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1.
Sci Rep ; 10(1): 16219, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004978

RESUMO

COVID-19 pandemic has resulted in 16,114,449 cases with 646,641 deaths from the 217 countries, or territories as on July 27th 2020. Due to multifaceted issues and challenges in the implementation of the safety and preventive measures, inconsistent coordination between societies-governments and most importantly lack of specific vaccine to SARS-CoV-2, the spread of the virus that initially emerged at Wuhan is still uprising after taking a heavy toll on human life. In the present study, we mapped immunogenic epitopes present on the four structural proteins of SARS-CoV-2 and we designed a multi-epitope peptide based vaccine that, demonstrated a high immunogenic response with a vast application on world's human population. On codon optimization and in-silico cloning, we found that candidate vaccine showed high expression in E. coli and immune simulation resulted in inducing a high level of both B-cell and T-cell mediated immunity. The results predicted that exposure of vaccine by administrating three injections significantly subsidized the antigen growth in the system. The proposed candidate vaccine found promising by yielding desired results and hence, should be validated by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2.


Assuntos
Epitopos/imunologia , Simulação de Acoplamento Molecular , Vacinas de Subunidades/imunologia , Vacinas Virais/imunologia , Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/imunologia , Antígenos Virais/imunologia , Linfócitos B/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos/química , Antígenos HLA/química , Antígenos HLA/imunologia , Humanos , Imunogenicidade da Vacina , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Receptores Toll-Like/imunologia , Vacinas de Subunidades/química , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/imunologia , Vacinas Virais/química
3.
Medicine (Baltimore) ; 99(41): e22504, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031288

RESUMO

In clinical trials of tofacitinib for rheumatoid arthritis (RA), Japanese and Korean patients had higher incidence of herpes zoster (HZ) than subjects from elsewhere; however, post-market data from Asia are lacking. Hence, we investigated the incidence of HZ and its risk factors in Taiwanese RA patients receiving tofacitinib. At a medical center in Taichung, Taiwan, we enrolled patients with active RA treated with tofacitinib between January 4, 2015 and December 9, 2017, following unsuccessful methotrexate therapy and no tofacitinib exposure RA patients as a control group. Demographic characteristics, interferon-gamma levels, and lymphocyte counts were compared. Among 125 tofacitinib-treated RA patients, 7 developed HZ, an incidence rate of 3.6/100 person-years. Patients with HZ had shorter disease duration than those without, but higher frequency of prior HZ. Baseline interferon-gamma levels and HLA-DR activated T cell counts were positively correlated and significantly lower in patients with HZ than without. Strikingly, 5/7 HZ cases occurred within 4 months of starting tofacitinib therapy. Incidence of HZ in tofacitinib-treated Taiwanese RA patients is lower than rates in Japan or Korea, and commensurate with the global average. HZ may occur soon after commencing tofacitinib therapy. The role of interferon-gamma and activated T cells in tofacitinib-related HZ deserves further investigation.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Linfócitos T , Idoso , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Interferon gama/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologia
4.
Adv Exp Med Biol ; 1255: 29-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949388

RESUMO

T cells recognize peptides bound to major histocompatibility complex (MHC) class I and class II molecules at the cell surface. This recognition is accomplished by the expression of T cell receptors (TCR) which are required to be diverse and adaptable in order to accommodate the various and vast number of antigens presented on the MHCs. Thus, determining TCR repertoires of effector T cells is necessary to understand the immunological process in responding to cancer progression, infection, and autoimmune development. Furthermore, understanding the TCR repertoires will provide a solid framework to predict and test the antigen which is more critical in autoimmunity. However, it has been a technical challenge to sequence the TCRs and provide a conceptual context in correlation to the vast number of TCR repertoires in the immunological system. The exploding field of single-cell sequencing has changed how the repertoires are being investigated and analyzed. In this review, we focus on the biology of TCRs, TCR signaling and its implication in autoimmunity. We discuss important methods in bulk sequencing of many cells. Lastly, we explore the most pertinent platforms in single-cell sequencing and its application in autoimmunity.


