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1.
Cell ; 156(4): 678-90, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24529373

RESUMO

Erk1/2 activation contributes to mouse ES cell pluripotency. We found a direct role of Erk1/2 in modulating chromatin features required for regulated developmental gene expression. Erk2 binds to specific DNA sequence motifs typically accessed by Jarid2 and PRC2. Negating Erk1/2 activation leads to increased nucleosome occupancy and decreased occupancy of PRC2 and poised RNAPII at Erk2-PRC2-targeted developmental genes. Surprisingly, Erk2-PRC2-targeted genes are specifically devoid of TFIIH, known to phosphorylate RNA polymerase II (RNAPII) at serine-5, giving rise to its initiated form. Erk2 interacts with and phosphorylates RNAPII at its serine 5 residue, which is consistent with the presence of poised RNAPII as a function of Erk1/2 activation. These findings underscore a key role for Erk1/2 activation in promoting the primed status of developmental genes in mouse ES cells and suggest that the transcription complex at developmental genes is different than the complexes formed at other genes, offering alternative pathways of regulation.


Assuntos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , Fator de Transcrição TFIIH/metabolismo , Animais , Cromatina/metabolismo , Células-Tronco Embrionárias/metabolismo , Ativação Enzimática , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Nucleossomos/metabolismo , Fosforilação , Complexo Repressor Polycomb 2/metabolismo
2.
Cell ; 153(7): 1552-66, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23791182

RESUMO

Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Receptor Notch1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
3.
Nat Immunol ; 16(6): 653-62, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25867473

RESUMO

The methylcytosine dioxygenase TET1 ('ten-eleven translocation 1') is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.


Assuntos
Linfócitos B/fisiologia , Citosina/análogos & derivados , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/fisiologia , Linfoma de Células B/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , 5-Metilcitosina/análogos & derivados , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Instabilidade Cromossômica , Citosina/metabolismo , Metilação de DNA , Reparo do DNA , Proteínas de Ligação a DNA/genética , Epigênese Genética , Exoma/genética , Perfilação da Expressão Gênica , Humanos , Camundongos , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética
4.
Immunity ; 48(2): 327-338.e5, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29466758

RESUMO

Immunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T (Trm) cells remain parked in nonlymphoid tissues and often stably express CD69. We recently identified Trm cells within SLO, but the origin and phenotype of these cells remains unclear. Using parabiosis of "dirty" mice, we found that CD69 expression is insufficient to infer stable residence of SLO Trm cells. Restimulation of nonlymphoid memory CD8+ T cells within the skin or mucosa resulted in a substantial increase in bona fide Trm cells specifically within draining lymph nodes. SLO Trm cells derived from emigrants from nonlymphoid tissues and shared some transcriptional and phenotypic signatures associated with nonlymphoid Trm cells. These data indicate that nonlymphoid cells can give rise to SLO Trm cells and suggest vaccination strategies by which memory CD8+ T cell immunosurveillance can be regionalized to specific lymph nodes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Linfonodos/imunologia , Animais , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Feminino , Lectinas Tipo C/análise , Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL
5.
Nature ; 556(7699): 103-107, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29590091

RESUMO

A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.


Assuntos
Antibacterianos/classificação , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Retinoides/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Animais , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Benzoatos/química , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Benzoatos/toxicidade , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Gentamicinas/farmacologia , Gentamicinas/uso terapêutico , Humanos , Bicamadas Lipídicas/química , Staphylococcus aureus Resistente à Meticilina/citologia , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Mutação , Naftóis/química , Naftóis/farmacologia , Naftóis/uso terapêutico , Naftóis/toxicidade , Retinoides/química , Retinoides/uso terapêutico , Retinoides/toxicidade
6.
Cancer Immunol Immunother ; 72(6): 1461-1478, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36472588

