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1.
Front Med (Lausanne) ; 7: 556818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33304910

RESUMO

Background: Coronavirus disease (COVID-19) has swept around the globe and led to a worldwide catastrophe. Studies examining the disease progression of patients with non-severe disease on admission are scarce but of profound importance in the early identification of patients at a high risk of deterioration. Objectives: To elucidate the differences in clinical characteristics between patients with progressive and non-progressive COVID-19 and to determine the risk factors for disease progression. Study design: Clinical data of 365 patients with non-severe COVID-19 from 1 January 2020 to 18 March 2020 were retrospectively collected. Patients were stratified into progressive and non-progressive disease groups. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors for disease progression. Results: Compared with patients with non-progressive disease, those who progressed to severe COVID-19 were older and had significantly decreased lymphocyte and eosinophil counts; increased neutrophil and platelet counts; lower albumin levels; higher levels of lactate dehydrogenase, C-reactive protein (CRP), creatinine, creatinine kinase, and urea nitrogen; and longer prothrombin times. Hypertension, fever, fatigue, anorexia, bacterial coinfection, bilateral patchy shadowing, antibiotic and corticosteroid administration, and oxygen support had a significantly higher incidence among patients with progressive disease. A significantly longer duration of hospital stay was also observed in patients with progressive disease. Bilateral patchy shadowing (OR = 4.82, 95% CI: 1.33-17.50; P = 0.017) and elevated levels of creatinine (OR =6.24, 95% CI: 1.42-27.40; P = 0.015), and CRP (OR = 7.28, 95% CI: 2.56-20.74; P < 0.001) were independent predictors for disease progression. Conclusion: The clinical characteristics of patients with progressive and non-progressive COVID-19 were significantly different. Bilateral patchy shadowing and increased levels of creatinine, and CRP were independent predictors of disease progression.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32850746

RESUMO

Objectives: Coronavirus disease 2019 (COVID-19) is sweeping the globe and has resulted in infections in millions of people. Patients with COVID-19 face a high fatality risk once symptoms worsen; therefore, early identification of severely ill patients can enable early intervention, prevent disease progression, and help reduce mortality. This study aims to develop an artificial intelligence-assisted tool using computed tomography (CT) imaging to predict disease severity and further estimate the risk of developing severe disease in patients suffering from COVID-19. Materials and Methods: Initial CT images of 408 confirmed COVID-19 patients were retrospectively collected between January 1, 2020 and March 18, 2020 from hospitals in Honghu and Nanchang. The data of 303 patients in the People's Hospital of Honghu were assigned as the training data, and those of 105 patients in The First Affiliated Hospital of Nanchang University were assigned as the test dataset. A deep learning based-model using multiple instance learning and residual convolutional neural network (ResNet34) was developed and validated. The discrimination ability and prediction accuracy of the model were evaluated using the receiver operating characteristic curve and confusion matrix, respectively. Results: The deep learning-based model had an area under the curve (AUC) of 0.987 (95% confidence interval [CI]: 0.968-1.00) and an accuracy of 97.4% in the training set, whereas it had an AUC of 0.892 (0.828-0.955) and an accuracy of 81.9% in the test set. In the subgroup analysis of patients who had non-severe COVID-19 on admission, the model achieved AUCs of 0.955 (0.884-1.00) and 0.923 (0.864-0.983) and accuracies of 97.0 and 81.6% in the Honghu and Nanchang subgroups, respectively. Conclusion: Our deep learning-based model can accurately predict disease severity as well as disease progression in COVID-19 patients using CT imaging, offering promise for guiding clinical treatment.

3.
J Mol Histol ; 51(5): 531-540, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32785873

RESUMO

Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger (P-Rex) proteins control many fundamental cellular functions including cell migration, actin cytoskeletal rearrangement and adhesion in many cancers. However, P-Rex1 expression and its prognostic effect and possible clinical value are not clearly elucidated in human oral squamous cell carcinoma (OSCC). Here, OSCC tissue microarrays were used to verify the expression levels of P-Rex1, coinhibitory immune checkpoints and tumor associated macrophage (TAM) markers, and to analyze the relationship between PREX1 expression levels and clinicopathological characteristics in OSCC. The study found that P-Rex1 expression was elevated in OSCC compared to dysplasia and normal mucosa (P < 0.0001). In addition, patients who expressed high PREX1 had a poorer prognosis than those who expressed low PREX1 (P = 0.0070). Furthermore, positive correlations were found between P-Rex1 expression and the immune checkpoints PD-L1, Galectin-9 and B7-H4, and the TAM markers CD68, CD206 and CD163. In short, these findings implicated that overexpression of P-Rex1 may predict a poor prognosis in human OSCC.