Assuntos
Receptores de Antígenos de Linfócitos T/genética , Análise de Sequência , Análise de Célula Única , Animais , Autoimunidade/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
Eur Rev Med Pharmacol Sci ; 24(17): 9182-9187, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32965012

RESUMO

COVID-19 pandemic has underlined that unknown viral infections, which jump from animals to humans, can be extremely dangerous. In case of new viruses as SARS-CoV2, available drugs can fail to contrast the virus aggressiveness leading patients to death. Long time is necessary to create a vaccine, but immediate solutions are necessary to stop the mortality COVID-19 related. We have learned that the immune-system is the key to reduce the severity of COVID-19 and, through its modulation, it has been possible saving people's life. In this short communication, we discuss the use of nutraceuticals to modulate and stimulate the immune answer for reducing the severity of COVID-19 symptoms. The nutraceuticals are safe and can be administered to all ages. In addition, combination of natural anti-viral elements and immune-stimulating molecules already successfully tested against others upper-respiratory tract infections-could be efficient against SARS-CoV2. We believe that these natural molecules could really be a valid ally against COVID-19, especially in this moment in which a SARS-CoV2 vaccine is still not available.


Assuntos
Infecções por Coronavirus/terapia , Suplementos Nutricionais , Pneumonia Viral/terapia , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Lactobacillus/fisiologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Selênio/farmacologia , Selênio/uso terapêutico , Índice de Gravidade de Doença , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Replicação Viral/efeitos dos fármacos
6.
Anticancer Res ; 40(9): 4875-4883, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878775

RESUMO

BACKGROUND/AIM: Some reports showed encouraging efficacy of immune checkpoint inhibitors among patients who experienced immune-related adverse events (irAEs). Thus, characterization of T-cell repertoire and immune signatures in peripheral blood mononuclear cells (PBMCs) and tumors before and after immune checkpoint inhibitors treatment should contribute to better understanding of irAE-provoked anticancer immune responses. MATERIALS AND METHODS: We applied expression analysis of immune-related genes and T-cell receptor sequencing in tumor and PBMCs from five patients with renal cell carcinoma before combined immunotherapy and at the onset of severe irAEs. RESULTS: We found that the cluster of differentiation 8 (CD8)/forkhead box P3(FOXP3), granzyme B(GZMB)/CD3, perforin 1(PRF1)/CD3 and programmed cell death 1(PD1)/CD8 expression ratios were significantly elevated in PBMCs at the onset of irAEs. In addition, we found expansion of certain T-cell clones in metastatic tissue after irAEs, which were already increased in peripheral blood at the onset of irAEs. CONCLUSION: irAE-provoked T-cells may also circulate and attack distant tumors, leading to durable response in patients with irAEs.


Assuntos
Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Imunoterapia/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Perfilação da Expressão Gênica , Genes Codificadores dos Receptores de Linfócitos T/genética , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia
8.
Anticancer Res ; 40(10): 5481-5487, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988870

RESUMO

BACKGROUND/AIM: γδ T cells mediate cytotoxicity against prostate cancer (PCa) cells in vitro; however, the clinical efficacy of γδ T cell-targeted immunotherapy for recurrent and metastatic PCa is unsatisfactory. We hypothesized that the resistance of recurrent and metastatic PCa to γδ T cells is related to the presence of prostate cancer stem cells (PCSCs), and we examined their relationship. MATERIALS AND METHODS: PCa spheres (prostaspheres) were generated from five PCa cell lines, and their susceptibility to cytotoxicity by γδ T cells was investigated. Expression of stemness-related markers was evaluated by qRT-PCR. RESULTS: Prostasphere-derived cancer cells were resistant to lysis by γδ T cells and expressed higher levels of several stemness markers, including CD133, NANOG, SOX2, and OCT4, than the parental PCa cell lines. CONCLUSION: Ex vivo-expanded γδ T cells are not effective against PCSCs.


