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1.
Neurodegener Dis Manag ; 13(2): 75-84, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36562349

RESUMO

Aim: Evaluate timing of motor improvement with carbidopa/levodopa (CD/LD) and apomorphine sublingual film (SL-APO) in patients with Parkinson's disease and OFF episodes. Methods: A post hoc pooled analysis from two studies assessed Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) scores and investigator-rated FULL ON. Results: At 15 and 30 min following the prescribed first daily CD/LD dose, mean improvements in MDS-UPDRS-III scores were -6.7 and -16.3, respectively, and FULL ON was achieved by 6.5 and 41.8% of patients. Following an optimized SL-APO dose, mean improvements in MDS-UPDRS-III scores were -13.9 and -22.9, and FULL ON was achieved by 34.7 and 81.0% of patients. Conclusion: Concomitant administration of SL-APO with carbidopa/levodopa may be useful for delayed ON.


Assuntos
Levodopa , Doença de Parkinson , Humanos , Levodopa/uso terapêutico , Carbidopa/uso terapêutico , Apomorfina , Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Combinação de Medicamentos
2.
Neuro Oncol ; 25(5): 886-898, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-36394567

RESUMO

BACKGROUND: Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. METHODS: As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. RESULTS: Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. CONCLUSIONS: We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.


Assuntos
Galectina 3 , Glioma , Camundongos , Humanos , Animais , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Galectina 3/genética , Ligantes , Linhagem Celular Tumoral , Glioma/patologia , Imunidade , Microambiente Tumoral/genética
4.
Handchir Mikrochir Plast Chir ; 54(2): 149-154, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35419784

RESUMO

BACKGROUND: The biological mechanism of Dupuytren's contracture needs to be further studied in order to minimize postoperative recurrence and provide a pathological basis for the development of new therapeutic targets. METHODS: HE staining, immunohistochemistry, PCR and western blotting were performed in pathological palmar aponeurosis specimens and normal palmar aponeurosis tissues for comparative study. RESULTS: (1) TNF-α expression was up-regulated: TNF-α mRNA was more highly expressed in the pathological tissues of DD patients than in the CT group, P < 0.05, and the difference between the two groups was statistically significant; (2) Dkk-1 expression was down-regulated: Dkk-1 mRNA was lower expressed in the pathological tissues of DD patients than in the CT group, P < 0.05, and the difference between the two groups was statistically significant; (3) TGF-ß1 expression was up-regulated: TGF-ß1 mRNA was higher expressed in the pathological tissues of DD patients than in the CT group, P < 0.05, and the difference between the two groups was statistically significant; (4) Pearson correlation analysis suggested that TNF-α expression was positively correlated with TGF-ß1 expression, TNF-α expression was negatively correlated with DKK-1 expression, and TGF-ß1 expression was negatively correlated with DKK-1 expression. CONCLUSION: TNF-α, DKK-1 and TGF-ß1 may play a role in the pathogenesis of palmar aponeurosis contracture, and there is a relationship between them. The study of the relationship between the three and their related signaling pathways provides a therapeutic target and a basis for the prevention and early treatment of palmar aponeurotic contracture.


Assuntos
Contratura de Dupuytren , Peptídeos e Proteínas de Sinalização Intercelular , Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa , Contratura de Dupuytren/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , RNA Mensageiro/genética , Fator de Crescimento Transformador beta1/genética , Fator de Necrose Tumoral alfa/genética
5.
Neurotherapeutics ; 19(2): 635-648, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35226341

RESUMO

Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.


Assuntos
Anti-Inflamatórios , Edema Encefálico , Neoplasias Encefálicas , Receptor para Produtos Finais de Glicação Avançada , Animais , Anti-Inflamatórios/farmacologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Lesões Encefálicas/complicações , Neoplasias Encefálicas/cirurgia , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Humanos , Camundongos , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores
6.
IEEE Trans Med Imaging ; 40(10): 2589-2599, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33577451

RESUMO

Multi-contrast magnetic resonance (MR) image registration is useful in the clinic to achieve fast and accurate imaging-based disease diagnosis and treatment planning. Nevertheless, the efficiency and performance of the existing registration algorithms can still be improved. In this paper, we propose a novel unsupervised learning-based framework to achieve accurate and efficient multi-contrast MR image registration. Specifically, an end-to-end coarse-to-fine network architecture consisting of affine and deformable transformations is designed to improve the robustness and achieve end-to-end registration. Furthermore, a dual consistency constraint and a new prior knowledge-based loss function are developed to enhance the registration performances. The proposed method has been evaluated on a clinical dataset containing 555 cases, and encouraging performances have been achieved. Compared to the commonly utilized registration methods, including VoxelMorph, SyN, and LT-Net, the proposed method achieves better registration performance with a Dice score of 0.8397± 0.0756 in identifying stroke lesions. With regards to the registration speed, our method is about 10 times faster than the most competitive method of SyN (Affine) when testing on a CPU. Moreover, we prove that our method can still perform well on more challenging tasks with lacking scanning information data, showing the high robustness for the clinical application.


