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1.
J Clin Invest ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33492309

RESUMO

The immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFNg production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.

2.
Methods Mol Biol ; 2236: 9-17, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33237536

RESUMO

While myeloid-derived suppressor cells (MDSCs) in humans and mice have been intensively investigated, there is limited knowledge of these cells in nonhuman primates (NHPs). NHPs serve as critical models for late-stage testing of several biomedical inventions before proceeding with clinical trials and it is therefore important to fully understand their immune compartments and similarities with humans. Here, using antihuman cross-reactive antibodies, we provide flow cytometric analysis protocols for identification of MDSCs in the blood of rhesus macaques, one of the major NHP species as experimental models. Discrepancies and similarities between rhesus and human MDSCs are discussed.

3.
Front Oncol ; 10: 564694, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194641

RESUMO

Background: Mutation-caused loss-of-function of factors involved in DNA damage response (DDR) is responsible for the development and progression of ~20% of prostate cancer (PCa). Some mutations can be used in cancer risk assessment and informed treatment decisions. Methods: Target capture-based deep sequencing of 11 genes was conducted with total DNA purified from the proband's peripheral blood. Sanger sequencing was conducted to screen potential germline mutations in the proband's family members. Targeted sequencing of a panel of 1,021 genes was done with DNA purified from the tumor tissue. Results: Two previously unreported germline mutations in the DDR pathway, BRCA2 (c.8474_8487delCATACCCTATACAG, p.A2825Vfs*15) and PALB2 (c.472delC, p.Q158Rfs*19) were identified in a patient with metastatic PCa. A specific therapeutic regimen including androgen deprivation therapy, locally radical radiotherapy, and systemic platinum chemotherapy worked well against his cancer. In addition, the metastatic ovarian cancer in the proband's half-sister harboring the same BRCA2 germline mutation also responded well to platinum chemotherapy. Conclusions: The newly identified germline mutations in DDR plays important role in PCa development. Since specific regimen worked well against this cancer, screening of DDR mutation could provide better management for patients with these mutation-mediated PCa.

4.
J Pathol ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009820

RESUMO

Neuroendocrine prostate cancer (NEPC) is a more aggressive subtype of castration-resistant prostate cancer (CRPC). Although it is well established that PHF8 can enhance prostate cancer cell proliferation, whether PHF8 is involved in prostate cancer initiation and progression is relatively unclear. By comparing the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with or without Phf8 knockout, we systemically examined the role of PHF8 in prostate cancer development. We found that PHF8 plays a minimum role in initiation and progression of adenocarcinoma. However, PHF8 is essential for NEPC because not only is PHF8 highly expressed in NEPC but also animals without Phf8 failed to develop NEPC. Mechanistically, PHF8 transcriptionally upregulates FOXA2 by demethylating and removing the repressive histone markers on the promoter region of the FOXA2 gene, and the upregulated FOXA2 subsequently regulates the expression of genes involved in NEPC development. Since both PHF8 and FOXA2 are highly expressed in NEPC tissues from patients or patient-derived xenografts, the levels of PHF8 and FOXA2 can either individually or in combination serve as NEPC biomarkers and targeting either PHF8 or FOXA2 could be potential therapeutic strategies for NEPC treatment. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

5.
J Immunother Cancer ; 8(2)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32907925

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells. METHODS: We developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders. RESULTS: We observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC. CONCLUSIONS: This study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation.

6.
EBioMedicine ; 59: 102956, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32805626

RESUMO

BACKGROUND: Tumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer. METHODS: Single-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia. FINDINGS: Genetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94). INTERPRETATION: This study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.