Assuntos
Linfócitos Intraepiteliais/imunologia , Células-Tronco Neoplásicas/imunologia , Neoplasias da Próstata/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Antígeno AC133/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Masculino , Proteína Homeobox Nanog/genética , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Fatores de Transcrição SOXB1/genética , Linfócitos T
9.
Nat Commun ; 11(1): 4367, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868763

RESUMO

Invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT), and γδ T cells are innate T cells that acquire memory phenotype in the thymus and share similar biological characteristics. However, how their effector differentiation is developmentally regulated is still unclear. Here, we identify analogous effector subsets of these three innate T cell types in the thymus that share transcriptional profiles. Using single-cell RNA sequencing, we show that iNKT, MAIT and γδ T cells mature via shared, branched differentiation rather than linear maturation or TCR-mediated instruction. Simultaneous TCR clonotyping analysis reveals that thymic maturation of all three types is accompanied by clonal selection and expansion. Analyses of mice deficient of TBET, GATA3 or RORγt and additional in vivo experiments corroborate the predicted differentiation paths, while human innate T cells from liver samples display similar features. Collectively, our data indicate that innate T cells share effector differentiation processes in the thymus.


Assuntos
Diferenciação Celular , Imunidade Inata , Linfócitos T/metabolismo , Timo/imunologia , Animais , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Humanos , Fígado/citologia , Fígado/imunologia , Ativação Linfocitária , Camundongos , Células T Invariáveis Associadas à Mucosa/metabolismo , Células T Matadoras Naturais/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Células Th17/metabolismo , Timo/citologia
10.
Adv Mater ; 32(40): e2004210, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32864794

RESUMO

For rapid response against the prevailing COVID-19 (coronavirus disease 19), it is a global imperative to exploit the immunogenicity of existing formulations for safe and efficient vaccines. As the most accessible adjuvant, aluminum hydroxide (alum) is still the sole employed adjuvant in most countries. However, alum tends to attach on the membrane rather than entering the dendritic cells (DCs), leading to the absence of intracellular transfer and process of the antigens, and thus limits T-cell-mediated immunity. To address this, alum is packed on the squalene/water interphase is packed, forming an alum-stabilized Pickering emulsion (PAPE). "Inheriting" from alum and squalene, PAPE demonstrates a good biosafety profile. Intriguingly, with the dense array of alum on the oil/water interphase, PAPE not only adsorbs large quantities of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antigens, but also harbors a higher affinity for DC uptake, which provokes the uptake and cross-presentation of the delivered antigens. Compared with alum-treated groups, more than six times higher antigen-specific antibody titer and three-fold more IFN-γ-secreting T cells are induced, indicating the potent humoral and cellular immune activations. Collectively, the data suggest that PAPE may provide potential insights toward a safe and efficient adjuvant platform for the enhanced COVID-19 vaccinations.


Assuntos
Adjuvantes Imunológicos/química , Vacinas Virais/química , Compostos de Alúmen/química , Animais , Antígenos Virais/química , Antígenos Virais/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Emulsões , Células HEK293 , Humanos , Interferon gama/metabolismo , Camundongos Endogâmicos BALB C , Pandemias , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia
11.
Cell ; 183(1): 158-168.e14, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32979941

RESUMO

SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.