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is a lethal and metastatic malignancy resistant to therapy. Elucidating how pancreatic tumor-specific T cells differentiate and are maintained in vivo could inform novel therapeutic avenues to promote T cell antitumor activity. Here, we show that the spleen is a critical site harboring tumor-specific CD8 T cells that functionally segregate based on differential Cxcr3 and Klrg1 expression. Cxcr3+ Klrg1- T cells express the memory stem cell marker Tcf1, whereas Cxcr3-Klrg1 + T cells express GzmB consistent with terminal differentiation. We identify a Cxcr3+ Klrg1+ intermediate T cell subpopulation in the spleen that is highly enriched for tumor specificity. However, tumor-specific T cells infiltrating primary tumors progressively downregulate both Cxcr3 and Klrg1 while upregulating exhaustion markers PD-1 and Lag-3. We show that antigen-specific T cell infiltration into PDA is Cxcr3 independent. Further, Cxcr3-deficiency results in enhanced antigen-specific T cell IFNγ production in primary tumors, suggesting that Cxcr3 promotes loss of effector function. Ultimately, however, Cxcr3 was critical for mitigating cancer cell dissemination following immunotherapy with CD40 agonist + anti-PD-L1 or T cell receptor engineered T cell therapy targeting mesothelin. In the absence of Cxcr3, splenic Klrg1 + GzmB + antitumor T cells wain while pancreatic cancer disseminates suggesting a role for these cells in eliminating circulating metastatic tumor cells. Intratumoral myeloid cells are poised to produce Cxcl10, whereas splenic DC subsets produce Cxcl9 following immunotherapy supporting differential roles for these chemokines on T cell differentiation. Together, our study supports that Cxcr3 mitigates tumor cell dissemination by impacting peripheral T cell fate rather than intratumoral T cell trafficking.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores CXCR3 , Neoplasias Pancreáticas
7.
PLoS Pathog ; 17(1): e1009292, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33507952

RESUMO

The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/fisiologia , Tropismo Viral , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , COVID-19/genética , Epitélio/imunologia , Epitélio/virologia , Humanos , Interferons/genética , Interferons/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , SARS-CoV-2/efeitos dos fármacos , Tropismo Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
8.
Am J Respir Crit Care Med ; 205(11): 1290-1299, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35290169

RESUMO

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).


Assuntos
Tratamento Farmacológico da COVID-19 , Anticorpos Monoclonais Humanizados/uso terapêutico , Método Duplo-Cego , Humanos , Inflamação
9.
PLoS Pathog ; 16(8): e1008760, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790753

RESUMO

Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lung can be infected, it is not known if all cell types contribute equally to establish the antiviral state in the host. Here, we use single-cycle influenza A viruses (scIAVs) to characterize the early immune response to IAV in vitro and in vivo. We found that the magnitude of virus replication contributes to antiviral gene expression within infected cells prior to the induction of a global response. We also developed a scIAV that is only capable of undergoing primary transcription, the earliest stage of virus replication. Using this tool, we uncovered replication stage-specific responses in vitro and in vivo. Using several innate immune receptor knockout cell lines, we identify RIG-I as the predominant antiviral detector of primary virus transcription and amplified replication in vitro. Through a Cre-inducible reporter mouse, we used scIAVs expressing Cre-recombinase to characterize cell type-specific responses in vivo. Individual cell types upregulate unique sets of antiviral genes in response to both primary virus transcription and amplified replication. We also identified antiviral genes that are only upregulated in response to direct infection. Altogether, these data offer insight into the early mechanisms of antiviral gene activation during influenza A infection.


Assuntos
Células Epiteliais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/imunologia , Replicação Viral , Células A549 , Animais , Antivirais/farmacologia , Proteína DEAD-box 58/metabolismo , Cães , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Células HEK293 , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Vírus da Influenza A/isolamento & purificação , Influenza Humana/tratamento farmacológico , Influenza Humana/patologia , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Receptores Imunológicos
11.
Mol Cell ; 53(6): 979-92, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24656132

RESUMO

Monomethylation of lysine 4 on histone H3 (H3K4me1) is a well-established feature of enhancers and promoters, although its function is unknown. Here, we uncover roles for H3K4me1 in diverse cell types. Remarkably, we find that MLL3/4 provokes monomethylation of promoter regions and the conditional repression of muscle and inflammatory response genes in myoblasts. During myogenesis, muscle genes are activated, lose MLL3 occupancy, and become H3K4-trimethylated through an alternative COMPASS complex. Monomethylation-mediated repression was not restricted to skeletal muscle. Together with H3K27me3 and H4K20me1, H3K4me1 was associated with transcriptional silencing in embryonic fibroblasts, macrophages, and human embryonic stem cells (ESCs). On promoters of active genes, we find that H3K4me1 spatially demarcates the recruitment of factors that interact with H3K4me3, including ING1, which, in turn, recruits Sin3A. Our findings point to a unique role for H3K4 monomethylation in establishing boundaries that restrict the recruitment of chromatin-modifying enzymes to defined regions within promoters.