7.
Oncol Lett ; 20(3): 2881-2887, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32782604

RESUMO

The present study sought to estimate the applicability of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), vascular endothelial growth factor A (VEGFA) expression and CD163+ tumor-associated macrophage (TAM) ratio as prognostic factors in bladder cancer (BCa). A total of 127 patients with bladder urothelial cancer who underwent radical cystectomy at Daping Hospital were recruited between January 2013 and January 2017, including 45 cases of non-muscle invasive BCa (NMIBC) and 82 of MIBC. Immunohistochemical detection of APE1, VEGFA and CD163, as well as multiple immunofluorescence staining for APE1, VEGFA, CD163 and CD34, were performed on tissue samples. For APE1 and VEGFA, the staining was graded based on intensity (0-3), while CD163 was graded (0-3) based on the percentage of positively stained cells. The prognostic value of APE1, VEGF and CD163 was assessed using Kaplan-Meier and Cox regression analysis. The results suggested that in BCa, high APE1 expression was associated with high VEGFA expression and more infiltration of CD163+ TAM. Furthermore, high expression of APE1 was associated with lymphovascular invasion of BCa, as well as reduced survival time. This indicates that APE1 may be associated with CD163+ TAM infiltration in BCa, with VEGFA as a possible influencing factor.

8.
Int J Cardiol ; 313: 99-104, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32223966

RESUMO

BACKGROUND: The causal role of interleukins (ILs) for cardiovascular disease has not been fully elucidated. We conducted a Mendelian randomization study to investigate the associations of circulating ILs with coronary artery disease (CAD), atrial fibrillation (AF), and ischemic stroke. METHODS AND RESULTS: Single-nucleotide polymorphisms associated with IL-1ß, IL-1 receptor antagonist (IL-1ra), IL-2 receptor subunit alpha, IL-6, IL-16, IL-17 and IL-18 were identified from genome-wide association studies. Summary-level data of the outcomes were obtained from three large consortia. Genetic predisposition to higher IL-1ra levels were significantly associated with CAD. The odds ratio was 1.36 (95% confidence interval (CI), 1.14-1.63; P = 5.37 × 10-4) per one standard deviation increase in IL-1ra levels. Genetically higher IL-6 levels, predicted by a variant in the IL6R gene and corresponding to reduced IL-6 bio-function, were significantly inversely associated with CAD and AF. The odds ratios per one standard deviation increase in IL-6 levels were 0.64 (95%CI, 0.54-0.76; P = 2.22 × 10-7) for CAD and 0.70 (95%CI, 0.62-0.80; P = 1.34 × 10-7) for AF. There was a suggestive positive association of IL-1ra with cardioembolic stroke and suggestive inverse associations of IL-6 with any ischemic stroke, cardioembolic stroke, and small vessel stroke, and of IL-16 with CAD. The other ILs were not associated with any outcome. CONCLUSIONS: These results strengthen the evidence that IL-6 inhibition may offer a therapeutic approach for prevention of CAD, AF, and ischemic stroke. In contrast, IL-1 inhibition through raised IL-1ra levels may confer increased risk of CAD and cardioembolic stroke. The role of IL-16 for CAD warrants further investigation.

9.
Cell Rep ; 30(12): 3964-3971.e7, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209459

RESUMO

Although intramuscular (i.m.) administration is the most commonly used route for licensed vaccines, subcutaneous (s.c.) delivery is being explored for several new vaccines under development. Here, we use rhesus macaques, physiologically relevant to humans, to identify the anatomical compartments and early immune processes engaged in the response to immunization via the two routes. Administration of fluorescently labeled HIV-1 envelope glycoprotein trimers displayed on liposomes enables visualization of targeted cells and tissues. Both s.c. and i.m. routes induce efficient immune cell infiltration, activation, and antigen uptake, functions that are tightly restricted to the skin and muscle, respectively. Antigen is also transported to different lymph nodes depending on route. However, these early differences do not translate into significant differences in the magnitude or quality of antigen-specific cellular and humoral responses over time. Thus, although some distinct immunological differences are noted, the choice of route may instead be motivated by clinical practicality.

10.
J Clin Invest ; 130(5): 2332-2346, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945015

RESUMO

BACKGROUNDThe live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1.METHODSWe performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified.RESULTSAll BPZE1 vaccinees showed robust B. pertussis-specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1-specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1.CONCLUSIONThe breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission.TRIAL REGISTRATIONClinicalTrials.gov NCT02453048, NCT00870350.FUNDINGILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.