Assuntos
Convalescença , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Adulto , Anticorpos Antivirais/imunologia , Infecções Assintomáticas , Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia
12.
Rinsho Ketsueki ; 61(8): 953-958, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32908060

RESUMO

Expanded human bone marrow-derived mesenchymal stromal/stem cells (MSC) have been used in the treatment of acute graft-versus-host disease (GVHD). It is currently accepted that the use of allogeneic off-the-shelf MSC has therapeutic efficacy with no apparent serious early-onset adverse effects; however, further development would be needed to overcome the current situation of MSC therapy for intractable GVHD. In the emerging recognition of the importance of extracellular vesicles (EV) as modulators of cell-cell communication physiologically and pathologically, we recently revealed that human bone marrow MSC-derived EV ameliorate GVHD clinically and pathologically through the preservation of peripheral naïve T-cell populations in a murine model. In this article, we summarize future perspectives on MSC-based therapy for GVHD.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Humanos , Camundongos , Linfócitos T
13.
Cell ; 183(1): 13-15, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32976799

RESUMO

Understanding which arms of the immune response are responsible for protection against SARS-CoV-2 infection is key to predicting long-term immunity and to inform vaccine design. Two studies in this issue of Cell collectively suggest that, although SARS-CoV-2 infection may blunt long-lived antibody responses, immune memory might still be achieved through virus-specific memory T cells.


Assuntos
Infecções por Coronavirus , Pandemias , Pneumonia Viral , Linfócitos T , Linfócitos B , Betacoronavirus
14.
PLoS One ; 15(8): e0238380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866185

RESUMO

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq on a prospective cohort of pancreatic tumor specimens and compared multiple approaches for gene expression-based immunophenotyping analysis compared to quantitative immunohistology. Our analyses demonstrated that while gene expression analyses provide additional information on the complexity of the tumor immune environment, they are limited in sensitivity by the low overall immune infiltrate in pancreatic cancer. As an alternative approach, we identified a set of genes that were enriched in highly T cell infiltrated pancreatic tumors, and demonstrate that these can identify patients with improved outcome in a reference population. These data demonstrate that the poor immune infiltrate in pancreatic cancer can present problems for analyses that use gene expression-based tools; however, there remains enormous potential in using these approaches to understand the relationships between diverse patterns of infiltrating cells and their impact on patient treatment outcomes.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
PLoS Pathog ; 16(9): e1008887, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956412

RESUMO

Despite the availability of multiple antibiotics, tuberculosis (TB) remains a major health problem worldwide, with one third of the population latently infected and ~2 million deaths annually. The only available vaccine for TB, Bacillus Calmette Guérin (BCG), is ineffective against adult pulmonary TB. Therefore, alternate strategies that enhance vaccine efficacy are urgently needed. Vaccine efficacy and long-term immune memory are critically dependent on central memory T (TCM) cells, whereas effector memory T (TEM) cells are important for clearing acute infections. Recently, it has been shown that inhibition of the Kv1.3 K+ ion channel, which is predominantly expressed on TEM but not TCM cells, profoundly enhances TCM cell differentiation. We exploited this phenomenon to improve TCM:TEM cell ratios and protective immunity against Mycobacterium tuberculosis infection in response to BCG vaccination of mice. We demonstrate that luteolin, a plant-derived Kv1.3 K+ channel inhibitor, profoundly promotes TCM cells by selectively inhibiting TEM cells, and significantly enhances BCG vaccine efficacy. Thus, addition of luteolin to BCG vaccination may provide a sustainable means to improve vaccine efficacy by boosting host immunity via modulation of memory T cell differentiation.


Assuntos
Vacina BCG/imunologia , Memória Imunológica/efeitos dos fármacos , Canal de Potássio Kv1.3 , Luteolina/farmacologia , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Animais , Canal de Potássio Kv1.3/antagonistas & inibidores , Canal de Potássio Kv1.3/imunologia , Camundongos , Tuberculose/prevenção & controle
16.
PLoS Pathog ; 16(9): e1008879, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32997728

