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1.
Cell ; 186(7): 1448-1464.e20, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-37001504

RESUMO

Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sellhi state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumor immunity, including BATF3-dependent DCs, IL-12, and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.


Assuntos
Neoplasias Pulmonares , Neutrófilos , Humanos , Neoplasias Pulmonares/genética , Transdução de Sinais/genética , Imunoterapia , Interferons
2.
Magn Reson Chem ; 58(9): 820-829, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32167622

RESUMO

Conservation treatment of degraded archaeological osseous materials is still an open challenge, since no specific conservation protocol is currently available for restorers or museum curators. This work aims to test the efficiency of two original consolidant solutions in consolidating archaeological material. Archaeological osseous materials remain rare and sparsely available, it is a real drawback for optimization of conservation treatments, therefore in the present work a set of representative samples was chosen. The consolidants tested were a solution of disodium sebacate and a novel polyalcohol (SG1.2) obtained by esterification of 5 succinic diacids with 6 molecules of glycerol at 150°C. Characterization studies of archaeological bones, combining SEM microscopy, IR spectroscopy and high-resolution solid-state 13 C NMR investigations, have been carried out to assess the effective permeation of bone by the consolidant solutions and to determine their chemical interactions with the residual components of archaeological bones. Although both water solutions significantly impregnate bone, we show that, the solution with disodium sebacate leads to chemical attack on the mineral component due to preferential precipitation of endogenous calcium by the sebacate ions. Such deleterious behaviour is not observed at all with the SG1,2 chemicals. The added value of the polyalcohol treatment as strengthening agent suitable for archaeological bony materials should be further demonstrated by mechanical and ageing tests.

3.
Science ; 381(6657): 515-524, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37535729

RESUMO

Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.


Assuntos
Polaridade Celular , Quimiocina CXCL9 , Neoplasias de Cabeça e Pescoço , Macrófagos , Osteopontina , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral , Humanos , Quimiocina CXCL9/análise , Quimiocina CXCL9/metabolismo , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Macrófagos/imunologia , Osteopontina/análise , Osteopontina/metabolismo , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Polaridade Celular/imunologia
4.
Cancer Discov ; 9(7): 834-836, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262745

RESUMO

Macrophages modulate tumor response to chemotherapy; in this issue, Lossos and colleagues show that high-dose alkylating agents instigate a synthetic lethal program in lymphoma cells that is independent of DNA damage and involves recruitment and priming of macrophages for antibody-mediated tumor phagocytosis. These findings implicate chemotherapy-elicited macrophages as critical effectors of lymphoma clearance during biological therapy.See related article by Lossos et al., p. 944.


Assuntos
Linfoma , Neoplasias , Alquilantes , Humanos , Macrófagos/efeitos dos fármacos , Fagocitose
5.
Cell Rep ; 27(10): 3062-3080.e11, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167148

RESUMO

Extracellular vesicles (EVs), including exosomes, modulate multiple aspects of cancer biology. Tumor-associated macrophages (TAMs) secrete EVs, but their molecular features and functions are poorly characterized. Here, we report methodology for the enrichment, quantification, and proteomic and lipidomic analysis of EVs released from mouse TAMs (TAM-EVs). Compared to source TAMs, TAM-EVs present molecular profiles associated with a Th1/M1 polarization signature, enhanced inflammation and immune response, and a more favorable patient prognosis. Accordingly, enriched TAM-EV preparations promote T cell proliferation and activation ex vivo. TAM-EVs also contain bioactive lipids and biosynthetic enzymes, which may alter pro-inflammatory signaling in the cancer cells. Thus, whereas TAMs are largely immunosuppressive, their EVs may have the potential to stimulate, rather than limit, anti-tumor immunity.


Assuntos
Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Animais , Anticorpos/uso terapêutico , Células da Medula Óssea/citologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mapas de Interação de Proteínas , Proteoma/análise , Proteômica , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Transplante Homólogo
6.
Dis Markers ; 2016: 6597970, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27212785

RESUMO

There is a need for new noninvasive biomarkers (NIBMs) able to assess cholestasis and fibrosis in chronic cholestatic liver diseases (CCLDs). Tumorigenesis can arise from CCLDs. Therefore, autoantibodies to tumor-associated antigens (TAA) may be early produced in response to abnormal self-antigen expression caused by cholestatic injury. Vascular endothelial growth factor receptor-3 (VEGFR-3) has TAA potential since it is involved in cholangiocytes and lymphatic vessels proliferations during CCLDs. This study aims to detect autoantibodies directed at VEGFR-3 during bile duct ligation- (BDL-) induced cholestatic injury in rat sera and investigate whether they could be associated with traditional markers of liver damage, cholestasis, and fibrosis. An ELISA was performed to detect anti-VEGFR-3 autoantibodies in sera of rats with different degree of liver injury and results were correlated with aminotransferases, total bilirubin, and the relative fibrotic area. Mean absorbances of anti-VEGFR-3 autoantibodies were significantly increased from week one to week five after BDL. The highest correlation was observed with total bilirubin (R (2) = 0.8450, P = 3.04e - 12). In conclusion, anti-VEGFR-3 autoantibodies are early produced during BDL-induced cholestatic injury, and they are closely related to cholestasis, suggesting the potential of anti-VEGFR-3 autoantibodies as NIBMs of cholestasis in CCLDs and justifying the need for further investigations in patients with CCLD.


Assuntos
Autoanticorpos/metabolismo , Bilirrubina/metabolismo , Colestase/imunologia , Hepatopatias/imunologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/imunologia , Animais , Antígenos de Neoplasias/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Wistar
7.
Int J Inflam ; 2015: 943497, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25954568

RESUMO

Inflammation is a central feature of liver fibrosis as suggested by its role in the activation of hepatic stellate cells leading to extracellular matrix deposition. During liver injury, inflammatory cells are recruited in the injurious site through chemokines attraction. Thus, inflammation could be a target to reduce liver fibrosis. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. The aim of this review is to describe the role of inflammation and the immune response in the pathogenesis of liver fibrosis and detail the mechanisms of inhibition of both events by medicinal plants in order to reduce liver fibrosis.

8.
Chin Med ; 9(1): 27, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25606051

RESUMO

During chronic liver injury, hepatic stellate cells (HSC) are activated and proliferate, which causes excessive extracellular matrix (ECM) deposition, leading to scar formation and fibrosis. Medicinal plants are gaining popularity as antifibrotic agents, and are often safe, cost-effective, and versatile. This review aims to describe the protective role and mechanisms of medicinal plants in the inhibition of HSC activation and ECM deposition during the pathogenesis of liver fibrosis. A systematic literature review on the anti-fibrotic mechanisms of hepatoprotective plants was performed in PubMed, which yielded articles about twelve relevant plants. Many of these plants act via disruption of the transforming growth factor beta 1 signaling pathway, possibly through reduction in oxidative stress. This reduction could explain the inhibition of HSC activation and reduction in ECM deposition. Medicinal plants could be a source of anti-liver fibrosis compounds.

9.
Adv Pharmacol Sci ; 2014: 373295, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25505905

RESUMO

Following chronic liver injury, hepatocytes undergo apoptosis leading to activation of hepatic stellate cells (HSC). Consequently, activated HSC proliferate and produce excessive extracellular matrix, responsible for the scar formation. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Treatment strategies should take into account the versatility of its pathogenesis and act on all the cell lines involved to reduce liver fibrosis. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. This review will describe the role of hepatocytes and HSC in the pathogenesis of liver fibrosis and detail the mechanisms of modulation of apoptosis of both cell lines by twelve known hepatoprotective plants in order to reduce liver fibrosis.

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