11.
Onco Targets Ther ; 12: 7725-7735, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576137

RESUMO

Objectives: Tumor-infiltrating lymphocytes (TILs) play a crucial role in anti-tumor immunity. Basic studies have found that stimulator of interferon genes (STING), activated by sensing DNA damage, plays a role in recruiting and activating TILs in tumors. However, the correlation between base excision repair (BER) pathway, STING pathway and TILS and their effect on prognosis in upper urinary tract urothelial carcinoma (UTUC) are still unclear. The aim of this study was to investigate the prognostic effect of those proteins expression for disease-free survival (DFS) and overall survival (OS) and explore the correlation between these makers. Methods: We evaluated immunohistochemical expression of BER pathway (APE1, NTH1, OGG1, XRCC1, polß), STING pathway (STING, IRF3), TILs (CD4, CD8, CD20) and PD-L1, PD-L2 in 88 UTUC patients to determine the predictive significance in DFS, OS and the correlation between them. Results: We found that interferon regulatory factor3 (IRF3) (HR: 0.451, 95% CI 0.243-0.837, p=0.024) and CD8 (HR: 0.522, 95% CI 0.295-0.926, p=0.014) are independent prognostic factors for DFS, APE1 (HR: 1.932, 95% CI 1.005-3.714, P=0.048), polß (HR: 2.620, 95% CI 1.373-5.000, P=0.003), CD8 (HR: 0.323, 95% CI 0.151-0.693, P=0.004) were independent prognostic factors for OS. A model consisting of stage, grade, lymphovascular invasion and expression of APE1, polß, IRF3, CD4, CD8 that predicts 3-year OS. Furthermore, DNA damage repair protein polß is associated with CD8+ T cells in TME. Conclusion: We found that DNA damage, IRF3 and TILs are independent predictors for prognosis. We also provided clinical evidence that DNA damage repair-activated STING pathway can induce the recruitment and activation of TILs, which is consistent with preclinical models.

13.
Cancer Immunol Immunother ; 68(4): 687-697, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30684003

RESUMO

In cancer, infection and inflammation, the immune system's function can be dysregulated. Instead of fighting disease, immune cells may increase pathology and suppress host-protective immune responses. Myeloid cells show high plasticity and adapt to changing conditions and pathological challenges. Despite their relevance in disease pathophysiology, the identity, heterogeneity and biology of myeloid cells is still poorly understood. We will focus on phenotypical and functional markers of one of the key myeloid regulatory subtypes, the myeloid derived suppressor cells (MDSC), in humans, mice and non-human primates. Technical issues regarding the isolation of the cells from tissues and blood, timing and sample handling of MDSC will be detailed. Localization of MDSC in a tissue context is of crucial importance and immunohistochemistry approaches for this purpose are discussed. A minimal antibody panel for MDSC research is provided as part of the Mye-EUNITER COST action. Strategies for the identification of additional markers applying state of the art technologies such as mass cytometry will be highlighted. Such marker sets can be used to study MDSC phenotypes across tissues, diseases as well as species and will be crucial to accelerate MDSC research in health and disease.


Assuntos
Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Animais , Biomarcadores , Separação Celular/métodos , Humanos , Imunofenotipagem/métodos , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Primatas
14.
Gut ; 68(11): 2032-2043, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635406