RESUMO

The Human T-cell leukemia virus type 1 (HTLV-1) orf I-encoded accessory protein p8 is cleaved from its precursor p12, and both proteins contribute to viral persistence. p8 induces cellular protrusions, which are thought to facilitate transfer of p8 to target cells and virus transmission. Host factors interacting with p8 and mediating p8 transfer are unknown. Here, we report that vasodilator-stimulated phosphoprotein (VASP), which promotes actin filament elongation, is a novel interaction partner of p8 and important for p8 and HTLV-1 Gag cell-to-cell transfer. VASP contains an Ena/VASP homology 1 (EVH1) domain that targets the protein to focal adhesions. Bioinformatics identified a short stretch in p8 (amino acids (aa) 24-45) which may mediate interactions with the EVH1 domain of VASP. Co-immunoprecipitations confirmed interactions of VASP:p8 in 293T, Jurkat and HTLV-1-infected MT-2 cells. Co-precipitation of VASP:p8 could be significantly blocked by peptides mimicking aa 26-37 of p8. Mutational studies revealed that the EVH1-domain of VASP is necessary, but not sufficient for the interaction with p8. Further, deletion of the VASP G- and F-actin binding domains significantly diminished co-precipitation of p8. Imaging identified areas of partial co-localization of VASP with p8 at the plasma membrane and in protrusive structures, which was confirmed by proximity ligation assays. Co-culture experiments revealed that p8 is transferred between Jurkat T-cells via VASP-containing conduits. Imaging and flow cytometry revealed that repression of both endogenous and overexpressed VASP by RNA interference or by CRISPR/Cas9 reduced p8 transfer to the cell surface and to target Jurkat T-cells. Stable repression of VASP by RNA interference in chronically infected MT-2 cells impaired both p8 and HTLV-1 Gag transfer to target Jurkat T-cells, while virus release was unaffected. Thus, we identified VASP as a novel interaction partner of p8, which is important for transfer of HTLV-1 p8 and Gag to target T-cells.


Assuntos
Moléculas de Adesão Celular , Adesões Focais , Produtos do Gene gag , Vírus Linfotrópico T Tipo 1 Humano , Proteínas dos Microfilamentos , Fosfoproteínas , Linfócitos T , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Adesões Focais/química , Adesões Focais/genética , Adesões Focais/metabolismo , Adesões Focais/virologia , Produtos do Gene gag/química , Produtos do Gene gag/genética , Produtos do Gene gag/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/química , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Células Jurkat , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Domínios Proteicos , Linfócitos T/química , Linfócitos T/metabolismo , Linfócitos T/virologia
17.
Nat Commun ; 11(1): 4505, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908148

RESUMO

Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Aberrant patterns of DNA methylation in gametes may set the stage for transmission into future generations. Here, we describe a viable hypomorphic allele of dnmt1 in zebrafish that causes widespread demethylation of CpG dinucleotides in sperm and somatic tissues. We find that homozygous mutants are essentially normal, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by genotypically wildtype fish. We further find that about 200 differentially methylated regions in sperm DNA of transmitting and non-transmitting males, including hypermethylated sites associated with runx3 and rptor genes, whose reduced activities are associated with impaired larval T cell development. Our results indicate a particular sensitivity of larval T cell development to transgenerationally inherited epimutations.


Assuntos
Diferenciação Celular/genética , Genes Recessivos , Larva/crescimento & desenvolvimento , Linfopoese/genética , Linfócitos T/fisiologia , Alelos , Animais , Animais Geneticamente Modificados , Subunidade alfa 3 de Fator de Ligação ao Core/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Epigênese Genética , Feminino , Genética , Larva/citologia , Masculino , Mutação , Proteína Regulatória Associada a mTOR/genética , Espermatozoides/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
18.
Medicine (Baltimore) ; 99(37): e22170, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925784