4.
EBioMedicine ; 57: 102880, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32645614

RESUMO

BACKGROUND: Information regarding risk factors associated with severe coronavirus disease (COVID-19) is limited. This study aimed to develop a model for predicting COVID-19 severity. METHODS: Overall, 690 patients with confirmed COVID-19 were recruited between 1 January and 18 March 2020 from hospitals in Honghu and Nanchang; finally, 442 patients were assessed. Data were categorised into the training and test sets to develop and validate the model, respectively. FINDINGS: A predictive HNC-LL (Hypertension, Neutrophil count, C-reactive protein, Lymphocyte count, Lactate dehydrogenase) score was established using multivariate logistic regression analysis. The HNC-LL score accurately predicted disease severity in the Honghu training cohort (area under the curve [AUC]=0.861, 95% confidence interval [CI]: 0.800-0.922; P<0.001); Honghu internal validation cohort (AUC=0.871, 95% CI: 0.769-0.972; P<0.001); and Nanchang external validation cohort (AUC=0.826, 95% CI: 0.746-0.907; P<0.001) and outperformed other models, including CURB-65 (confusion, uraemia, respiratory rate, BP, age ≥65 years) score model, MuLBSTA (multilobular infiltration, hypo-lymphocytosis, bacterial coinfection, smoking history, hypertension, and age) score model, and neutrophil-to-lymphocyte ratio model. The clinical significance of HNC-LL in accurately predicting the risk of future development of severe COVID-19 was confirmed. INTERPRETATION: We developed an accurate tool for predicting disease severity among COVID-19 patients. This model can potentially be used to identify patients at risks of developing severe disease in the early stage and therefore guide treatment decisions. FUNDING: This work was supported by the National Nature Science Foundation of China (grant no. 81972897) and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2015).


Assuntos
Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Índice de Gravidade de Doença , Betacoronavirus , Proteína C-Reativa/análise , Síndrome da Liberação de Citocina/patologia , Feminino , Humanos , Hipertensão/patologia , L-Lactato Desidrogenase/análise , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Pandemias , Prognóstico , Estudos Retrospectivos
5.
Mol Ther Methods Clin Dev ; 18: 390-401, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32695841

RESUMO

Development of the CRISPR-Cas9 gene-editing system has given rise to a new era of gene editing with wide applications in biology, medicine, agriculture, and other fields. However, the overexpression of Cas9 nuclease causes off-target effects and may trigger an immune response in vivo. Therefore, we constructed a self-restricting CRISPR-Cas9 system, where the target gene sequence corresponding to the guide RNA (gRNA) is inserted on either end of the Cas9 promoter. When double-strand breaks (DSBs) are induced in the target gene sequence, the Cas9 promoter is cut off and transcription ceases. With this system, expression of Cas9 protein at 60 h after transfection is only 10% that of the wild-type system, with about 70% promoter deletion efficiency. The target site editing efficiency and homologous recombination efficiency of the self-restricting system remain at about 50% and 30%, respectively, while the frequency of off-target indel formation decreased by 76.7%. Further, the number of indel types was also reduced from 13 to 2. Because this system does not include additional gRNA sequences, the possibility of introducing new off-target mutations is decreased. Importantly, this system is composed of a single plasmid, which could potentially be easily introduced in vivo using a viral vector or nanoparticles.

6.
Front Oncol ; 10: 615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32435615

RESUMO

The loss of major histocompatibility complex class I (MHC I) molecules is an important mechanism by which cancer cells escape immunosurveillance in head and neck squamous cell carcinoma (HNSCC). Several long non-coding RNAs (lncRNAs) have been implicated in immune response and regulation including antigen processing and presentation. However, few studies on lncRNAs regulating MHC I expression in HNSCC have been conducted. In this study, MHC I related lncRNAs were identified from the The Cancer Genome Atlas (TCGA) HNSCC database. One of the lncRNAs, long intergenic non-protein coding RNA 2195 (LINC02195), was found to be associated with genes encoding MHC I molecules and patient prognosis in the TCGA database. KEGG and GO analyses suggested that LINC02195 was closely related to antigen processing and presentation. qRT-PCR revealed high expression of LINC02195 in human HNSCC tissues and HNSCC cell lines compared with normal mucosal tissues. in situ hybridization of the HNSCC tissue microarray revealed a correlation between high LINC02195 expression and a favorable prognosis in our patient cohort. Silencing of LINC02195 decreased MHC I protein expression, as evidenced by western blotting. Multiplex immunochemistry was performed to reveal the positive correlation between high LINC02195 expression and an increased number of CD8+ and CD4+ T cells in the tumor microenvironment. Based on our study, LINC02195 is a promising prognostic marker and a target for future therapeutic interventions.

