Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Sci Rep ; 13(1): 142, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599909

RESUMO

The vaping of electronic cigarettes (E-cigarettes) has recently emerged as a popular alternative to traditional cigarette smoking, but its association with bladder cancer (BC) risk remains to be established. BC patients exhibit high rates of recurrent disease, possibly as a consequence of the field cancerization effect. We have shown that BC-derived extracellular vesicles (BCEVs) can permanently alter recipient urothelial cells in predisposed fields such that they become fully transformed malignant cells. To model the role that BCEVs may play in this potentially oncogenic setting, we treated TCCSUP BC cells with cigarette smoke extract, unflavored E-liquid, or menthol flavored E-liquid. Those treated BCEVs were then tested for their tumorigenic potential. We found that these smoking- and E-cigarette-related BCEVs were able to promote oxidative stress, inflammatory signaling, and DNA damage in recipient SV-HUC urothelial cells. Strikingly, menthol E-liquid-induced BCEVs significantly increased rates of malignant urothelial cell transformation. While further in vivo validation of the simultaneous effects of E-liquid and E-liquid-induced BCEVs on field cancerization is needed, these data highlight the possibility that E-cigarettes may compound user risk in a manner that can contribute to higher rates of BC incidence or recurrence.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Vesículas Extracelulares , Neoplasias da Bexiga Urinária , Humanos , Mentol , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Nicotiana , Vesículas Extracelulares/patologia , Aromatizantes
2.
Front Immunol ; 13: 909979, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990699

RESUMO

CD3-engaging bispecific antibodies (BsAbs) enable the formation of an immune synapse between T cells and tumor cells, resulting in robust target cell killing not dependent on a preexisting tumor specific T cell receptor. While recent studies have shed light on tumor cell-specific factors that modulate BsAb sensitivity, the T cell-intrinsic determinants of BsAb efficacy and response durability are poorly understood. To better clarify the genes that shape BsAb-induced T cell responses, we conducted targeted analyses and a large-scale unbiased in vitro CRISPR/Cas9-based screen to identify negative regulators of BsAb-induced T cell proliferation. These analyses revealed that CD8+ T cells are dependent on CD4+ T cell-derived signaling factors in order to achieve sustained killing in vitro. Moreover, the mammalian target of rapamycin (mTOR) pathway and several other candidate genes were identified as intrinsic regulators of BsAb-induced T cell proliferation and/or activation, highlighting promising approaches to enhancing the utility of these potent therapeutics.


Assuntos
Anticorpos Biespecíficos , Neoplasias , Anticorpos Biespecíficos/farmacologia , Formação de Anticorpos , Humanos , Ativação Linfocitária/genética , Receptores de Antígenos de Linfócitos T
3.
Stem Cell Res Ther ; 12(1): 533, 2021 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-34627375

RESUMO

BACKGROUND: Chemosenstive non-stem cancer cells (NSCCs) constitute the bulk of tumors and are considered as part of the cancer stem cell (CSC) niche in the tumor microenvironment (TME). Tumor-derived extracellular vesicles (EVs) mediate the communication between tumors and the TME. In this study, we sought to investigate the impacts of EVs released by NSCCs on the maintenance of CSC properties and chemoresistance. METHODS: We employed murine MB49 bladder cancer (BC) sub-lines representing CSCs and NSCCs as a model system. Chemotherapy drugs were used to treat NSCCs in order to collect conditioned EVs. The impacts of NSCC-derived EVs on CSC progression were evaluated through sphere formation, cytotoxicity, migration, and invasion assays, and by analyzing surface marker expression on these BC cells. Differential proteomic analyses were conducted to identify cargo protein candidates involved in the EV-mediated communication between NSCCs and CSCs. RESULTS: NSCC-derived EVs contained cargo proteins enriched in proteostasis-related functions, and significantly altered the development of CSCs such that they were more intrinsically chemoresistant, aggressive, and better able to undergo self-renewal. CONCLUSIONS: We thus identified a novel communication mechanism whereby NSCC-EVs can alter the relative fitness of CSCs to promote disease progression and the acquisition of chemoresistance.


