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1.
Cancer Lett ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34775002

RESUMO

Diffuse-type gastric carcinoma (DGC) has a poor prognosis due to its rapid diffusive infiltration and frequent peritoneal dissemination. DGC is associated with massive fibrosis caused by aberrant proliferation of cancer-associated fibroblasts (CAFs). Previously, we reported that direct heterocellular interaction between cancer cells and CAFs is important for the peritoneal dissemination of DGC. In this study, we aimed to identify and target the molecules that mediate such heterocellular interactions. Monoclonal antibodies (mAbs) against intact DGC cells were generated and subjected to high-throughput screening to obtain several mAbs that inhibit the adhesion of DGC cells to CAFs. Immunoprecipitation and mass spectrometry revealed that all mAbs recognized integrin α5 complexed with integrin ß1. Blocking integrin α5 in DGC cells or fibronectin, a ligand of integrin α5ß1, deposited on CAFs abrogated the heterocellular interaction. Administration of mAbs or knockout of integrin α5 in DGC cells suppressed their invasion led by CAFs in vitro and peritoneal dissemination in a mouse xenograft model. Altogether, these findings demonstrate that integrin α5 mediates the heterotypic cancer cell-fibroblast interaction during peritoneal dissemination of DGC and may thus be a therapeutic target.

2.
J Epidemiol ; 2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34776499

RESUMO

BACKGROUND: Tokyo, the capital of Japan, is a densely populated city of >13 million people and thus at high risk of epidemic severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. A serologic survey of anti-SARS-CoV-2 IgG would provide valuable data for assessing the city's SARS-CoV-2 infection status. This cross-sectional study therefore estimated the anti-SARS-CoV-2 IgG seroprevalence in Tokyo. METHODS: Leftover serum of 23,234 hospital visitors was tested for antibodies against SARS-CoV-2 using an iFlash 3000 chemiluminescence immunoassay analyzer (Shenzhen YHLO Biotech) with an iFlash-SARS-CoV-2 IgG kit (YHLO) and iFlash-SARS-CoV-2 IgG-S1 kit (YHLO). Serum samples with a positive result (≥10 AU/mL) in either of these assays were considered seropositive for anti-SARS-CoV-2 IgG. Participants were randomly selected from patients visiting 14 Tokyo hospitals between September 1, 2020, and March 31, 2021. No participants were diagnosed with coronavirus disease 2019 (COVID-19), and none exhibited COVID-19-related symptoms at the time of blood collection. RESULTS: The overall anti-SARS-CoV-2 IgG seroprevalence among all participants was 1.83% (95% confidence interval [CI]: 1.66%-2.01%). The seroprevalence in March 2021, the most recent month of this study, was 2.70% (95% CI: 2.16%-3.34%). After adjusting for population age, sex, and region, the estimated seroprevalence in Tokyo was 3.40%, indicating that 470,778 individuals had a history of SARS-CoV-2 infection. CONCLUSIONS: The estimated number of individuals in Tokyo with a history of SARS-CoV-2 infection was 3.9-fold higher than the number of confirmed cases. Our study enhances understanding of the SARS-CoV-2 epidemic in Tokyo.

3.
J Biol Chem ; : 101248, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34582888

RESUMO

Wilms' tumor 1-associating protein (WTAP) is a core component of the N6-methyladenosine (m6A)-methyltransferase complex, along with VIRMA, CBLL1, ZC3H13 (KIAA0853), RBM15/15B, and METTL3/14, which generate m6A, a key RNA modification that affects various process of RNA metabolism. WTAP also interacts with splicing factors; however, despite strong evidence suggesting a role of Drosophila WTAP homolog fl(2)d in alternative splicing (AS), its role in splicing regulation in mammalian cells remains elusive. Here we demonstrate using RNAi coupled with RNA-seq that WTAP, VIRMA, CBLL1, and ZC3H13 modulate AS, promoting exon skipping and intron retention in AS events that involve short introns/exons with higher GC content and introns with weaker polypyrimidine-tract and branch points. Further analysis of GC-rich sequences involved in AS events regulated by WTAP, together with minigene assay analysis, revealed potential G-quadruplex formation at splice sites where WTAP has an inhibitory effect. We also found that several AS events occur in the last exon of one isoform of MSL1 and WTAP, leading to competition for polyadenylation. Proteomic analysis also suggested that WTAP/CBLL1 interaction promotes recruitment of the 3'-end processing complex. Taken together, our results indicate that the WTAP complex regulates AS and alternative polyadenylation via inhibitory mechanisms in GC-rich sequences.