RESUMO

BACKGROUND: Evidence suggests that metastasis is chiefly responsible for the poor prognosis of colon adenocarcinoma (COAD). The tumor microenvironment plays a vital role in regulating this biological process. However, the mechanisms involved remain unclear. The aim of this study was to identify crucial metastasis-related biomarkers in the tumor microenvironment and investigate its association with tumor-infiltrating immune cells. METHODS: We obtained gene expression profiles and clinical information from The Cancer Genome Atlas database. According to the "Estimation of STromal and Immune cells in MAlignant Tumor tissue using Expression data" algorithm, each sample generated the immune and stromal scores. Following correlation analysis, the metastasis-related gene was identified in The Cancer Genome Atlas database and validated in the GSE40967 dataset from Gene Expression Omnibus. The correlation between metastasis-related gene and infiltrating immune cells was assessed using the Tumor IMmune Estimation Resource database. RESULTS: The analysis included 332 patients; the metastatic COAD samples showed a low immune score. Correlation analysis results showed that interferon regulatory factor 1 (IRF1) was associated with tumor stage, lymph node metastasis, and distant metastasis. Furthermore, significant associations between IRF1 and CD8+ T cells, T cell (general), dendritic cells, T-helper 1 cells, and T cell exhaustion were demonstrated by Spearmans correlation coefficients and P values. CONCLUSIONS: The present findings suggest that IRF1 is associated with metastasis and the degree of immune infiltration of CD8+ T cells (general), dendritic cells, T-helper 1 cells, and T cell exhaustion in COAD. These results may provide information for immunotherapy in colon cancer.


Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Fator Regulador 1 de Interferon/imunologia , Linfócitos T/imunologia , Biomarcadores Tumorais , Linfócitos T CD8-Positivos/metabolismo , Bases de Dados Genéticas , Células Dendríticas/metabolismo , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/imunologia , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral
19.
Signal Transduct Target Ther ; 5(1): 192, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895366

Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Regulação da Expressão Gênica/imunologia , Linfopenia/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/genética , Infecções por Coronavirus/mortalidade , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/mortalidade , Progressão da Doença , Feminino , Receptor Celular 2 do Vírus da Hepatite A/sangue , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Contagem de Linfócitos , Linfopenia/diagnóstico , Linfopenia/genética , Linfopenia/mortalidade , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/genética , Pneumonia Viral/mortalidade , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Linfócitos T/virologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(5): 654-660, 2020 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-32897219

RESUMO

OBJECTIVE: To investigate the effect of ß-arrestin1 overexpression on tumor progression in a NCG mouse model bearing T-cell acute lymphocytic leukemia (T-ALL) Molt-4 cell xenograft. METHODS: Molt-4 cells were tagged with firefly-luciferase (F-Luc) by lentiviral infection, and fluorescence intensity of the cells was detected using a luminescence detector. Molt-4 cell lines with ß-arrestin1 overexpression or knockdown were constructed by lentivirus infection and injected via the tail vein in sub-lethal irradiated NCG mice. Body weight changes and survival time of the xenografted mice were observed, and the progression of T-ALL in the mice was evaluated using an in vivo fluorescence imaging system. Sixteen days after xenografting, the mice were euthanatized and tumor cell infiltration was observed in the slices of the liver and spleen. RESULTS: We successfully tagged Molt-4 cells with F-Luc and overexpressed or knocked down ß-arrestin1 in the tagged cells. Bioluminescent imaging showed obvious luminescence catalyzed by F-Luc in Molt-4 cells. After injection of Molt-4-Luc cells into irradiated NCG mice, a gradual enhancement of luminescence in the xenografted mice was observed over time, while the body weight of the mice decreased. Compared with the control mice, the mice xenografted with ß-arrestin1-overexpressing Molt-4 cells had significantly prolonged survival time (P < 0.001), while the survival time of the mice xenografted with Molt-4 cells with ß- arrestin1 knockdown was significantly shortened (P < 0.001). Histological examination revealed fewer infiltrating tumor cells in the liver and spleen of the mice xenografted with ß-arrestin1-overexpressing Molt-4 cells in comparison with the mice bearing parental Molt-4 cell xenografts. CONCLUSIONS: ß-arrestin1 overexpression suppresses tumor progression in mice bearing Molt-4 cell xenograft.


Assuntos
Linfócitos T , Animais , Progressão da Doença , Xenoenxertos , Humanos , Camundongos , Transplante Heterólogo , beta-Arrestina 1
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