Male; NADH Dehydrogenase; Non-Fibrillar Collagens; Pemphigoid, Bullous; Polymorphism, Single Nucleotide; Collagen Type XVII
PubMed: 31824475
DOI: 10.3389/fimmu.2019.02200 -
PloS One 2014BPAG1a and BPAG1b (BPAG1a/b) constitute two major isoforms encoded by the dystonin (Dst) gene and show homology with MACF1a and MACF1b. These proteins are members of the...
BPAG1a and BPAG1b (BPAG1a/b) constitute two major isoforms encoded by the dystonin (Dst) gene and show homology with MACF1a and MACF1b. These proteins are members of the plakin family, giant multi-modular proteins able to connect the intermediate filament, microtubule and microfilament cytoskeletal networks with each other and to distinct cell membrane sites. They also serve as scaffolds for signaling proteins that modulate cytoskeletal dynamics. To gain better insights into the functions of BPAG1a/b, we further characterized their C-terminal region important for their interaction with microtubules and assessed the role of these isoforms in the cytoskeletal organization of C2.7 myoblast cells. Our results show that alternative splicing does not only occur at the 5' end of Dst and Macf1 pre-mRNAs, as previously reported, but also at their 3' end, resulting in expression of additional four mRNA variants of BPAG1 and MACF1. These isoform-specific C-tails were able to bundle microtubules and bound to both EB1 and EB3, two microtubule plus end proteins. In the C2.7 cell line, knockdown of BPAG1a/b had no major effect on the organization of the microtubule and microfilament networks, but negatively affected endocytosis and maintenance of the Golgi apparatus structure, which became dispersed. Finally, knockdown of BPAG1a/b caused a specific decrease in the directness of cell migration, but did not impair initial cell adhesion. These data provide novel insights into the complexity of alternative splicing of Dst pre-mRNAs and into the role of BPAG1a/b in vesicular transport, Golgi apparatus structure as well as in migration in C2.7 myoblasts.
Topics: Actin Cytoskeleton; Alternative Splicing; Animals; Carrier Proteins; Cell Line; Cell Movement; Cytoskeletal Proteins; Cytoskeleton; Dystonin; Endocytosis; Golgi Apparatus; Mice; Microtubule-Associated Proteins; Microtubules; Molecular Sequence Data; Myoblasts; Nerve Tissue Proteins; Protein Isoforms
PubMed: 25244344
DOI: 10.1371/journal.pone.0107535 -
RNA (New York, N.Y.) Oct 2014IRBIS is a computational pipeline for detecting conserved complementary regions in unaligned orthologous sequences. Unlike other methods, it follows the... (Comparative Study)
Comparative Study
IRBIS is a computational pipeline for detecting conserved complementary regions in unaligned orthologous sequences. Unlike other methods, it follows the "first-fold-then-align" principle in which all possible combinations of complementary k-mers are searched for simultaneous conservation. The novel trimming procedure reduces the size of the search space and improves the performance to the point where large-scale analyses of intra- and intermolecular RNA-RNA interactions become possible. In this article, I provide a rigorous description of the method, benchmarking on simulated and real data, and a set of stringent predictions of intramolecular RNA structure in placental mammals, drosophilids, and nematodes. I discuss two particular cases of long-range RNA structures that are likely to have a causal effect on single- and multiple-exon skipping, one in the mammalian gene Dystonin and the other in the insect gene Ca-α1D. In Dystonin, one of the two complementary boxes contains a binding site of Rbfox protein similar to one recently described in Enah gene. I also report that snoRNAs and long noncoding RNAs (lncRNAs) have a high capacity of base-pairing to introns of protein-coding genes, suggesting possible involvement of these transcripts in splicing regulation. I also find that conserved sequences that occur equally likely on both strands of DNA (e.g., transcription factor binding sites) contribute strongly to the false-discovery rate and, therefore, would confound every such analysis. IRBIS is an open-source software that is available at http://genome.crg.es/~dmitri/irbis/.
Topics: Animals; Base Sequence; Caenorhabditis elegans; Conserved Sequence; Drosophila melanogaster; Exons; Genes; Humans; Introns; Molecular Sequence Data; RNA Splicing; RNA, Small Nucleolar; Sequence Homology, Nucleic Acid; Software
PubMed: 25142064
DOI: 10.1261/rna.045088.114 -
The Journal of Investigative Dermatology May 2021Bullous pemphigoid (BP) is an autoimmune blistering disease that targets the hemidesmosomal proteins BP180 and BP230/BPAG1e. Whereas the role of anti-BP180 antibodies...
