Acute Myopericarditis After the Third Vaccination of BNT162b2 in a Middle-Aged Man.

Messenger ribonucleic acid (mRNA) vaccines against coronavirus disease 2019 (COVID-19) are highly effective in preventing and decreasing disease severity, but the duration of the effect is attenuated over time and repeated vaccination is required. A 41-year-old Japanese male presented to our hospital with chest pain three days after receiving the third dose of the BNT162b2 mRNA vaccine. After various examinations, such as endomyocardial biopsy and viral polymerase chain reaction (PCR) testing of endomyocardial biopsy tissue, we made the diagnosis of acute myopericarditis associated with booster vaccination.

Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for Δ160E-Induced Cardiomyopathy.

Background: The Δ160E mutation in , which encodes troponin T, is a rare pathogenic variant identified in patients with hypertrophic cardiomyopathy and is associated with poor prognosis. Thus, a convenient human model recapitulating the pathological phenotype caused by Δ160E is required for therapeutic development.

Methods: We identified a heterozygous in-frame deletion mutation (c.

Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes.

Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts in phenotypic analysis for proof of concept for gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression of plakophilin-2 from a patient with AC carrying a heterozygous frameshift PKP2 mutation.

Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes.

Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.

Adeno-associated virus-mediated gene delivery promotes S-phase entry-independent precise targeted integration in cardiomyocytes.

Post-mitotic cardiomyocytes have been considered to be non-permissive to precise targeted integration including homology-directed repair (HDR) after CRISPR/Cas9 genome editing. Here, we demonstrate that direct delivery of large amounts of transgene encoding guide RNA (gRNA) and repair template DNA via intra-ventricular injection of adeno-associated virus (AAV) promotes precise targeted genome replacement in adult murine cardiomyocytes expressing Cas9. Neither systemic injection of AAV nor direct injection of adenovirus promotes targeted integration, suggesting that high copy numbers of single-stranded transgenes are required in cardiomyocytes.

Defective repair capacity of variant proteins of the DNA glycosylase NTHL1 for 5-hydroxyuracil, an oxidation product of cytosine.

The NTHL1 gene encodes DNA glycosylase, which is involved in base excision repair, and biallelic mutations of this gene result in NTHL1-associated polyposis (NAP), a hereditary disease characterized by colorectal polyposis and multiple types of carcinomas. However, no proper functional characterization of variant NTHL1 proteins has been done so far. Herein, we report functional evaluation of variant NTHL1 proteins to aid in the accurate diagnosis of NAP.

Mutation Spectrum Induced by 8-Bromoguanine, a Base Damaged by Reactive Brominating Species, in Human Cells.

To date, the types of mutations caused by 8-bromoguanine (8BrG), a major base lesion induced by reactive brominating species during inflammation, in human cells and the 8BrG repair system remain largely unknown. In this study, we performed a forward mutation assay using a shuttle vector plasmid containing a single 8BrG in three kinds of human cell lines and revealed that 8BrG in DNA predominantly induces a G → T mutation but can also induce G → C, G → A, and delG mutations in human cells. Next, we tested whether eight kinds of DNA glycosylases (MUTYH, MPG, NEIL1, OGG1, SMUG1, TDG, UNG2, and NTHL1) are capable of repairing 8BrG mispairs with any of the four bases using a DNA cleavage activity assay.

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma.

Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.

Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer.

The effects of abnormalities in the DNA glycosylases NEIL1, NEIL2, and NEIL3 on human cancer have not been fully elucidated. In this paper, we found that the median somatic total mutation loads and the median somatic single nucleotide mutation loads exhibited significant inverse correlations with the median NEIL1 and NEIL2 expression levels and a significant positive correlation with the median NEIL3 expression level using data for 13 cancer types from the Cancer Genome Atlas (TCGA) database. A subset of the cancer types exhibited reduced NEIL1 and NEIL2 expressions and elevated NEIL3 expression, and such abnormal expressions of NEIL1, NEIL2, and NEIL3 were also significantly associated with the mutation loads in cancer.

Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population.