7.
Int J Med Sci ; 17(6): 799-806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218701

RESUMO

Our study investigated the expression of malic enzyme 2 (ME2) in human oral squamous cell carcinoma (OSCC) and associated pathological and clinical pattern. We demonstrated that human OSCC tissues expressed a high level of ME2, and the overexpression of ME2 is closely connected to a high pathological grade, lymphatic metastasis, large tumor size and human papillomavirus (HPV) (P < 0.001). Similarly, high levels of ME2 expression in OSCC tissue were shown to be correlated with poor prognosis (P < 0.05). The expression of ME2 was correlated with Slug, SOX2, and aldehyde dehydrogenase-1 (ALDH1) immunoreactivity.ME2 was shown to be overexpressed in OSCC tissue and indicated a poor prognosis for OSCC. ME2 may be correlated with several immune markers.

8.
Am J Clin Pathol ; 153(5): 618-629, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31977029

RESUMO

OBJECTIVES: Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and interferon-induced transmembrane protein 3 (IFITM3) are commonly induced by type I interferon. The study aims to investigate the expression and clinical significance of IFIT1 and IFITM3 in head and neck squamous cell carcinoma (HNSCC). METHODS: Immunohistochemistry was applied on tissue microarray to reveal IFIT1 and IFITM3 expression in 275 HNSCC, 69 dysplasia, and 42 normal mucosa samples. The clinicopathologic features associated with IFIT1 and IFITM3 expression in HNSCC patients were analyzed. RESULTS: IFIT1 and IFITM3 were highly expressed in HNSCC tissues. High expression of IFIT1 and IFITM3 predicts a negative prognosis for patients (P < .01). IFIT1 and IFITM3 expression was associated with programmed cell death ligand 1, B7-H4, V-domain Ig suppressor of T-cell activation, indoleamine 2,3-dioxygenase, and macrophage marker immunoreactivity. CONCLUSIONS: IFIT1 and IFITM3 were overexpressed in HNSCC and indicated poor prognoses for patients with HNSCC. IFIT1 and IFITM3 expression was correlated with several immune checkpoint molecules and tumor-associated macrophage markers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Taxa de Sobrevida
9.
Cancer Immunol Res ; 8(2): 179-191, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31771985

RESUMO

CMTM6, a regulator of PD-L1 expression, also modulates tumor immunity. Little is known about the function of CMTM6 and its mechanism of action in head and neck squamous cell carcinoma (HNSCC). In this study, we found by IHC analysis that CMTM6 overexpression predicted a poor prognosis for patients with HNSCC. We discovered that CMTM6 expression was correlated with increased activity through the Wnt/ß-catenin signaling pathway, which is essential for tumorigenesis, maintenance of cancer stem cells (CSC), and the epithelial-to-mesenchymal transition (EMT) characteristic of multiple cancers. We used short hairpin RNA to eliminate expression of CMTM6, which led, in HNSCC cells, to reduced expression of nuclear ß-catenin as well as inhibition of stem cell-like properties, TGFß-induced EMT, and cell proliferation. Consistent with these results, we identified a significant positive correlation between expression of CMTM6 and EMT- and CSC-related genes in The Cancer Genome Atlas (TCGA). We found positive correlations for both RNA and protein between expression of CMTM6 and immune checkpoint components. CMTM6 silencing-induced PD-L1 downregulation delayed SCC7 tumor growth and increased CD8+ and CD4+ T-cell infiltration. The proportions of PD-1+, TIM-3+, VISTA+, LAG-3+, and B7-H3+ exhausted T cells were decreased significantly in the CMTM6 knockdown group. CMTM6 thus regulates stemness, EMT, and T-cell dysfunction and may be a promising therapeutic target in the treatment of HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/imunologia , Proteínas de Membrana/antagonistas & inibidores , Células-Tronco Neoplásicas/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Animais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Feminino , Técnicas de Inativação de Genes , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imunidade Celular/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Gradação de Tumores , Células-Tronco Neoplásicas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Taxa de Sobrevida , Via de Sinalização Wnt
10.
Cancer Immunol Res ; 7(10): 1700-1713, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387897