RESUMO

OBJECTIVE: Chronic hepatitis B (CHB) virus infection is a global health problem. Finding a cure for CHB remains a challenging task. DESIGN: In this study, poly I:C was employed as an adjuvant for HBV therapeutic vaccine (referred to as pHBV-vaccine) and the feasibility and efficiency of pHBV-vaccine in CHB treatment were evaluated in HBV-carrier mice. RESULTS: We found that pHBV-vaccine decreased HBsAg and HBV DNA efficiently and safely in HBV-carrier mice. Further investigation showed that pHBV-vaccine promoted maturation and antigen presentation ability of dendritic cells in vivo and in vitro. This vaccine successfully restored the exhaustion of antigen-specific CD8+ T cells and partly broke the immune tolerance established in HBV-carrier mice. pHBV-vaccine also enhanced the proliferation and polyfunctionality of HBV-specific CD11ahi CD8αlo cells. Importantly, we observed that T cell activation molecule KLRG1 was only expressed on HBV specific CD11ahi CD8αlo cells. Furthermore, pHBV-vaccine reduced the expression of Eomes and increased the serum IL-12 levels, which in turn promoted the generation of effector memory short-lived effector cells (SLECs) to exhibit a critical role in HBV clearance. SLECs induced by pHBV-vaccine might play a crucial role in protecting from HBV reinfection. CONCLUSIONS: Findings from this study provide a new basis for the development of therapeutic pHBV-vaccine, which might be a potential candidate for clinical CHB therapy.


Assuntos
Antivirais/uso terapêutico , Vacinas contra Hepatite B/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Poli I-C/uso terapêutico , Animais , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Hepatite B Crônica/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Endocr Connect ; 7(12): 1217-1225, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352407

RESUMO

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

16.
Endocr Connect ; 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352423

RESUMO

CONTEXT AND OBJECTIVES: Congenital adrenal hyperplasia (CAH) is one of the most prevalent, and potentially severe, genetic inborn errors of steroid synthesis directly affecting metabolism. Most patients are diagnosed and treated at an early age. There have been very limited reports of adults with CAH-associated adrenal myelolipomas. We aimed to analyze two families with CAH-associated giant adrenal myelolipomas caused by defects in CYP21A2 and CYP17A1 genes. PARTICIPANTS AND METHODS: A total of 14 individuals from two unrelated families were identified with either CYP21A2 or CYP17A1 mutations. Of note, 5 patients were found with adrenal myelolipomas. Total DNA isolated from the peripheral blood of the two probands was screened for potential mutations in the following susceptibility genes of CAH: CYP21A2, CYP11B1, CYP17A1, HSD17B3, HSD3B2, ARMC5, and STAR using Target Capture-Based Deep Sequencing; and Sanger sequencing was conducted for the family members to detect the potential mutations. RESULTS: In family 1, molecular genetics sequencing revealed a compound heterozygous mutation (c.293-13C>G / c.518T>A, p.I173N) in CYP12A2 in the patient and his brother. In family 2, all three female patients with adrenal myelolipomas were found to have a compound heterozygous mutation (c.1118A>T, p.H373L / c.1459_1467del9, p.D487_F489del) in CYP17A1. CONCLUSION: To avoid giant CAH-associated adrenal myelolipomas in adults, it is important to identify CAH early so appropriate treatment can be initiated to interrupt the chronic adrenal hyperstimulation resulting from increased ACTH. Genetic testing and counseling could be useful in CAH.

17.
Cancer Metastasis Rev ; 37(2-3): 355-368, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30094570

RESUMO

Therapeutic resistance has been and remains to be the major challenge in developing successful treatments for different cancers and therefore, understanding the underlying mechanisms in the development of therapeutic resistance is crucial in combating cancers. Multiple mechanisms underlie the development of therapeutic resistance, and the signaling pathways involved in cancer stem cell repopulation, enhanced epithelial-mesenchymal transition (EMT), inflammatory infiltration, and immunosuppression play pivotal roles in this process. Accumulating evidence indicates that the COX2/PGE2/EP axis plays crucial roles not only in tumor development including initiation and progression but also in the development of therapeutic resistance. In this review, we will first dissect the relationship between the COX2/PGE2/EP axis and therapeutic resistance by focusing on the roles of the COX2/PGE2/EP axis in cancer stem cell repopulation, EMT, and anti-cancer immunity. Then, we will summarize the currently available compounds/drugs targeting each component of this axis as well as some of the underlying mechanisms. We hope that better understanding the underlying mechanisms of the functional compounds will be helpful in seeking additive and/or synergistic effects against therapeutic resistance without or with minimal adverse consequence.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/etiologia , Neoplasias/metabolismo , Receptores de Prostaglandina/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclo-Oxigenase 2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos
18.
Clin Cancer Res ; 24(22): 5622-5634, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30012567

RESUMO

Purpose: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer.Experimental Design: By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer.Results: Treating TRAMP mice with metformin delays prostate cancer progression from low-grade prostatic intraepithelial neoplasia to high-grade PIN, undifferentiated to well-differentiated, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after androgen deprivation therapy (ADT) induced by surgically castration in mice, bicalutamide treatment in patients, and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells.Conclusions: Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting the COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment. Clin Cancer Res; 24(22); 5622-34. ©2018 AACR.