Assuntos
Vesículas Extracelulares , Neoplasias da Bexiga Urinária , Animais , Camundongos , Células-Tronco Neoplásicas , Proteômica , Microambiente Tumoral , Neoplasias da Bexiga Urinária/tratamento farmacológico
4.
Mol Cancer Ther ; 19(10): 2089-2104, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32847974

RESUMO

The sole inhibitory Fcγ receptor CD32b (FcγRIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to rituximab that can be ameliorated with a CD32b-blocking antibody. CD32b, therefore, represents an attractive tumor antigen for targeting with a monoclonal antibody (mAb). To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. Their complementarity-determining regions (CDR) bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcγRIIIa on immune effector cells. The NVS32b mAbs selectively target CD32b+ malignant cells and healthy B cells but not myeloid cells. They mediate potent killing of opsonized CD32b+ cells via antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) as well as complement-dependent cytotoxicity (CDC). In addition, NVS32b CDRs block the CD32b Fc-binding domain, thereby minimizing CD32b-mediated resistance to therapeutic mAbs including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b+ xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor and enhancement of dendritic cell maturation in response to immune complexes. Finally, the activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed using samples from patients with B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. The findings indicate the promising potential of NVS32b mAbs as a single agent or in combination with other mAb therapeutics for patients with CD32b+ malignant cells.


Assuntos
Linfoma de Células B/genética , Neoplasias de Plasmócitos/genética , Receptores de IgG/imunologia , Animais , Células CHO , Cricetulus , Humanos
5.
Sci Immunol ; 4(41)2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732517

RESUMO

Influenza A virus (IAV) infection-associated morbidity and mortality are a key global health care concern, necessitating the identification of new therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of γδ T cells in the lung that improved barrier functions, thereby enhancing antiviral resistance. Expansion of these protective γδ T cells required metabolic adaptation to a ketogenic diet because neither feeding mice a high-fat, high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD-mediated immune-metabolic integration represents a viable avenue toward preventing or alleviating influenza disease.


Assuntos
Dieta Cetogênica , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Linfócitos T/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/virologia
6.
Exp Gerontol ; 107: 130-135, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28822811

RESUMO

The worldwide population aged≥65years is increasing and the average life span is expected to increase another 10years by 2050. This extended lifespan is associated with a progressive decline in immune function and a paradoxical state of low-grade, chronic inflammation that may contribute to susceptibility to viral infection, and reduced responses to vaccination. Here we review the effects of aging on innate immune responses to viral pathogens including elements of recognition, signaling, and production of inflammatory mediators. We specifically focus on age-related changes in key pattern recognition receptor signaling pathways, converging on altered cytokine responses, including a notable impairment of antiviral interferon responses. We highlight an emergent change in innate immunity that arises during aging - the dampening of the dynamic range of responses to multiple sources of stimulation - which may underlie reduced efficiency of immune responses in aging.


Assuntos
Envelhecimento/imunologia , Células Dendríticas/imunologia , Imunidade Inata , Inflamassomos/imunologia , Monócitos/imunologia , Idoso , Citocinas/imunologia , Humanos , Transdução de Sinais
7.
Nat Rev Immunol ; 17(1): 7-20, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27890913

RESUMO

The respiratory immune response consists of multiple tiers of cellular responses that are engaged in a sequential manner in order to control infections. The stepwise engagement of effector functions with progressively increasing host fitness costs limits tissue damage. In addition, specific mechanisms are in place to promote disease tolerance in response to respiratory infections. Environmental factors, obesity and the ageing process can alter the efficiency and regulation of this tiered response, increasing pathology and mortality as a result. In this Review, we describe the cell types that coordinate pathogen clearance and tissue repair through the serial secretion of cytokines, and discuss how the environment and comorbidity influence this response.


Assuntos
Sistema Respiratório/imunologia , Animais , Humanos
8.
Sci Signal ; 10(509)2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29233916

RESUMO

Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid-inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors. We found that monocytes from older adults exhibited decreased abundance of the adaptor protein TRAF3 (tumor necrosis factor receptor-associated factor 3) because of its increased proteasomal degradation with age, thereby impairing the primary RIG-I signaling pathway for the induction of type I IFNs. We determined that monocytes from older adults also failed to effectively stimulate the production of the IFN regulatory transcription factor IRF8, which compromised IFN induction through secondary RIG-I signaling. IRF8 played a central role in IFN induction in monocytes, because knocking down IRF8 in monocytes from younger adults was sufficient to replicate the IFN defects observed in monocytes from older adults, whereas restoring IRF8 expression in older adult monocytes was sufficient to restore RIG-I-induced IFN responses. Aging thus compromises both the primary and secondary RIG-I signaling pathways that govern expression of type I IFN genes, thereby impairing antiviral resistance to IAV.