RESUMO

Immunosuppression is common in head and neck squamous cell carcinoma (HNSCC). In previous studies, the TIGIT/CD155 pathway was identified as an immune-checkpoint signaling pathway that contributes to the "exhaustion" state of infiltrating T cells. Here, we sought to explore the clinical significance of TIGIT/CD155 signaling in HNSCC and identify the therapeutic effect of the TIGIT/CD155 pathway in a transgenic mouse model. TIGIT was overexpressed on tumor-infiltrating CD8+ and CD4+ T cells in both HNSCC patients and mouse models, and was correlated with immune-checkpoint molecules (PD-1, TIM-3, and LAG-3). TIGIT was also expressed on murine regulatory T cells (Treg) and correlated with immune suppression. Using a human HNSCC tissue microarray, we found that CD155 was expressed in tumor and tumor-infiltrating stromal cells, and also indicated poor overall survival. Multispectral IHC indicated that CD155 was coexpressed with CD11b or CD11c in tumor-infiltrating stromal cells. Anti-TIGIT treatment significantly delayed tumor growth in transgenic HNSCC mouse models and enhanced antitumor immune responses by activating CD8+ T-cell effector function and reducing the population of Tregs. In vitro coculture studies showed that anti-TIGIT treatment significantly abrogated the immunosuppressive capacity of myeloid-derived suppressor cells (MDSC), by decreasing Arg1 transcripts, and Tregs, by reducing TGFß1 secretion. In vivo depletion studies showed that the therapeutic efficacy by anti-TIGIT mainly relies on CD8+ T cells and Tregs. Blocking PD-1/PD-L1 signaling increased the expression of TIGIT on Tregs. These results present a translatable method to improve antitumor immune responses by targeting TIGIT/CD155 signaling in HNSCC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Virais/antagonistas & inibidores , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/metabolismo , Receptores Virais/metabolismo
11.
J Exp Clin Cancer Res ; 38(1): 278, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238980

RESUMO

BACKGROUND: Partial epithelial mesenchymal transition (p-EMT) was found to play a potential role in the initial stage of metastasis in human head and neck squamous cell carcinoma (HNSCC). Some long noncoding RNAs (lncRNAs) have been reported to function as promoters or inhibitors of cancer metastasis. This study aimed to identify p-EMT-related lncRNAs in HNSCC. METHODS: Differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DEGs) in HNSCC obtained from The Cancer Genome Atlas (TCGA) were screened out by using the "edgeR" package. DE-lncRNAs in the Oral squamous cell carcinoma (OSCC) lncRNA microarray dataset GSE84805 were screened out by using the "limma" package. Slug-related lncRNAs were determined by Pearson correlation analysis (|Pearson correlation coefficient| ≥ 0.4, p < 0.01) based on TCGA. Survival analysis were performed for the overlapping DE-lncRNAs by using the "Survival" package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to predict the potential functions of MYOSLID. RT-qPCR and In Site Hybridization (ISH) were used to explore the MYOSLID expression and its clinical significance in HNSCC specimens. Immunohistochemical staining, siRNA, wound healing assay, transwell assay, and western blot were used to explore the biological function and potential molecular mechanisms. RESULTS: MYOSLID was identified as a Slug-related lncRNA and with prognostic value among the 9 overlapping DE-lncRNAs. GO and KEGG analyses revealed that MYOSLID was closely related to important biological processes and pathways that regulate cancer metastasis. The results of univariate and multivariate Cox regression analysis based on TCGA and HNSCC tissue microarray data suggested MYOSLID was an independent prognostic factor. MYOSLID expression in HNSCC was closely correlated with Slug, PDPN and LAMB3. The knockdown of MYOSLID in OSCC cell line significantly inhibited cell migration and invasion compared to those in the control cells. In addition, the knockdown of MYOSLID significantly reduced Slug, PDPN and LAMB3 expression levels. However, the knockdown of MYOSLID had no effect on the expression levels of the EMT biomarkers E-cadherin and Vimentin. CONCLUSIONS: Our study revealed that MYOSLID expression was closely related to the p-EMT program in HNSCC, and it might be a new predictive biomarker for aggressive HNSCC.