Assuntos
Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Metformina/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Biópsia , Ciclo Celular/genética , Linhagem Celular , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Leucócitos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
19.
Cancer Biol Ther ; 19(9): 766-772, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29947576

RESUMO

Von Hippel-Landau (VHL) disease is characterized by malignant and benign tumors in multiple organs. Sunitinib, a tyrosine kinase inhibitor, has been clinically available for treating sporadic patients with recurrent or unresectable and metastatic clear renal cell carcinomas (cRCCs) and metastatic lesions of the lung, but its effect on VHL disease-associated tumors remains poorly understood. This retrospective case series examined the effect of sunitinib on RCC, hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors in patients with confirmed VHL. Of note, three patients with VHL disease who were treated with sunitinib were identified from a review of their medical records. The efficacy of sunitinib was evaluated by comparing computed tomography (CT) or magnetic resonance imaging (MRI) scans conducted before and after treatment. Adverse side effects associated with sunitinib were assessed and recorded. All three patients with VHL disease exhibited clinical improvement after treatment with sunitinib. Patient 1 exhibited a decrease in the size of both their pheochromocytoma and RCC after 19 months of sunitinib treatment. RCCs in Patients 2 and 3 exhibited stable response to sunitinib for approximately 1 and 6 years, respectively. All the patients reported tolerable side effects. Therefore sunitinib treatment was associated with either partial response or stable control of VHL-related RCCs, pheochromocytomas and pancreatic neuroendocrine tumor (NET) with acceptable side effects. Further evaluation of sunitinib in patients with VHL disease in larger prospective studies is warranted.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Sunitinibe/uso terapêutico , Doença de von Hippel-Lindau/tratamento farmacológico , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/etiologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Sunitinibe/administração & dosagem , Sunitinibe/efeitos adversos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/genética
20.
Eur J Immunol ; 48(9): 1470-1480, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29935120

RESUMO

Listeria monocytogenes (LM) is a foodborne Gram-positive intracellular pathogen that can cause listeriosis in humans and animals. Although phagocytes are known to be involved in the response to this infection, the role of neutrophils is not entirely clear. Here, we have demonstrated that soon after LM infection, a large number of IFN-γ-producing neutrophils quickly accumulated in the spleen, blood, and peritoneal cavity. Both in vivo and in vitro experiments demonstrated that neutrophils were an important source of IFN-γ. IFN-γ played a critical protective role against acute LM infection, as demonstrated by the poor survival of Ifng-/- mice. Moreover, IFN-γ promoted bacterial clearance by the neutrophils, thereby inhibiting LM-induced neutrophil apoptosis and spleen damage. In addition to this, IFN-γ could effectively drive macrophage-mediated phagocytosis of apoptotic neutrophils, which was accompanied with TGF-ß secretion and was involved in protection against tissue injury. Importantly, by phagocytizing apoptotic neutrophils, macrophages obtained myeloperoxidase, an important bactericidal molecule only produced by neutrophils, which further promoted the antibacterial activity of macrophages. These findings demonstrate that neutrophils are an important source of IFN-γ at the early stage of LM infection, which is characterized by both LM elimination and tissue-protective effects.


Assuntos
Interferon gama/imunologia , Listeria monocytogenes/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Animais , Apoptose/imunologia , Proteínas de Homeodomínio/genética , Interferon gama/genética , Listeriose/imunologia , Listeriose/microbiologia , Listeriose/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peroxidase/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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