4.
Respir Med Case Rep ; 34: 101501, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485050

RESUMO

The patient was an 80-year-old woman with combined pulmonary fibrosis and emphysema. She was diagnosed with pulmonary pleomorphic carcinoma in the right upper lobe, which relapsed 18 months after the operation. Computed tomography showed a mass in contact with the posterior wall of the lower part of the stomach. The patient was treated with two cycles of pembrolizumab, but the disease progressed. She was treated with S-1 as second-line therapy, resulting in tumor-shrinking after two cycles. Progression was not observed over the next twelve months. We report a rare case involving S-1 after immune checkpoint inhibitor treatment.

5.
JACS Au ; 1(5): 578-585, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34467321

RESUMO

Growth factor receptors are activated through dimerization by the binding of their ligands and play pivotal roles in normal cell function. However, the aberrant activity of the receptors has been associated with cancer malignancy. One of the main causes of the aberrant receptor activation is the overexpression of receptors and the resultant formation of unliganded receptor dimers, which can be activated in the absence of external ligand molecules. Thus, the unliganded receptor dimer is a promising target to inhibit aberrant signaling in cancer. Here, we report an aptamer that specifically binds to fibroblast growth factor receptor 2b and inhibits the aberrant receptor activation and signaling. Our investigation suggests that this aptamer inhibits the formation of the receptor dimer occurring in the absence of external ligand molecules. This work presents a new inhibitory function of aptamers and the possibility of oligonucleotide-based therapeutics for cancer.

6.
Elife ; 102021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34431785

RESUMO

Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1, and p53. MLL-ELL activated gene expression in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.


Assuntos
Carcinogênese/genética , Histona Acetiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Animais , Transformação Celular Neoplásica , Feminino , Células HEK293 , Histona Acetiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Leucina Linfoide-Mieloide/metabolismo
7.
Nat Immunol ; 22(8): 947-957, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239121

RESUMO

One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Quimiocina CXCL1/metabolismo , Neoplasias Colorretais/imunologia , Células Supressoras Mieloides/imunologia , Receptor 2 Toll-Like/imunologia , Microambiente Tumoral/imunologia , Alarminas/genética , Alarminas/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7
8.
Int Immunopharmacol ; 98: 107884, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34246041

RESUMO

Performing a cohort-based SARS-CoV-2 antibody assay is crucial for understanding infection status and future decision-making. The objective of this study was to examine consecutive antibody seroprevalence changes among hospital staff, a high-risk population. A two-time survey was performed in May and October 2020 for 545 hospital staff to investigate the changes in the results of the rapid kit test and chemiluminescence immunoassay (CLIA). The seroprevalence of each assay was summarized at both the survey periods. The proportion of seropositive individuals in the CLIA for each survey period and the number of confirmed COVID-19 cases in Central Fukushima were then compared. We chose 515 participants for the analysis. The proportion of IgM seroprevalence in CLIA increased from 0.19% in May to 0.39% in October, and IgG seroprevalence decreased from 0.97% in May to 0.39% in October. The proportion of IgM seroprevalence in the rapid kit test decreased from 7.96% in May to 3.50% in October, and IgG seroprevalence decreased from 7.77% in May to 2.14% in October. The IgG and IgM antibody seroprevalence among hospital staff in rural Central Fukushima decreased; the seroprevalence among hospital staff was consistent with the number of confirmed COVID-19 cases in the Central Fukushima area. Although it is difficult to interpret the results of the antibody assay in a population with a low prior probability, constant follow-up surveys of antibody titers among hospital staff had several merits in obtaining a set of criteria regarding the accuracy of measures against COVID-19 and estimating the COVID-19 infection status among hospital staff.