Biallelic germline mutations of MUTYH, the gene encoding DNA glycosylase, cause MUTYH-associated polyposis (MAP), characterized by multiple colorectal adenomas and carcinoma(s). However, a considerable number of MUTYH variants are still functionally uncharacterized. Herein, we report the results of functional evaluation of nine missense-type MUTYH variant proteins in the Japanese population.

Novel roles for LIX1L in promoting cancer cell proliferation through ROS1-mediated LIX1L phosphorylation.

Herein, we report the characterization of Limb expression 1-like, (LIX1L), a putative RNA-binding protein (RBP) containing a double-stranded RNA binding motif, which is highly expressed in various cancer tissues. Analysis of MALDI-TOF/TOF mass spectrometry and RNA immunoprecipitation-sequencing of interacting proteins and the microRNAs (miRNAs) bound to LIX1L revealed that LIX1L interacts with proteins (RIOK1, nucleolin and PABPC4) and miRNAs (has-miRNA-520a-5p, -300, -216b, -326, -190a, -548b-3p, -7-5p and -1296) in HEK-293 cells. Moreover, the reduction of phosphorylated Tyr(136) (pTyr(136)) in LIX1L through the homeodomain peptide, PY136, inhibited LIX1L-induced cell proliferation in vitro, and PY136 inhibited MKN45 cell proliferation in vivo.

NEIL1 p.Gln282Stop variant is predominantly localized in the cytoplasm and exhibits reduced activity in suppressing mutations.

Human NEIL1 protein is a DNA glycosylase known to be involved in the repair of oxidized DNA lesions. A c.C844T germline variant of the NEIL1 gene has recently been identified in the Japanese population, however, the p.

CD44-SLC1A2 fusion transcripts in primary colorectal cancer.

A CD44-SLC1A2 fusion has recently been discovered in a subset of primary gastric cancers, and an APIP-SLC1A2 fusion has been described in a colon cancer cell line (SNU-C1); however, whether such SLC1A2 fusions occur in primary colorectal cancer (CRC) and whether such fusions are specific for gastrointestinal cancers remain uncertain. In the present study, we examined 90 primary CRCs and 112 primary non-small cell lung cancers (NSCLCs) for CD44-SLC1A2 and APIP-SLC1A2 fusion transcripts using RT-PCR and subsequent sequencing analyses. Although the expression of both types of SLC1A2 fusion transcripts was not detected in any of the NSCLCs, the expression of CD44-SLC1A2, but not the APIP-SLC1A2 fusion transcript, was detected in one (1.

CLCA2 as a novel immunohistochemical marker for differential diagnosis of squamous cell carcinoma from adenocarcinoma of the lung.

Recent progress in targeted therapy for lung cancer has revealed that accurate differential diagnosis between squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the lung is essential. To identify a novel immunohistochemical marker useful for differential diagnosis between the two subtypes of lung cancer, we first selected 24 SCC-specific genes and 6 ADC-specific genes using data (case number, 980) from the Cancer Genome Atlas (TCGA) database. Among the genes, we chose the CLCA2 gene, which is involved in chloride conductance and whose protein expression in lung cancer is yet to be characterized, and evaluated its protein expression status in 396 cases of primary lung cancer at Hamamatsu University Hospital.

RSPO fusion transcripts in colorectal cancer in Japanese population.

R-spondin (RSPO) gene fusions have recently been discovered in a subset of human colorectal cancer (CRC) in the U.S. population; however, whether the fusion is recurrent in CRC arising in patients from the other demographic areas and whether it is specific for CRC remain uncertain.

Impaired 8-hydroxyguanine repair activity of MUTYH variant p.Arg109Trp found in a Japanese patient with early-onset colorectal cancer.

Purpose: The biallelic inactivation of the 8-hydroxyguanine repair gene MUTYH leads to MUTYH-associated polyposis (MAP), which is characterized by colorectal multiple polyps and carcinoma(s). However, only limited information regarding MAP in the Japanese population is presently available. Since early-onset colorectal cancer (CRC) is a characteristic of MAP and might be caused by the inactivation of another 8-hydroxyguanine repair gene, OGG1, we investigated whether germline MUTYH and OGG1 mutations are involved in early-onset CRC in Japanese patients.

A novel somatic FGFR3 mutation in primary lung cancer.

The recent discovery of mutations and fusions of oncokinase genes in a subset of lung cancers (LCs) is of considerable clinical interest, since LCs containing such mutations or fusion transcripts are reportedly sensitive to kinase inhibitors. To better understand the role of the recently identified fibroblast growth factor receptor 3 (FGFR3) mutations and fusions in pulmonary carcinogenesis, we examined 214 LCs for mutations in the mutation cluster region of the FGFR3 gene using sequencing analysis. We also examined 190 LCs for the FGFR3-TACC3 and FGFR3-BAIAP2L1 fusion transcripts using reverse transcription-polymerase chain reaction (RT-PCR) analysis.

TNK2 gene amplification is a novel predictor of a poor prognosis in patients with gastric cancer.

Backgrounds And Objectives: We previously examined the amplification status of 10 kinase genes (PIK3CA, EPHB3, TNK2, PTK7, EGFR, MET, ERBB2, HCK, SRC, and AURKA) in gastric cancer (GC). This study aimed to determine the prognostic significance of these gene amplifications in GC.

Methods: A survival analysis was performed for GC patients.

Recovery of kidney function by rituximab-based therapy in a patient with Waldenström's macroglobulinemia-related nephropathy presenting cast nephropathy and interstitial lymphocytic infiltration.

A 60-year-old man with Waldenström's macroglobulinemia (WM) was admitted to our hospital for evaluation of rapid progressive renal deterioration despite 3 cycles of oral melphalan and prednisolone (MP) therapy. Renal biopsy just before introducing hemodialysis revealed cast nephropathy and severe tubulo-interstitial infiltration of B lymphocytes. After 6 cycles of rituximab, cyclophosphamide, vincristine and prednisolone (R-COP) therapy, his renal function improved enough to discontinue hemodialysis.

The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer.

Background: Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer.

Methods And Results: A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified.

Transcriptional repression of Cdc25B by IER5 inhibits the proliferation of leukemic progenitor cells through NF-YB and p300 in acute myeloid leukemia.

The immediately-early response gene 5 (IER5) has been reported to be induced by γ-ray irradiation and to play a role in the induction of cell death caused by radiation. We previously identified IER5 as one of the 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TMPP)-induced transcriptional responses in AML cells, using microarrays that encompassed the entire human genome. However, the biochemical pathway and mechanisms of IER5 function in regulation of the cell cycle remain unclear.

What can be seen by 18F-FDG PET in atherosclerosis imaging? The effect of foam cell formation on 18F-FDG uptake to macrophages in vitro.

Unlabelled: (18)F-FDG PET is a promising tool for detecting vulnerable plaques, depending on the extent of macrophage infiltration; however, it is still not clear which stage of the lesion can be detected by (18)F-FDG PET.

Methods: In this study, we investigated the effect of foam cell formation on (18)F-FDG uptake using cultured mouse peritoneal macrophages.

Results: (18)F-FDG accumulation was increased by foam cell formation, but the uptake was decreased to the control level after complete differentiation to foam cells.

JmjC-domain containing histone demethylase 1B-mediated p15(Ink4b) suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia.

The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation.

Small GTPase RAB45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells.

Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. BCR-ABL transforming activity is mediated by critical downstream signaling pathways that are aberrantly activated by tyrosine kinases. However, the mechanisms of BCR-ABL anti-apoptotic effects and the signaling pathways by which BCR-ABL influences apoptosis in BCR-ABL-expressing cells are poorly defined.

Down-regulation of Thanatos-associated protein 11 by BCR-ABL promotes CML cell proliferation through c-Myc expression.

Bcr-Abl activates various signaling pathways in chronic myelogenous leukemia (CML) cells. The proliferation of Bcr-Abl transformed cells is promoted by c-Myc through the activation of Akt, JAK2 and NF-κB. However, the mechanism by which c-Myc regulates CML cell proliferation is unclear.