Assuntos
Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Algoritmos
7.
Clin Cancer Res ; 26(11): 2740-2753, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32019861

RESUMO

PURPOSE: Unlike most cancers, no clear epidemiological correlation between diabetes (Db) and malignant glioma progression exists. Because hyperglycemia activates proinflammatory pathways through the receptor for advanced glycation endproducts (RAGE), we hypothesized that Db can also promote malignant glioma progression. EXPERIMENTAL DESIGN: We compared the growth of two phenotypically diverse syngeneic glioma models in control and diabetic mice. Tumor growth and antitumor immune responses were evaluated in orthotopic and heterotopic models and correlated to RAGE and RAGE ligand expression. RESULTS: Irrespective of tumor implantation site, growth of a "classical" glioma model, GL261, increased in hyperglycemic mice and was mediated by upregulation of RAGE and its ligand, HMGB1. However, growth of a "mesenchymal" glioma subtype, K-Luc, depended on tumor implantation site. Whereas heterotopic K-Luc tumors progressed rapidly in Db mice, intracranial K-Luc tumors grew slower. We further showed that hyperglycemia inhibited the innate antitumor inflammatory responses in both models. Although this contributed to the accelerated growth of heterotopic tumors, suppression of tumor inflammatory responses dampened the growth of orthotopic K-Luc gliomas. CONCLUSIONS: Hyperglycemia may enhance glioma growth through promotion of RAGE expression and suppression of antitumor immune responses. However, abrogation of the proinflammatory milieu in tumors may also dampen the growth of inflammatory glioma subtypes in the brains of diabetic mice. This dichotomy in glioma growth response to hyperglycemia may partly explain why conflicting epidemiological studies show both an increased risk and a protective effect of Db in patients with malignant gliomas.


Assuntos
Neoplasias Encefálicas/patologia , Diabetes Mellitus Experimental/fisiopatologia , Glioma/patologia , Hiperglicemia/complicações , Imunidade Inata/imunologia , Animais , Apoptose , Neoplasias Encefálicas/etiologia , Movimento Celular , Proliferação de Células , Glioma/etiologia , Humanos , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Invasividade Neoplásica , Prognóstico , Células Tumorais Cultivadas
8.
Cancer Lett ; 439: 91-100, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30076898

RESUMO

S100B, a member of the multigene family of Ca2+-binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1-5 µM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro. In vivo, however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Cloridrato de Duloxetina/farmacologia , Glioma/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Células Mieloides/efeitos dos fármacos , Subunidade beta da Proteína Ligante de Cálcio S100/antagonistas & inibidores , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioma/genética , Glioma/metabolismo , Humanos , Estimativa de Kaplan-Meier , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células Mieloides/metabolismo , Células Mieloides/patologia , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
9.
PLoS One ; 11(12): e0165118, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27936099

RESUMO

Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.


Assuntos
Arginase/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Macrófagos/metabolismo , Microglia/metabolismo , Proteínas de Neoplasias/genética , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Arginase/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , Ativação de Macrófagos , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/patologia , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Especificidade de Órgãos , Cultura Primária de Células , Transdução de Sinais , Fatores de Tempo , Microambiente Tumoral/genética
10.
PLoS One ; 11(2): e0148139, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26829221

RESUMO

Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Imunoterapia , Nanotubos de Carbono/química , Oligodesoxirribonucleotídeos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Glioma/patologia , Inflamação/patologia , Lipídeos/química , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Polietilenoglicóis/química , Baço/patologia , Temozolomida , Resultado do Tratamento
11.
Cancer Res ; 74(24): 7285-7297, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25326491

RESUMO

Interaction of RAGE (the receptor for advanced glycation endproducts) with its ligands can promote tumor progression, invasion, and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anticancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) have not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and noninvasive glioma models, animal survival was prolonged in RAGE knockout (Ager(-/-)) mice. However, the improvement in survival in Ager(-/-) mice was not due to changes in tumor growth rate but rather to a reduction in tumor-associated inflammation. Furthermore, RAGE ablation in the TME abrogated angiogenesis by downregulating the expression of proangiogenic factors, which prevented normal vessel formation, thereby generating a leaky vasculature. These alterations were most prominent in noninvasive gliomas, in which the expression of VEGF and proinflammatory cytokines were also lower in tumor-associated macrophages (TAM) in Ager(-/-) mice. Interestingly, reconstitution of Ager(-/-) TAM with wild-type microglia or macrophages normalized tumor vascularity. Our results establish that RAGE signaling in glioma-associated microglia and TAM drives angiogenesis, underscoring the complex role of RAGE and its ligands in gliomagenesis.