Bullous pemphigoid (BP) is an autoimmune blistering disease that targets the hemidesmosomal proteins BP180 and BP230/BPAG1e. Whereas the role of anti-BP180 antibodies has been extensively characterized, the pathogenicity of anti-BPAG1e antibodies remains unclear. The purpose of this study is to elucidate the role of antibodies to BPAG1e in the experimental bullous pemphigoid models. We generated Bpag1 conditional knockout mice, where the knockout of Bpag1 is restricted to keratin 5-expressing epithelial cells. Bpag1 conditional knockout mice were immunized with the C-terminal portion of BPAG1e, and the splenocytes were injected into Rag2 mice intravenously. The recipient mice presented with erosion on the feet and tails. Microscopic examination showed subepidermal blisters and a linear deposition of IgG at the dermal-epidermal junction. To assess the potential role of trauma on BP development, we inflicted surface wounds on the dorsum of the Rag2 recipient mice after adoptive transfer. The wounded Rag2 mice had increased morbidity and severity of BP-like symptoms. Moreover, the depletion of B cells from splenocytes abolished a subepidermal blistering phenotype in vivo. These findings demonstrate that antibodies to BPAG1e might play a pathogenic role in causing subepidermal blistering, and external factors, including trauma, might be a trigger for BP development.
Topics: Animals; Autoantibodies; DNA-Binding Proteins; Disease Models, Animal; Dystonin; Immunization; Mice; Mice, Inbred C57BL; Pemphigoid, Bullous
PubMed: 33069726
DOI: 10.1016/j.jid.2020.08.031 -
Cureus Aug 2023We report a case of a 3-year-old Saudi female patient as the first case reported in Saudi Arabia who is homozygous for dystonin c.3370C>T, p.(Gln1124*). At the age of 3...
We report a case of a 3-year-old Saudi female patient as the first case reported in Saudi Arabia who is homozygous for dystonin c.3370C>T, p.(Gln1124*). At the age of 3 months, the girl started to develop numerous vesicles and bullae involving the dorsum of the feet that were not on a pressure site, with remission and aggravation, but she had no mucosal lesions or nail affection. The patient was diagnosed with epidermolysis bullosa simplex.
PubMed: 37692655
DOI: 10.7759/cureus.43206 -
Molecular Biology of the Cell May 2022The spectraplakin family of proteins includes ACF7/MACF1 and BPAG1/dystonin in mammals, VAB-10 in in zebrafish, and Short stop (Shot), the sole member. Spectraplakins...
The spectraplakin family of proteins includes ACF7/MACF1 and BPAG1/dystonin in mammals, VAB-10 in in zebrafish, and Short stop (Shot), the sole member. Spectraplakins are giant cytoskeletal proteins that cross-link actin, microtubules, and intermediate filaments, coordinating the activity of the entire cytoskeleton. We examined the role of Shot during cell migration using two systems: the in vitro migration of tissue culture cells and in vivo through border cell migration. RNA interference (RNAi) depletion of Shot increases the rate of random cell migration in tissue culture cells as well as the rate of wound closure during scratch-wound assays. This increase in cell migration prompted us to analyze focal adhesion dynamics. We found that the rates of focal adhesion assembly and disassembly were faster in Shot-depleted cells, leading to faster adhesion turnover that could underlie the increased migration speeds. This regulation of focal adhesion dynamics may be dependent on Shot being in an open confirmation. Using border cells as an in vivo model for cell migration, we found that RNAi depletion led to precocious border cell migration. Collectively, these results suggest that spectraplakins not only function to cross-link the cytoskeleton but may regulate cell-matrix adhesion.
Topics: Actins; Animals; Cell Movement; Cytoskeletal Proteins; Drosophila; Drosophila Proteins; Focal Adhesions; Mammals; Microfilament Proteins; Microtubules; Zebrafish
PubMed: 35235367
DOI: 10.1091/mbc.E21-09-0434 -
The Journal of Investigative Dermatology Sep 2019Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion...
Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion molecules, known as BP180 and BP230. Homologues to these proteins are found in the brain, and it is hypothesized that neurologic disease leads to the production of autoantibodies that can cross-react with their cutaneous forms. To better understand the link between BP and neurologic disease, we evaluated primary demographic features (age, sex, race, ethnicity, and elapsed time between onset of skin symptoms and BP diagnosis), severity of BP, and IgG and IgE autoantibody levels in BP control individuals and patients with BP with preceding Parkinson disease, dementia, and stroke. The main findings of this study are that patients with BP with preceding neurologic disease have a shorter elapsed time between onset of skin disease and BP diagnosis and that patients with preceding Parkinson disease or dementia, but not stroke, are significantly older than patients with BP without neurologic disease. However, no significant differences in clinical presentation, BP severity scores, or autoantibody (IgG and IgE) responses were observed among the groups. These findings suggest that, despite the age difference, the clinical phenotype of BP is not affected by preceding neurologic disease.
