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1.
Cancer Cell ; 42(5): 759-779.e12, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38744245

RESUMO

The lack of comprehensive diagnostics and consensus analytical models for evaluating the status of a patient's immune system has hindered a wider adoption of immunoprofiling for treatment monitoring and response prediction in cancer patients. To address this unmet need, we developed an immunoprofiling platform that uses multiparameter flow cytometry to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types and gene expression profiles. An independent analysis of 17,800 open-source transcriptomes with the same approach corroborated these findings. Continuous immunotype-based signature scores were developed to correlate systemic immunity with patient responses to different cancer treatments, including immunotherapy, prognostically and predictively. Our approach and findings illustrate the potential utility of a simple blood test as a flexible tool for stratifying cancer patients into therapy response groups based on systemic immunoprofiling.


Assuntos
Imunoterapia , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/sangue , Imunoterapia/métodos , Citometria de Fluxo/métodos , Transcriptoma , Prognóstico , Perfilação da Expressão Gênica/métodos , Feminino , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia
2.
Sci Rep ; 10(1): 12296, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704001

RESUMO

Platelets are anucleate blood cells with reported roles in hemostasis and immune responses, which possess a functional receptor for bacterial lipopolysaccharides (LPSs), the well-known inducers of inflammation. However, LPSs effects on platelets are contradictory. Here we aim to investigate mechanisms of platelet functioning in the presence of LPS and to find the cause of the discrepancy in the previously published data. Cell activity was analyzed by flow cytometry, western blotting, and aggregometry. Thrombus growth was assessed by fluorescent microscopy. LPS' activity was checked by their capability to induce PMN activation. However, LPSs did not substantially affect either thrombus growth in flow chambers, irreversible platelet aggregation, or platelet responses to strong activation. Platelet aggregation in response to 1 µM of ADP was significantly inhibited by LPSs. Flow cytometry analysis revealed that platelet activation responses to weak stimulation were also diminished by LPSs, while VASP phosphorylation was weakly increased. Additionally, LPSs were capable of inhibition of ADP-induced P2-receptor desensitization. Incubation of platelets with a pan-PDE inhibitor IBMX significantly enhanced the LPSs-induced platelet inhibition, implying cAMP/cGMP dependent mechanism. The discrepancy in the previously published data could be explained by LPS-induced weak inhibition of platelet activation and the prevention of platelet desensitization.


Assuntos
Plaquetas/imunologia , Plaquetas/metabolismo , Lipopolissacarídeos/imunologia , Ativação Plaquetária , Difosfato de Adenosina/metabolismo , Adolescente , Adulto , Biomarcadores , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ativação Plaquetária/imunologia , Agregação Plaquetária/imunologia , Testes de Função Plaquetária , Transdução de Sinais , Adulto Jovem
3.
Thromb Haemost ; 119(6): 906-915, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30934104

RESUMO

Factor XIIIa (fXIIIa) is a transglutaminase that plays a crucial role in fibrin clot stabilization and regulation of fibrinolysis. It is known to bind to procoagulant platelets. In contrast, the zymogen fXIII interaction with platelets is not well characterized. We investigated the interaction of zymogen fXIII with activated platelet subpopulations. Confocal microscopy and flow cytometry using fluorescently labelled factors and antibodies. Phosphatidylserine (PS)-positive activated platelets bound 700 to 800 molecules/cell of fXIII at 100 nM, while both PS-negative activated platelets and resting platelets bound 200 to 400 molecules/cell. The binding was reversible, calcium-independent and linear within the fXIII concentration range of up to 1,000 nM. fXIII predominantly bound to the caps of procoagulant platelets and co-localized with fibrinogen. Exogenous fibrinogen promoted fXIII binding by activated PS-negative platelets; this effect was abolished by the integrin αIIbß3 antagonist monafram. The fXIII binding was 1.5- to 3-fold decreased for platelets from four patients with grey platelet syndrome, and was variable for platelets from six patients with Glanzmann's thrombasthenia. Strong platelet stimulation, fibrinogen and αIIbß3 play essential roles in fXIII binding, without any of them fXIII does not bind to platelets. The preferential binding in the cap-like structures might be important for increasing local fXIII concentration in platelet thrombi.


Assuntos
Afibrinogenemia/metabolismo , Plaquetas/fisiologia , Fator VIII/metabolismo , Fibrinogênio/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombastenia/metabolismo , Afibrinogenemia/genética , Coagulação Sanguínea , Precursores Enzimáticos , Fibrinólise , Humanos , Ativação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Ligação Proteica
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