Assuntos
Glioma/genética , Neovascularização Patológica/metabolismo , Receptores Imunológicos/genética , Microambiente Tumoral/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Transdução de Sinais/genética
12.
J Neuroimmunol ; 274(1-2): 71-7, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25042352

RESUMO

Factors released by glioma-associated microglia/macrophages (GAMs) play an important role in the growth and infiltration of tumors. We have previously demonstrated that the co-chaperone stress-inducible protein 1 (STI1) secreted by microglia promotes proliferation and migration of human glioblastoma (GBM) cell lines in vitro. In the present study, in order to investigate the role of STI1 in a physiological context, we used a glioma model to evaluate STI1 expression in vivo. Here, we demonstrate that STI1 expression in both the tumor and in the infiltrating GAMs and lymphocytes significantly increased with tumor progression. Interestingly, high expression of STI1 was observed in macrophages and lymphocytes that infiltrated brain tumors, whereas STI1 expression in the circulating blood monocytes and lymphocytes remained unchanged. Our results correlate, for the first time, the expression of STI1 and glioma progression, and suggest that STI1 expression in GAMs and infiltrating lymphocytes is modulated by the brain tumor microenvironment.


Assuntos
Neoplasias Encefálicas/imunologia , Glioma/imunologia , Proteínas de Choque Térmico/imunologia , Macrófagos/imunologia , Microglia/imunologia , Animais , Neoplasias Encefálicas/metabolismo , Receptor 1 de Quimiocina CX3C , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Citometria de Fluxo , Expressão Gênica/imunologia , Glioma/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Quimiocinas/genética , Microambiente Tumoral/imunologia
13.
Clin Cancer Res ; 19(14): 3764-75, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23719262

RESUMO

PURPOSE: S100B is member of a multigenic family of Ca(2+)-binding proteins, which is overexpressed by gliomas. Recently, we showed that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAM). EXPERIMENTAL DESIGN: We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100B(high)) or underexpressed (S100B(low)) S100B and compared their growth characteristics to intracranial wild-type (S100B(wt)) tumors. RESULTS: Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100B(low) tumors, S100B(wt) and S100B(high) intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, receptor for advanced glycation end products (RAGE), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that C-C motif ligand 2 (CCL2) was upregulated in S100B(high) tumors. Furthermore, analysis of The Cancer Genome Atlas's glioma data bank showed a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. CONCLUSIONS: These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy.


Assuntos
Neoplasias Encefálicas/imunologia , Fatores Quimiotáticos/metabolismo , Glioma/imunologia , Macrófagos/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Caprilatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CCL2/metabolismo , Fatores Quimiotáticos/antagonistas & inibidores , Fatores Quimiotáticos/fisiologia , Quimiotaxia , Ativação Enzimática , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/imunologia , Transplante de Neoplasias , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/antagonistas & inibidores , Subunidade beta da Proteína Ligante de Cálcio S100/fisiologia , Carga Tumoral , Regulação para Cima
14.
Clin Cancer Res ; 18(20): 5628-38, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22904105

RESUMO

PURPOSE: Recently, we showed that intratumoral delivery of low-dose, immunostimulatory CpG oligodeoxynucleotides conjugated with carbon nanotubes (CNT-CpG) was more effective than free CpG and not only eradicated intracranial (i.c.) gliomas but also induced antitumor immunity that protected mice from subsequent i.c. or systemic tumor rechallenge. Here, we examined whether the same "intracerebral immunotherapy" strategy could be applied to the treatment of metastatic brain tumors. EXPERIMENTAL DESIGN: Mice with both i.c. and s.c. melanomas were injected intratumorally with CNT-CpG into either location. Antitumor responses were assessed by flow cytometry, bioluminescent imaging, and animal survival. RESULTS: When given s.c., CNT-CpG response was mostly local, and it only modestly inhibited the growth of i.c. melanomas. However, i.c. CNT-CpG abrogated the growth of not only brain but also s.c. tumors. Furthermore, compared with s.c. injections, i.c. CNT-CpG elicited a stronger inflammatory response that resulted in more potent antitumor cytotoxicity and improved in vivo trafficking of effector cells into both i.c. and s.c. tumors. To investigate factors that accounted for these observations, CNT-CpG biodistribution and cellular inflammatory responses were examined in both tumor locations. Intracranial melanomas retained the CNT-CpG particles longer and were infiltrated by Toll-like receptor (TLR-9)-positive microglia. In contrast, myeloid-derived suppressive cells were more abundant in s.c. tumors. Although depletion of these cells before s.c. CNT-CpG therapy enhanced its cytotoxic responses, antitumor responses to brain melanomas were unchanged. CONCLUSIONS: These findings suggest that intracerebral CNT-CpG immunotherapy is more effective than systemic therapy in generating antitumor responses that target both brain and systemic melanomas.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imunoterapia , Melanoma , Neoplasias Experimentais , Oligodesoxirribonucleotídeos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Nanotubos de Carbono , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Distribuição Tecidual
15.
J Neurooncol ; 106(3): 543-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21984063