Topics: Age Factors; Age of Onset; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Comorbidity; Dementia; Dystonin; Female; Humans; Incidence; Male; Middle Aged; Non-Fibrillar Collagens; Parkinson Disease; Pemphigoid, Bullous; Risk Factors; Severity of Illness Index; Sex Factors; Stroke; Time Factors; Collagen Type XVII
PubMed: 30876802
DOI: 10.1016/j.jid.2019.01.034 -
BMC Pediatrics Jun 2021MYCN amplification and age are two critical prognostic factors of pediatric neuroblastoma. Previously, we had revealed the prognosis of MYCN target genes. However, the...
BACKGROUND
MYCN amplification and age are two critical prognostic factors of pediatric neuroblastoma. Previously, we had revealed the prognosis of MYCN target genes. However, the prognostic effects of age related genes in neuroblastoma are unclear.
METHODS
The prognostic significance of age and MYCN amplification was determined through multivariate cox regression and Kaplan-Meier survival analysis. Genes differentially expressed in MYCN non-amplified younger neuroblastoma patients were identified using Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. The prognostic effects of age related genes ALCAM, CACNA2D3, DST, EPB41L4A and KIF1B in pediatric neuroblastoma patients were determined by Kaplan-Meier survival.
RESULTS
In a pediatric pan-cancer analysis, age was associated with the overall survival of pediatric B-lineage acute lymphoblastic leukemia, neuroblastoma and wilms tumor in TARGET dataset. Moreover, the prognostic effects of age in neuroblastoma were validated using two independent neuroblastoma cohorts. Furthermore, age and MYCN amplification were independent prognostic factors in pediatric neuroblastoma. Compared with MYCN non-amplified older neuroblastoma patients, MYCN non-amplified younger neuroblastoma patients had better clinical outcomes. ALCAM, CACNA2D3, DST, EPB41L4A and KIF1B were highly expressed in MYCN non-amplified younger neuroblastoma patients. And the higher expression levels of ALCAM, CACNA2D3, DST, EPB41L4A or KIF1B were associated with better prognosis of MYCN non-amplified neuroblastoma patients. DST was an independent prognostic factor in MYCN non-amplified neuroblastoma patients and MYCN non-amplified neuroblastoma younger patients with higher DST expression levels had the best clinical overall survival.
CONCLUSIONS
Age related gene DST was an independent prognostic factor in MYCN non-amplified neuroblastoma. MYCN non-amplified younger neuroblastoma patients with higher DST expression levels had the best clinical overall survival.
Topics: Child; Dystonin; Gene Amplification; Gene Expression; Humans; N-Myc Proto-Oncogene Protein; Neuroblastoma; Prognosis
PubMed: 34116676
DOI: 10.1186/s12887-021-02753-6 -
Anti-BP180 Autoantibodies Are Present in Stroke and Recognize Human Cutaneous BP180 and BP180-NC16A.Frontiers in Immunology 2019Current evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP...
Current evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP autoantibodies in patients with stroke has not previously been investigated. Our study aimed to assess BP antigen-specific antibodies in stroke patients. One hundred patients with stroke and 100 matched healthy controls were randomly selected for measurement of anti-BP180/BP230 IgG autoantibodies by enzyme-linked immunosorbent assay (ELISA), salt-split indirect immunofluorescence (IIF), and immunoblotting against human cutaneous BP180 and BP180-NC16A. Anti-BP180 autoantibodies were found in 14 (14.0%) patients with stroke and 5 (5.0%) of controls by ELISA ( < 0.05). Sera from 13 (13.0%) patients with stroke and 3 (3.0%) controls reacted with 180-kDa proteins from human epidermal extract ( < 0.05). 11 (11.0%) of stroke and 2 (2.0%) of control sera recognized the human recombinant full length BP180 and NC16A ( < 0.05). The anti-BP180-positive patients were significantly younger than the negative patients at the time of stroke ( < 0.001). Development of anti-BP180 autoantibodies occurs at a higher frequency after stroke, suggesting BP180 as a relatively common autoantigen after stroke and providing novel insights into BP pathogenesis in aging.
Topics: Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Chromatography, Affinity; Dystonin; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunoglobulin G; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Skin; Stroke; Collagen Type XVII
PubMed: 30863396
DOI: 10.3389/fimmu.2019.00236