Assuntos
Cromatina , Regulação da Expressão Gênica no Desenvolvimento , Histonas/genética , Desenvolvimento Muscular/genética , Mioblastos/metabolismo , Animais , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Elementos Facilitadores Genéticos , Fibroblastos/citologia , Fibroblastos/metabolismo , Genoma , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Humanos , Proteína 1 Inibidora do Crescimento , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Mioblastos/citologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Complexo Correpressor Histona Desacetilase e Sin3 , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
12.
Genes Dev ; 28(18): 1983-8, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25170018

RESUMO

Polycomb-repressive complex 2 (PRC2) facilitates the maintenance and inheritance of chromatin domains repressive to transcription through catalysis of methylation of histone H3 at Lys27 (H3K27me2/3). However, through its EZH2 subunit, PRC2 also binds to nascent transcripts from active genes that are devoid of H3K27me2/3 in embryonic stem cells. Here, biochemical analyses indicated that RNA interaction inhibits SET domain-containing proteins, such as PRC2, nonspecifically in vitro. However, CRISPR-mediated truncation of a PRC2-interacting nascent RNA rescued PRC2-mediated deposition of H3K27me2/3. That PRC2 activity is inhibited by interactions with nascent transcripts supports a model in which PRC2 can only mark for repression those genes silenced by transcriptional repressors.


Assuntos
Complexo Repressor Polycomb 2/metabolismo , RNA/metabolismo , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/fisiologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Ativação Enzimática , Regulação da Expressão Gênica , Inativação Gênica , Histonas/metabolismo , Camundongos , Complexo Repressor Polycomb 2/genética , Ligação Proteica , Células Sf9
13.
Sheng Li Xue Bao ; 74(5): 783-791, 2022 Oct 25.
Artigo em Zh | MEDLINE | ID: mdl-36319101

RESUMO

As COVID-19 pandemic approaching its third year, more data have shown that obesity and hypertriglyceridemia are the high-risk factors for the major complications such as acute respiratory distress syndrome, thromboembolism, coagulopathy and cytokine storm, which are responsible for the majority of disease severity and mortality. In this review article, we have analyzed the public available clinical reports and laboratory research results of the COVID-19 studies by researchers and clinicians of many nations around the world. Many of these reports covered COVID-19 patients of different ethnic groups. We suggested that obesity and high triglycerides are high risks for severe COVID-19 and death. We also summarized the possible underlying molecular mechanism likely connecting the severe COVID-19 with obesity and hypertriglyceridemia. From public health perspective, we highlight the importance of the healthy diet and lifestyle in fighting against SARS-CoV-2 virus in long period of time.


Assuntos
COVID-19 , Hipertrigliceridemia , Humanos , Pandemias , SARS-CoV-2 , Obesidade , Índice de Gravidade de Doença
14.
Int J Obes (Lond) ; 45(1): 143-154, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33214705

RESUMO

Lipocalin 2 (Lcn2), as an antimicrobial peptide is expressed in intestine, and the upregulation of intestinal Lcn2 has been linked to inflammatory bowel disease. However, the role of Lcn2 in shaping gut microbiota during diet-induced obesity (DIO) remains unknown. We found that short-term high fat diet (HFD) feeding strongly stimulates intestinal Lcn2 expression and secretion into the gut lumen. As the HFD feeding prolongs, fecal Lcn2 levels turn to decrease. Lcn2 deficiency accelerates the development of HFD-induced intestinal inflammation and microbiota dysbiosis. Moreover, Lcn2 deficiency leads to the remodeling of microbiota-derived metabolome, including decreased production of short-chain fatty acids (SCFAs) and SCFA-producing microbes. Most importantly, we have identified Lcn2-targeted bacteria and microbiota-derived metabolites that potentially play roles in DIO and metabolic dysregulation. Correlation analyses suggest that Lcn2-targeted Dubosiella and Angelakisella have a novel role in regulating SCFAs production and obesity. Our results provide a novel mechanism involving Lcn2 as an antimicrobial host factor in the control of gut microbiota symbiosis during DIO.


Assuntos
Microbioma Gastrointestinal/fisiologia , Lipocalina-2/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
J Immunol ; 203(4): 936-945, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31235552

RESUMO

Resident memory T cells (TRM) in the lung are vital for heterologous protection against influenza A virus (IAV). Environmental factors are necessary to establish lung TRM; however, the role of T cell-intrinsic factors like TCR signal strength have not been elucidated. In this study, we investigated the impact of TCR signal strength on the generation and maintenance of lung TRM after IAV infection. We inserted high- and low-affinity OT-I epitopes into IAV and infected mice after transfer of OT-I T cells. We uncovered a bias in TRM formation in the lung elicited by lower affinity TCR stimulation. TCR affinity did not impact the overall phenotype or long-term maintenance of lung TRM Overall, these findings demonstrate that TRM formation is negatively correlated with increased TCR signal strength. Lower affinity cells may have an advantage in forming TRM to ensure diversity in the Ag-specific repertoire in tissues.


Assuntos
Memória Imunológica/imunologia , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia
16.
Proc Natl Acad Sci U S A ; 115(38): 9610-9615, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30181264

RESUMO

Influenza virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. To define the antiviral response at the earliest stages of infection we used a series of single-cycle reporter viruses. These viral probes demonstrated cells in vivo harbor a range in magnitude of virus replication. Transcriptional profiling of cells supporting different levels of replication revealed tiers of IFN-stimulated gene expression. Uninfected cells and cells with blunted replication expressed a distinct and potentially protective antiviral signature, while cells with high replication expressed a unique reserve set of antiviral genes. Finally, we used these single-cycle reporter viruses to determine the antiviral landscape during virus spread, which unveiled disparate protection of epithelial cell subsets mediated by IFN in vivo. Together these results highlight the complexity of virus-host interactions within the infected lung and suggest that magnitude and round of replication tune the antiviral response.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Pulmão/virologia , Replicação Viral/imunologia , Animais , Cães , Células Epiteliais/imunologia , Células Epiteliais/virologia , Perfilação da Expressão Gênica/métodos , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Vírus da Influenza A/isolamento & purificação , Influenza Humana/imunologia , Influenza Humana/patologia , Interferons/imunologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , RNA Viral/isolamento & purificação , Análise de Sequência de DNA
17.
Ann Diagn Pathol ; 52: 151719, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33640702

RESUMO

Pleomorphic giant cell carcinoma (PGCC) of the prostate is a rare entity categorized as a variant of prostatic acinar adenocarcinoma in the 2016 World Health Organization (WHO) classification system. PGCC differs from conventional prostatic adenocarcinoma by having bizarre, markedly enlarged, and pleomorphic cells. It differs from high grade urothelial carcinoma by negativity for urothelial differentiation markers, and can be distinguished from sarcomatoid carcinoma by lack of spindle cells. Including two new cases described herein, there have been 51 cases of prostate PGCC reported in the English literature. Clinical features shared by cases of prostate PGCC include poor prognosis, occurrence in older patients, and frequent association with prior therapy. Pathologic features common to cases of prostate PGCC include admixture with a high-grade conventional prostate carcinoma component and absent or reduced expression of prostate differentiation markers. More recent studies have begun to elucidate the molecular characteristics of PGCC, detecting specific mutations and chromosomal translocations, and showing evidence of a high degree of molecular instability in these tumors. We report novel findings in two cases of PGCC including a PIK3CA p.His1047Arg mutation not previously described. One of our cases is the first to clearly demonstrate chronological loss of prostate markers during dedifferentiation from prior conventional prostate carcinoma to PGCC. Herein, we present our two new cases and comprehensively review the literature on all reported cases of PGCC with critical commentary on findings in cases of this rare tumor.