Assuntos
Envelhecimento/imunologia , Proteína DEAD-box 58/imunologia , Imunidade Inata , Interferons/imunologia , Monócitos/imunologia , Transdução de Sinais/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Monócitos/citologia , Receptores Imunológicos
9.
Sci Signal ; 10(482)2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28588082

RESUMO

The unfolded protein response (UPR) is an ancient cellular pathway that detects and alleviates protein-folding stresses. The UPR components X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1α (IRE1α) promote type I interferon (IFN) responses. We found that Xbp1-deficient mouse embryonic fibroblasts and macrophages had impaired antiviral resistance. However, this was not because of a defect in type I IFN responses but rather an inability of Xbp1-deficient cells to undergo viral-induced apoptosis. The ability to undergo apoptosis limited infection in wild-type cells. Xbp1-deficient cells were generally resistant to the intrinsic pathway of apoptosis through an indirect mechanism involving activation of the nuclease IRE1α. We observed an IRE1α-dependent reduction in the abundance of the proapoptotic microRNA miR-125a and a corresponding increase in the amounts of the members of the antiapoptotic Bcl-2 family. The activation of IRE1α by the hepatitis C virus (HCV) protein NS4B in XBP1-proficient cells also conferred apoptosis resistance and promoted viral replication. Furthermore, we found evidence of IRE1α activation and decreased miR-125a abundance in liver biopsies from patients infected with HCV compared to those in the livers of healthy controls. Our results reveal a prosurvival role for IRE1α in virally infected cells and suggest a possible target for IFN-independent antiviral therapy.


Assuntos
Apoptose , Endorribonucleases/metabolismo , Hepatite C/virologia , Herpes Simples/virologia , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/metabolismo , Estomatite Vesicular/virologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Feminino , Hepacivirus/patogenicidade , Hepatite C/metabolismo , Hepatite C/patologia , Herpes Simples/metabolismo , Herpes Simples/patologia , Humanos , Fígado/virologia , Masculino , Camundongos , Camundongos Knockout , Simplexvirus/patogenicidade , Estomatite Vesicular/metabolismo , Estomatite Vesicular/patologia , Vírus da Estomatite Vesicular Indiana/patogenicidade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral , Proteína 1 de Ligação a X-Box/fisiologia
10.
Cell Rep ; 18(9): 2077-2087, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28249154

RESUMO

Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1ß (IL-1ß) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases ß-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1ß in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Gota/tratamento farmacológico , Gota/metabolismo , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neutrófilos/efeitos dos fármacos , Adolescente , Adulto , Idoso , Animais , Dieta Cetogênica/efeitos adversos , Feminino , Humanos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Ratos , Ácido Úrico/metabolismo , Adulto Jovem
11.
Science ; 352(6284): 463-6, 2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-27102485

RESUMO

Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.


Assuntos
Infecções Bacterianas/imunologia , Imunidade Inata/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Proteínas de Resistência a Myxovirus/fisiologia , Infecções por Orthomyxoviridae/imunologia , Infecções Respiratórias/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Infecções Bacterianas/etiologia , Caspase 1/metabolismo , Caspases/metabolismo , Caspases Iniciadoras , Feminino , Humanos , Imunidade Inata/genética , Influenza Humana/complicações , Interferon beta/imunologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Monócitos/imunologia , Proteínas de Resistência a Myxovirus/genética , Neutrófilos/imunologia , Infecções Respiratórias/microbiologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Carga Viral , Adulto Jovem
12.
Curr Protoc Toxicol ; Chapter 18: Unit 18.16.1-19, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22896008

RESUMO

Biological indicators have numerous and widespread utility in personalized medicine, but the measurement of these indicators also poses many technological and practical challenges. Blood/plasma has typically been used as the sample source with which to measure these indicators, but the invasiveness associated with sample procurement has led to increased interest in saliva as an attractive alternative. However, there are unique issues associated with the measurement of saliva biomarkers. These issues are compounded by the imperfect correlation between saliva and plasma with respect to biomarker profiles. In this manuscript, we address the technical challenges associated with saliva biomarker quantification. We describe a high-content microarray assay that employs both grating-coupled surface plasmon resonance imaging and surface plasmon-coupled emission modalities in a highly sensitive assay with a large dynamic range. This powerful approach provides the tools to map the proteome of saliva, which in turn should greatly enhance the utility of salivary biomarker profiles in personalized medicine.


Assuntos
Análise Serial de Proteínas/métodos , Proteoma/química , Proteômica/métodos , Saliva/química , Ressonância de Plasmônio de Superfície/métodos , Biomarcadores/química , Biomarcadores/metabolismo , Humanos , Análise Serial de Proteínas/instrumentação , Proteoma/metabolismo , Proteômica/instrumentação , Proteínas e Peptídeos Salivares/química , Proteínas e Peptídeos Salivares/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA