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1.
Cell ; 181(2): 424-441.e21, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32234521

RESUMO

KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8+ T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.


Assuntos
Envelhecimento/fisiologia , Carcinoma Ductal Pancreático/patologia , Remodelação Vascular/fisiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/microbiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Genes ras/genética , Humanos , Imunoterapia/métodos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Neoplasias Pancreáticas/patologia , Proteína do Retinoblastoma/imunologia , Transdução de Sinais/genética , Microambiente Tumoral , Remodelação Vascular/genética
2.
Cell ; 178(4): 807-819.e21, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398338

RESUMO

The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Glicosilação , Células HEK293 , Células Hep G2 , Xenoenxertos , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução Genética
4.
Nature ; 583(7814): 127-132, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555459

RESUMO

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8-10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.


Assuntos
Envelhecimento/patologia , Senescência Celular/imunologia , Cirrose Hepática/terapia , Longevidade/imunologia , Neoplasias Pulmonares/terapia , Receptores de Antígenos Quiméricos/imunologia , Rejuvenescimento , Linfócitos T/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Animais , Tetracloreto de Carbono , Feminino , Xenoenxertos , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo
6.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35082152

RESUMO

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Animais , Carcinoma Epitelial do Ovário/dietoterapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL
7.
Hepatology ; 69(4): 1768-1786, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30561826

RESUMO

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant-producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction-oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid-derived 2)-like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacological TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.


Assuntos
Auranofina/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxina Redutase 1/metabolismo , Animais , Antineoplásicos/uso terapêutico , Auranofina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Sorafenibe/uso terapêutico , Tiorredoxina Redutase 1/antagonistas & inibidores
8.
Nat Mater ; 17(4): 361-368, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29403054

RESUMO

Development of targeted nanoparticle drug carriers often requires complex synthetic schemes involving both supramolecular self-assembly and chemical modification. These processes are generally difficult to predict, execute, and control. We describe herein a targeted drug delivery system that is accurately and quantitatively predicted to self-assemble into nanoparticles based on the molecular structures of precursor molecules, which are the drugs themselves. The drugs assemble with the aid of sulfated indocyanines into particles with ultrahigh drug loadings of up to 90%. We devised quantitative structure-nanoparticle assembly prediction (QSNAP) models to identify and validate electrotopological molecular descriptors as highly predictive indicators of nano-assembly and nanoparticle size. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. This finding enables the computational design of nanomedicines based on quantitative models for drug payload selection.


Assuntos
Portadores de Fármacos/química , Nanomedicina/métodos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacocinética , Endocitose , Indóis/química , Camundongos , Nanopartículas/química , Tamanho da Partícula , Distribuição Tecidual
9.
Nat Cancer ; 5(2): 315-329, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38177458

RESUMO

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.


Assuntos
Neoplasias Gástricas , Humanos , Camundongos , Animais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Modelos Animais de Doenças , Mucosa Gástrica/patologia , Genótipo
10.
Nat Biotechnol ; 40(6): 862-873, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35165384

RESUMO

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity 'sensors' that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems. We demonstrate that sensor-validated tools streamline production of in vivo cancer models and that integrating sensor modules in pooled sgRNA libraries can aid interpretation of high-throughput base editing screens. Using this approach, we identify several previously uncharacterized mutant TP53 alleles as drivers of cancer cell proliferation and in vivo tumor development. We anticipate that the framework described here will facilitate the functional interrogation of cancer variants in cell and animal models.


Assuntos
Edição de Genes , Neoplasias , Animais , Sistemas CRISPR-Cas/genética , Neoplasias/genética , Nucleotídeos , RNA Guia de Cinetoplastídeos/genética
11.
Cancer Discov ; 12(10): 2308-2329, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-35758895

RESUMO

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. SIGNIFICANCE: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Antagonistas do Receptor A2 de Adenosina , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/patologia , Inflamação , Interleucina-6 , Neoplasias Renais/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Microambiente Tumoral/genética , Humanos
12.
Cancer Discov ; 10(7): 1038-1057, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376773

RESUMO

To study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors that are metastatic and castration-resistant. A subset of tumors with Trp53 alterations acquired spontaneous WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Using the EPO-GEMM approach and an orthogonal organoid-based model, we show that WNT pathway activation drives metastatic disease that is sensitive to pharmacologic WNT pathway inhibition. Thus, by leveraging EPO-GEMMs, we reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as therapeutic target in metastatic prostate cancer. SIGNIFICANCE: Our understanding of the factors driving metastatic prostate cancer is limited by the paucity of models of late-stage disease. Here, we develop EPO-GEMMs of prostate cancer and use them to identify and validate the WNT pathway as an actionable driver of aggressive metastatic disease.This article is highlighted in the In This Issue feature, p. 890.


Assuntos
Neoplasias da Próstata/genética , Engenharia Tecidual/métodos , Via de Sinalização Wnt/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Metástase Neoplásica
13.
Nat Med ; 25(3): 530, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30692700

RESUMO

In the version of this article originally published, there was an error in the legend for Extended Data Fig. 7. The legend for panel f was originally: "f, FACS analysis of IL7R-, CD62L- and CD45RA- expression on TRAC-1928ζ and TRAC-1XX CAR T cells at day 63 post CAR infusion (representative for at least n = 3 mice per group in one independent experiment)." The legend should have been: "f, FACS analysis of IL7R+, CD62L+ and CD45RA+ expression on TRAC-1928ζ and TRAC-1XX CAR T cells at day 63 post CAR infusion (representative for at least n = 3 mice per group in one independent experiment)." The error has been corrected in the HTML and PDF versions of this article.