Assuntos
Carcinoma de Células Gigantes/diagnóstico , Carcinoma de Células Gigantes/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma de Células Acinares/patologia , Desdiferenciação Celular , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Diagnóstico Diferencial , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores/métodos , Prognóstico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Urotélio/patologia
18.
Genes Dev ; 27(24): 2663-77, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24352422

RESUMO

Polycomb-repressive complex 2 (PRC2) comprises specific members of the Polycomb group of epigenetic modulators. PRC2 catalyzes methylation of histone H3 at Lys 27 (H3K27me3) through its Enhancer of zeste (Ezh) constituent, of which there are two mammalian homologs: Ezh1 and Ezh2. Several ancillary factors, including Jarid2, modulate PRC2 function, with Jarid2 facilitating its recruitment to target genes. Jarid2, like Ezh2, is present in poorly differentiated and actively dividing cells, while Ezh1 associates with PRC2 in all cells, including resting cells. We found that Jarid2 exhibits nucleosome-binding activity that contributes to PRC2 stimulation. Moreover, such nucleosome-binding activity is exhibited by PRC2 comprising Ezh1 (PRC2-Ezh1), in contrast to PRC2-Ezh2. The presence of Ezh1 helps to maintain PRC2 occupancy on its target genes in myoblasts where Jarid2 is not expressed. Our findings allow us to propose a model in which PRC2-Ezh2 is important for the de novo establishment of H3K27me3 in dividing cells, whereas PRC2-Ezh1 is required for its maintenance in resting cells.


Assuntos
Cromatina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Nucleossomos/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Camundongos , Mioblastos/metabolismo , Mioblastos/patologia , Células NIH 3T3 , Complexo Repressor Polycomb 2/deficiência , Complexo Repressor Polycomb 2/genética , Ligação Proteica , Estrutura Terciária de Proteína
19.
Thorax ; 75(4): 351-353, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32041741

RESUMO

The concept of chronic obstructive pulmonary disease (COPD) control has been proposed to guide treatment decisions in COPD. In this study, we aimed to validate the prospective value of this concept in the SPARK study population. Control was assessed based on COPD stability and impact. Patients with low impact and stability during weeks 1-12 were classified as controlled, and exacerbations were measured during a 52-week follow-up. Of the 2044 patients included a majority were non-controlled (80%), frequently due to high impact. During the follow-up, the rate of moderate/severe exacerbations was significantly lower in controlled patients (rate ratio, 0.56, 95% CI 0.48 to 0.65 p<0.0001) and time-to-first moderate/severe exacerbation was significantly delayed. This study demonstrated an association between control status and risk of exacerbations.


Assuntos
Glicopirrolato/administração & dosagem , Indanos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/administração & dosagem , Brometo de Tiotrópio/administração & dosagem , Idoso , Broncodilatadores/administração & dosagem , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Reprodutibilidade dos Testes , Testes de Função Respiratória , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Am J Respir Crit Care Med ; 199(1): 43-51, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30019939

RESUMO

RATIONALE: Chronic obstructive pulmonary disease exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n = 457) from the FLAME (Effect of Indacaterol Glycopyrronium vs. Fluticasone Salmeterol on COPD Exacerbations) study used the Exacerbations of COPD Tool (EXACT) to capture symptom-defined exacerbations. OBJECTIVES: To evaluate the effect of indacaterol/glycopyrronium versus salmeterol/fluticasone on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU). METHODS: All patients in FLAME used an electronic diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery, and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time to first symptom-defined (EXACT) exacerbation and assessed differences between symptom-defined and HCRU events in terms of number, severity, and concordance. MEASUREMENTS AND MAIN RESULTS: A nonsignificant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio, 0.83; 95% confidence interval [CI], 0.60-1.14; P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with indacaterol/glycopyrronium versus salmeterol/fluticasone (hazard ratio, 0.76; 95% CI, 0.56-1.03; P = 0.075). These results were consistent with data from the overall FLAME population. Of the symptom-defined (EXACT) events, 23.5% corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (κ index, 0.24; 95% CI, 0.15-0.33). CONCLUSIONS: Regardless of the exacerbation definition used, our findings support the use of long-acting ß2 agonists/long-acting muscarinic receptor antagonists as the preferred treatment option for patients at risk of future exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT01782326).


Assuntos
Broncodilatadores/uso terapêutico , Fluticasona/uso terapêutico , Glicopirrolato/uso terapêutico , Indanos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Quinolonas/uso terapêutico , Xinafoato de Salmeterol/uso terapêutico , Broncodilatadores/administração & dosagem , Progressão da Doença , Quimioterapia Combinada , Feminino , Fluticasona/administração & dosagem , Glicopirrolato/administração & dosagem , Humanos , Indanos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Quinolonas/administração & dosagem , Fatores de Risco , Xinafoato de Salmeterol/administração & dosagem , Inquéritos e Questionários
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