Assuntos
Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , COVID-19/epidemiologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Recursos Humanos em Hospital , Saúde da População Rural , SARS-CoV-2/imunologia , Adulto , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Estudos Soroepidemiológicos , Fatores de Tempo
9.
iScience ; 24(6): 102660, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34169237

RESUMO

The spatial organization of chromatin is known to be highly dynamic in response to environmental stress. However, it remains unknown how chromatin dynamics contributes to or modulates disease pathogenesis. Here, we show that upon influenza virus infection, the H4K20me3 methyltransferase Suv4-20h2 binds the viral protein NP, which results in the inactivation of Suv4-20h2 and the dissociation of cohesin from Suv4-20h2. Inactivation of Suv4-20h2 by viral infection or genetic deletion allows the formation of an active chromatin loop at the HoxC8-HoxC6 loci coincident with cohesin loading. HoxC8 and HoxC6 proteins in turn enhance viral replication by inhibiting the Wnt-ß-catenin mediated interferon response. Importantly, loss of Suv4-20h2 augments the pathology of influenza infection in vivo. Thus, Suv4-20h2 acts as a safeguard against influenza virus infection by suppressing cohesin-mediated loop formation.

10.
Genes Cells ; 26(7): 513-529, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33971063

RESUMO

The lysine methyltransferase SETDB1, an enzyme responsible for methylation of histone H3 at lysine 9, plays a key role in H3K9 tri-methylation-dependent silencing of endogenous retroviruses and developmental genes. Recent studies have shown that ubiquitination of human SETDB1 complements its catalytic activity and the silencing of endogenous retroviruses in human embryonic stem cells. However, it is not known whether SETDB1 ubiquitination is essential for its other major role in epigenetic silencing of developmental gene programs. We previously showed that SETDB1 contributes to the formation of H3K4/H3K9me3 bivalent chromatin domains that keep adipogenic Cebpa and Pparg genes in a poised state for activation and restricts the differentiation potential of pre-adipocytes. Here, we show that ubiquitin-resistant K885A mutant of SETDB1 represses adipogenic genes and inhibits pre-adipocyte differentiation similar to wild-type SETDB1. We show this was due to a compensation mechanism for H3K9me3 chromatin modifications on the Cebpa locus by other H3K9 methyltransferases Suv39H1 and Suv39H2. In contrast, the K885A mutant did not repress other SETDB1 target genes such as Tril and Gas6 suggesting SETDB1 represses its target genes by two mechanisms; one that requires its ubiquitination and another that still requires SETDB1 but not its enzyme activity.


Assuntos
Adipogenia , Epigênese Genética , Histona-Lisina N-Metiltransferase/metabolismo , Ubiquitinação , Células 3T3-L1 , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Células HEK293 , Código das Histonas , Histona-Lisina N-Metiltransferase/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Mutação de Sentido Incorreto
13.
J Biochem ; 169(4): 421-434, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33386847

RESUMO

Whole transcriptome analyses have revealed that mammalian genomes are massively transcribed, resulting in the production of huge numbers of transcripts with unknown functions (TUFs). Previous research has categorized most TUFs as noncoding RNAs (ncRNAs) because most previously studied TUFs do not encode open reading frames (ORFs) with biologically significant lengths [>100 amino acids (AAs)]. Recent studies, however, have reported that several transcripts harbouring small ORFs that encode peptides shorter than 100 AAs are translated and play important biological functions. Here, we examined the translational capacity of transcripts annotated as ncRNAs in human cells, and identified several hundreds of ribosome-associated transcripts previously annotated as ncRNAs. Ribosome footprinting and polysome profiling analyses revealed that 61 of them are potentially translatable. Among them, 45 were nonnonsense-mediated mRNA decay targets, suggesting that they are productive mRNAs. We confirmed the translation of one ncRNA, LINC00493, by luciferase reporter assaying and western blotting of a FLAG-tagged LINC00493 peptide. While proteomic analysis revealed that the LINC00493 peptide interacts with many mitochondrial proteins, immunofluorescence assays showed that its peptide is mitochondrially localized. Our findings indicate that some transcripts annotated as ncRNAs encode peptides and that unannotated peptides may perform important roles in cells.