14.
Nat Med ; 25(1): 82-88, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30559421

RESUMO

Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties1. CD19-specific CARs that comprise CD28 and CD3ζ signaling motifs2 have induced remarkable responses in patients with refractory leukemia3-5 and lymphoma6 and were recently approved by the US Food and Drug Administration7. These CARs program highly performing effector functions that mediate potent tumor elimination4,8 despite the limited persistence they confer on T cells3-6,8. Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion9,10, which may be accentuated by the redundancy of CD28 and CD3ζ signaling11,12 as well as the spatiotemporal constraints imparted by the structure of second-generation CARs2. Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles.


Assuntos
Linhagem da Célula , Imunoterapia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Animais , Calibragem , Linhagem Celular , Masculino , Camundongos , Domínios Proteicos , Receptores de Antígenos de Linfócitos T/química
15.
Science ; 362(6421): 1416-1422, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30573629

RESUMO

Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor-α and intercellular adhesion molecule-1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non-cell autonomous mechanisms involving NK cell surveillance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Citostáticos/uso terapêutico , Citotoxicidade Imunológica , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Apoptose , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Senescência Celular , Citostáticos/farmacologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno , Terapia de Alvo Molecular , Mutação , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Purinas/farmacologia , Purinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Proteína do Retinoblastoma/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Nat Med ; 20(10): 1138-46, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25216638

RESUMO

In solid tumors, resistance to therapy inevitably develops upon treatment with cytotoxic drugs or molecularly targeted therapies. Here, we describe a system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas (HCC) in vivo to identify genes likely to be involved in therapy resistance. Using a focused shRNA library targeting genes located within focal genomic amplifications of human HCC, we screened for genes whose inhibition increased the therapeutic efficacy of the multikinase inhibitor sorafenib. Both shRNA-mediated and pharmacological silencing of Mapk14 (p38α) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14-dependent activation of Mek-Erk and Atf2 signaling. Elevated Mapk14-Atf2 signaling predicted poor response to sorafenib therapy in human HCC, and sorafenib resistance of p-Mapk14-expressing HCC cells could be reverted by silencing Mapk14. Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/genética , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Fator 2 Ativador da Transcrição/metabolismo , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Immunother ; 35(9): 661-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23090075

RESUMO

Viral infections with cytomegalovirus (CMV) or human adenovirus (HAdV) after stem cell transplantation are still associated with a high morbidity and mortality. Transfer of T-cell immunity from a healthy individual to a stem cell transplant recipient, known as adoptive T-cell transfer, has been shown to be effective to prevent viral complications. Treatment efficacy will depend on the availability of functional T-cell lines with a strong T(helper)1 response. Ex vivo isolation of antigen-specific T cells could be performed on the basis of the cytokine capture technique or antigen-induced expression of activation markers. In this study, we compare the specificity, expansion/differentiation potential, and T(helper)1 response against CMV and HAdV after different isolation strategies. Antigen-specific T cells from healthy donors were isolated by antigen-induced expression of IFN-γ and/or CD137 after stimulation with the viral antigens hexon (HAdV) or pp65 (CMV). Isolation of antigen-specific T cells based on the expression of activation markers is feasible and less time consuming, but in contrast to isolation based on IFN-γ secretion, it leads to a reduction of T(helper)1 cells. Both isolated CD137(+) and isolated IFN-γ(+) T cells mainly consist of CD4(+) T(CentralMemory) and T(EffectorMemory) cells with high expansion potential and effective cytokine production. CD154(+) is mainly expressed on CD4(+)T cells and shows coexpression with IFN-γ on activated T cells, which cannot be found for CD137(+) cells. In conclusion, T-cell lines could be easily generated on the basis of IFN-γ(+) and/or expression of the activation marker CD137 but both approaches result in different T-cell populations, which may lead to divergent T-cell responses in vivo.


Assuntos
Antígenos Virais/imunologia , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Células Th1/imunologia , Relação CD4-CD8 , Ligante de CD40/metabolismo , Proteínas do Capsídeo/imunologia , Linhagem Celular , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Humanos , Imunoterapia Adotiva , Fenótipo , Fosfoproteínas/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Proteínas da Matriz Viral/imunologia
18.
Dtsch Med Wochenschr ; 137(27): 1406, 2012 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-22744870

RESUMO

HISTORY AND ADMISSION FINDINGS: A 42-year-old woman was referred with a bleeding in the upper gastrointestinal tract, varices in the fundus of the stomach and portal hypertension of unknown primary. INVESTIGATIONS: Ultrasound examinations showed splenomegaly as well as portal hypertension. Blood examinations revealed low levels of haemoglobin. CT imaging showed multiple arteriovenous malformations with arterioportal shunts within the liver which led to a volume-induced portal hypertension. The genetic analysis revealed no mutations in the activin receptor-like kinase (ALK) 1 or endoglin genes. DIAGNOSIS, TREATMENT AND COURSE: The patient was clinically diagnosed with hereditary hemorrhagic teleangiectasia, also known as Osler-Weber-Rendu disease. Because of the multiple arterioportal shunts within the liver and the resulting portal hypertension with live-threatening gastrointestinal bleeding, the only therapeutic option for the patient is liver transplantation. Therefore, an application for a standard exception was made at Eurotransplant and the patient is going to be liver transplantated within the next months. CONCLUSIONS: Osler-Weber-Rendu disease is an autosomal dominant hereditary disease which leads to arteriovenous malformations and which can affect different organ systems. The course of the disease can be rather benign, but it can also lead to live-threatening complications requiring fast interventions.


Assuntos
Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Hipertensão Portal/diagnóstico , Hipertensão Portal/etiologia , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Adulto , Feminino , Hemorragia Gastrointestinal/cirurgia , Humanos , Hipertensão Portal/cirurgia , Transplante de Fígado , Telangiectasia Hemorrágica Hereditária/cirurgia
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