RESUMO

High-mobility group A1 (HMGA1) protein is an architectural transcription factor widely expressed during embryonic development and tumor progression. The purpose of this research was to investigate the expression of HMGA1 in malignant gliomas with different WHO classification and to study the correlation of HMGA1 expression with tumor proliferation, invasion, and angiogenesis. Expression of HMGA1, Ki-67, MMP-9, VEGF-A, and MVD in malignant gliomas and their correlation were studied in 60 samples of different WHO classification by use of immunohistochemistry, and in 27 randomly selected samples by use of real-time quantitative PCR. Immunohistochemistry results showed that nuclear immunostaining of HMGA1 protein was not observed in normal brain tissues but was observed in 96.7% (58 of 60) of malignant gliomas including high (+++) in 15 (25.0%), moderate (++) in 28 (46.7%), and negligible to low (0-+) in 17 (28.3%) samples. Expression of HMGA1 protein was significantly higher in glioblastoma multiforme than in WHO grade II (P = 0.002) and WHO grade III gliomas (P = 0.024). HMGA1 protein expression correlated significantly with expression of Ki-67 (r = 0.530, P = 0.000), MMP-9 (r = 0.508, P = 0.000), VEGF-A (r = 0.316, P = 0.014), and MVD (r = 0.321, P = 0.012), but not with sex (r = 0.087, P = 0.510) and age (r = -0.121, P = 0.358). Real-time quantitative PCR results, also, were indicative of HMGA1 overexpression in glioblastoma multiforme compared with WHO grade II (P = 0.043) and WHO grade III (P = 0.031) gliomas. HMGA1 gene expression correlated significantly with gene expression of Ki-67 (r = 0.429, P = 0.025), MMP-9 (r = 0.443, P = 0.024), and VEGF-A (r = 0.409, P = 0.034). These results indicated that expression of HMGA1 correlates significantly with malignancy, proliferation, invasion, and angiogenesis of gliomas. We conclude that HMGA1 may be a potential biomarker and rational therapeutic target for human tumors.


Assuntos
Neoplasias Encefálicas , Proliferação de Células , Glioma , Proteína HMGA1a/metabolismo , Neovascularização Patológica/etiologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioma/complicações , Glioma/metabolismo , Glioma/patologia , Proteína HMGA1a/genética , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Mensageiro/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
16.
Brain Res ; 1384: 9-14, 2011 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-21300033

RESUMO

The high-mobility group A1 (HMGA1) protein is a non-histone architectural nuclear factor and participates in diverse biological processes, including gene transcription, embryogenesis, cell cycle regulation, apoptosis, and even neoplastic transformation. In our study, glioma stem cells (GSCs) expressing the surface marker CD133 from human glioblastoma cell line U251 were isolated using MACS column and were analyzed using immunofluorescence and flow cytometry (FCM). The different expression of HMGA1 was detected using real-time RT-PCR and Western blot at transcriptional and translational levels between U251 and isolated GSCs. The results show that GSCs were successfully isolated from U251 and cultured in serum-free medium (SMF). The percentage of GSCs in U251 was 0.32%±0.07%. HMGA1 expression was significantly higher in GSCs than in glioblastoma cells (P<0.05), up to 6.13±0.25-fold and 2.75±0.99-fold at transcriptional and translational levels, respectively. These results indicated HMGA1 is overexpressed in GSCs as compared to glioblastoma cell line U251, which points to the expression of HMGA1 being closely related to malignant proliferation, invasion, and differentiation of tumors from the prospective of tumor stem cells (TSCs). We conclude that HMGA1 may be a potential biomarker and rational therapeutic target for glioblastoma and GSC.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Proteínas HMGA/metabolismo , Células-Tronco Neoplásicas/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Citometria de Fluxo/métodos , Glioblastoma/patologia , Glioma/patologia , Proteínas HMGA/genética , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina , RNA Mensageiro/metabolismo
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