Assuntos
Fases de Leitura Aberta , Peptídeos , RNA Longo não Codificante/genética , RNA Mensageiro , Células HeLa , Humanos , Peptídeos/genética , Peptídeos/metabolismo , RNA Longo não Codificante/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
14.
Sci Signal ; 14(667)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33500333

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by excessive pulmonary vascular remodeling. However, despite advances in therapeutic strategies, patients with PAH bearing mutations in the bone morphogenetic protein receptor type 2 (BMPR2)-encoding gene present severe phenotypes and outcomes. We sought to investigate the effect of PER-like kinase (PERK), which participates in one of three major pathways associated with the unfolded protein response (UPR), on PAH pathophysiology in BMPR2 heterozygous mice. BMPR2 heterozygosity in pulmonary artery smooth muscle cells (PASMCs) decreased the abundance of the antiapoptotic microRNA miR124-3p through the arm of the UPR mediated by PERK. Hypoxia promoted the accumulation of unfolded proteins in BMPR2 heterozygous PASMCs, resulting in increased PERK signaling, cell viability, cellular proliferation, and glycolysis. Proteomic analyses revealed that PERK ablation suppressed PDGFRß-STAT1 signaling and glycolysis in hypoxic BMPR2 heterozygous PASMCs. Furthermore, PERK ablation or PERK inhibition ameliorated pulmonary vascular remodeling in the Sugen/chronic hypoxia model of PAH, irrespective of BMPR2 status. Hence, these findings suggest that PERK inhibition is a promising therapeutic strategy for patients with PAH with or without BMPR2 mutation.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/fisiologia , Miócitos de Músculo Liso , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar , eIF-2 Quinase/fisiologia , Animais , Hipóxia Celular , Sobrevivência Celular , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia
15.
Int Immunopharmacol ; 92: 107360, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33508702

RESUMO

OBJECTIVES: The objective of this study was to investigate the differences between the results of two serology assays for detection of COVID-19 among medical staff, who are at higher risks of infection. METHODS: The immunochromatography (ICG) rapid test kit and the chemiluminescence immunoassay (CLIA) quantitative antibody test were performed. The differences in IgM and IgG antibody prevalence in different serological assays were descriptively analyzed. RESULTS: A total of 637 participants were included in this research. Two staff were IgM positive in the CLIA quantitative antibody test (cutoff value: 10 AU/ml) of 51 staff who were IgM positive in the rapid test kit. Six staff were IgG positive in the CLIA quantitative antibody test of 56 staff who were IgG positive in the rapid test kit. The proportion of antibody positive staff differed greatly between the rapid test kit and the CLIA quantitative antibody test. CONCLUSIONS: There was a vast difference in the proportions of IgG and IgM antibody positive staff in the rapid test kit and the CLIA quantitative antibody test results. The results from the only rapid test kit might have to be interpreted with caution. Further studies to evaluate antibody testing accuracy are required to promote the understanding of each assay's characteristics and determine their purposes in each community.


Assuntos
COVID-19/sangue , Pessoal de Saúde , Imunoglobulina G/sangue , Imunoglobulina M/sangue , SARS-CoV-2 , Adolescente , Adulto , Idoso , COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Sorológicos , Adulto Jovem
16.
Sci Rep ; 10(1): 20094, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208886

RESUMO

Protein kinase R-like endoplasmic reticulum kinase (PERK) is one of the endoplasmic reticulum (ER) stress sensors. PERK loss-of-function mutations are known to cause Wolcott-Rallison syndrome. This disease is characterized by early-onset diabetes mellitus, skeletal dysplasia, and cardiac valve malformation. To understand the role of PERK in valve formation in vivo, we used an endothelial-specific PERK conditional knockout mice as well as in vitro PERK inhibition assays. We used ProteoStat dyes to visualize the accumulation of misfolded proteins in the endocardial cushion and valve mesenchymal cells (VMCs). Then, VMCs were isolated from E12.5 fetal mice, by fluorescence assisted cell sorting. Proteomic analysis of PERK-deleted VMCs identified the suppression of proteins related to fatty acid oxidation (FAO), especially carnitine palmitoyltransferase II (CPT2). CPT2 is a critical regulator of endocardial-mesenchymal transformation (EndoMT); however how TGF-ß downstream signaling controls CPT2 expression remains unclear. Here, we showed that PERK inhibition suppressed, not only EndoMT but also CPT2 protein expression in human umbilical vein endothelial cells (HUVECs) under TGF-ß1 stimulation. As a result, PERK inhibition suppressed mitochondrial metabolic activity. Taken together, these results demonstrate that PERK signaling is required for cardiac valve formation via FAO and EndoMT.


Assuntos
Endocárdio/embriologia , Ácidos Graxos/química , Valvas Cardíacas/embriologia , Valvas Cardíacas/metabolismo , Mesoderma/embriologia , Organogênese , eIF-2 Quinase/fisiologia , Animais , Endocárdio/metabolismo , Ácidos Graxos/metabolismo , Feminino , Masculino , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução
17.
Biochem Biophys Res Commun ; 533(4): 872-878, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33008600

RESUMO

Proteolytic cleavage at specific sites is a key event that modulates protein functions in biological processes. These cleavage sites are identified through mass spectrometry-based peptidomics of overlapping peptide sequences. Here, we assessed to what extent a recent capillary electrophoresis (CE) system interfaced with electrospray ionization-mass spectrometry (ESI-MS) contributes to identifying endogenous peptides present in a biological sample. Peptides released by a human endocrine cell line stimulated for secretion was analyzed for uncovering potential processing sites created by proprotein convertases (PCs) that cleave precursors in the secretory pathway. CE-ESI-MS was conducted, in comparison to a standard liquid chromatography (LC)-ESI-MS platform. LC and CE complemented each other in elucidating processing sites that match PC consensus sequences from known substrates. We suggest that the precursors BIGH3, STC1, LFNG, QSOX1 and CYTC are potential substrates for PCs, and that a CE-ESI system would come in handy and garner greater recognition as a robust tool in peptidomics.


Assuntos
Eletroforese Capilar , Peptídeos/química , Espectrometria de Massas por Ionização por Electrospray , Linhagem Celular Tumoral , Cromatografia Líquida , Humanos , Peptídeos/metabolismo , Pró-Proteína Convertases/metabolismo , Análise de Sequência de Proteína , Espectrometria de Massas em Tandem
18.
Int Heart J ; 61(5): 1059-1069, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921666

RESUMO

Because of its rigidity and non-steerability, the presence of a horizontal aortic root poses a major anatomical issue during transcatheter aortic valve replacement (TAVR) with Evolut self-expanding valve. Previous studies have elucidated the difficulties of coaxial implantation of the self-expanding valve in patients with horizontal aorta, often resulting in increased complications and a lower device success rate. To date, most patients with extremely horizontal aorta (aortic root angle ≥ 70°) have been excluded from major TAVR clinical trials. Therefore, available data on TAVR with Evolut in this challenging anatomy are limited, and standardized treatment strategies and clinical results remain unknown. Herein, we report a clinical case series of TAVR with Evolut in extremely horizontal aorta. Among seven patients (aged 80-92 years; STS score, 12.6% ± 7.9%) who underwent TAVR with Evolut system, aortic root angle ranged from 71° to 83° (mean, 75.1°± 4.5°). All patients achieved device success with dedicated strategies and were clinically stable at 3-month follow-up. None of the patients had more than mild paravalvular leakage (PVL) at any point during follow-up.Complications in three patients included complete atrioventricular block requiring a permanent pacemaker implantation, cerebral infarction because of atrial fibrillation 3 days after TAVR, and cardiac tamponade requiring pericardiocentesis. In this case series, Evolut self-expanding TAVR in extremely horizontal aorta was effective and feasible with a high device success rate. Based on anatomical features, some dedicated strategies majorly contribute to the success of this procedure. Large-scale multicenter studies are required to confirm our findings.


Assuntos
Aorta Torácica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Substituição da Valva Aórtica Transcateter/métodos , Idoso de 80 Anos ou mais , Aorta Torácica/anatomia & histologia , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Bloqueio Atrioventricular/epidemiologia , Bloqueio Atrioventricular/terapia , Estimulação Cardíaca Artificial , Tamponamento Cardíaco/epidemiologia , Infarto Cerebral/epidemiologia , Infarto Cerebral/etiologia , Angiografia por Tomografia Computadorizada , Feminino , Próteses Valvulares Cardíacas , Humanos , Masculino , Tomografia Computadorizada Multidetectores , Marca-Passo Artificial , Pericardiocentese , Complicações Pós-Operatórias/epidemiologia , Desenho de Prótese , Substituição da Valva Aórtica Transcateter/instrumentação , Resultado do Tratamento
19.
Cell Rep ; 32(13): 108200, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32997997

RESUMO

Uncontrolled self-renewal of hematopoietic progenitors induces leukemia. To self-renew, leukemia cells must continuously activate genes that were previously active in their mother cells. Here, we describe the circuitry of a transactivation system responsible for oncogenic self-renewal. MLL recruits RNA polymerase II (RNAP2) to unmethylated CpG-rich promoters by its CXXC domain and activates transcription by transcriptional regulators, including the AF4 family/ENL family/P-TEFb complex, DOT1L, and p300/CBP histone acetyl transferases. MOZ also targets a broad range of CpG-rich promoters through association with RNAP2 and MLL. Leukemic fusion proteins such as MOZ-TIF2 and MLL-AFX constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells. These results reveal that activation of unmethylated CpG-rich promoters mediated by MLL is the central mechanism of oncogenic self-renewal in MOZ-rearranged leukemia and indicate that the molecularly targeted therapies intended for MLL-rearranged leukemia can be applied for MOZ-rearranged leukemia.


Assuntos
Ilhas de CpG/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/metabolismo , Animais , Humanos , Camundongos , Mutação , Proteína de Leucina Linfoide-Mieloide/metabolismo
20.
EMBO J ; 39(20): e105130, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32914505

RESUMO

Silkworm ovarian germ cells produce the Siwi-piRNA-induced silencing complex (piRISC) through two consecutive mechanisms, the primary pathway and the secondary ping-pong cycle. Primary Siwi-piRISC production occurs on the outer mitochondrial membrane in an Ago3-independent manner, where Tudor domain-containing Papi binds unloaded Siwi via its symmetrical dimethylarginines (sDMAs). Here, we now show that secondary Siwi-piRISC production occurs at the Ago3-positive nuage Ago3 bodies, in an Ago3-dependent manner, where Vreteno (Vret), another Tudor protein, interconnects unloaded Siwi and Ago3-piRISC through their sDMAs. Upon Siwi depletion, Ago3 is phosphorylated and insolubilized in its piRISC form with cleaved RNAs and Vret, suggesting that the complex is stalled in the intermediate state. The Ago3 bodies are also enlarged. The aberrant morphology is restored upon Siwi re-expression without Ago3-piRISC supply. Thus, Siwi depletion aggregates the Ago3 bodies to protect the piRNA intermediates from degradation until the normal cellular environment returns to re-initiate the ping-pong cycle. Overall, these findings reveal a unique regulatory mechanism controlling piRNA biogenesis.


Assuntos
Proteínas Argonauta/metabolismo , Bombyx/metabolismo , Células Germinativas/metabolismo , Proteínas de Insetos/metabolismo , RNA Interferente Pequeno/metabolismo , Domínio Tudor/genética , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Proteínas Argonauta/genética , Bombyx/genética , Bombyx/crescimento & desenvolvimento , Núcleo Celular/genética , Núcleo Celular/metabolismo , Células Cultivadas , Cromatografia Líquida , Biologia Computacional , Feminino , Proteínas de Insetos/genética , Ovário/citologia , Ovário/metabolismo , Fosforilação , Interferência de RNA , RNA Interferente Pequeno/genética , RNA-Seq , Espectrometria de Massas em Tandem
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