Assuntos
Transição Epitelial-Mesenquimal/genética , Neoplasias de Cabeça e Pescoço/genética , RNA Longo não Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Queratinócitos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Fatores de Transcrição da Família Snail/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Vimentina/metabolismo
12.
Dis Markers ; 2019: 5421985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089395

RESUMO

Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) and transmembrane and immunoglobulin domain containing 2 (TMIGD2) are new immune checkpoint molecules of the B7:CD28 family; however, little research has been performed on these immune checkpoint molecules. In this study, we used oral squamous cells carcinoma (OSCC) tissue microarrays and immunohistochemistry methods to investigate the expression patterns of HHLA2 and TMIGD2 in OSCC. After comparing the HHLA2 and TMIGD2 expression levels in OSCC, dysplasia, and mucosa, we found increased HHLA2 expression in OSCC and dysplasia, while the TMIGD2 expression was decreased in OSCC and dysplasia. Using the Kaplan-Meier method and log-rank test, we found that higher HHLA2 or TMIGD2 expression levels in OSCC indicate poor prognosis. Furthermore, two-tailed Pearson's statistical analysis revealed that the HHLA2 expression levels in OSCC, dysplasia, and mucosa were positively correlated with the T cell immunoglobulin and mucin-domain containing-3 (TIM3), lymphocyte-activation gene 3 (LAG3), B7 homolog 3 protein (B7-H3), B7 homolog 4 protein (B7H4), and V-domain Ig suppressor of T cell activation (VISTA) levels, while the TMIGD2 expression levels in OSCC, dysplasia, and mucosa were inversely correlated with the TIM3, LAG3, and B7H3 levels. Our current study demonstrates that HHLA2 may serve as an immune target for OSCC therapy and that the TMIGD2 expression level in OSCC could forecast patient prognosis.


Assuntos
Biomarcadores Tumorais/genética , Antígenos CD28/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Imunoglobulinas/genética , Neoplasias Bucais/genética , Biomarcadores Tumorais/metabolismo , Antígenos CD28/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imunoglobulinas/metabolismo , Masculino , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia
13.
J Cell Mol Med ; 23(6): 4054-4062, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30907490

RESUMO

Microvesicles (MVs), which are cell-derived membrane vesicles present in body fluids, are closely associated with the development of malignant tumours. Saliva, one of the most versatile body fluids, is an important source of MVs. However, the association between salivary MVs (SMVs) and oral squamous cell carcinoma (OSCC), which is directly immersed in the salivary milieu, remains unclear. SMVs from 65 patients with OSCC, 21 patients with oral ulcer (OU), and 42 healthy donors were purified, quantified and analysed for their correlations with the clinicopathologic features and prognosis of OSCC patients. The results showed that the level of SMVs was significantly elevated in patients with OSCC compared to healthy donors and OU patients. Meanwhile, the level of SMVs showed close correlations with the lymph node status, and the clinical stage of OSCC patients. Additionally, the ratio of apoptotic to non-apoptotic SMVs was significantly decreased in OSCC patients with higher pathological grade. Consistently, poorer overall survival was observed in patients with lower ratio of apoptotic to non-apoptotic SMVs. In conclusion, the elevated level of SMVs is associated with clinicopathologic features and decreased survival in patients with OSCC, suggesting that SMVs are a potential biomarker and/or regulator of the malignant progression of OSCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Saliva/metabolismo , Apoptose/fisiologia , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Prognóstico
14.
ACS Nano ; 13(3): 2849-2857, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30803232

RESUMO

Although anti-PD-1 immunotherapy is widely used to treat melanoma, its efficacy still has to be improved. In this work, we present a therapeutic method that combines immunotherapy and starvation therapy to achieve better antitumor efficacy. We designed the CMSN-GOx method, in which mesoporous silica nanoparticles (MSN) are loaded with glucose oxidase (GOx) and then encapsulate the surfaces of cancer cell membranes to realize starvation therapy. By functionalizing the MSN's biomimetic surfaces, we can synthesize nanoparticles that can escape the host immune system and homologous target. These attributes enable the nanoparticles to have improved cancer targeting ability and enrichment in tumor tissues. Our synthetic CMSN-GOx complex can ablate tumors and induce dendritic cell maturity to stimulate an antitumor immune response. We performed an in vivo analysis of these nanoparticles and determined that our combined therapy CMSN-GOx plus PD-1 exhibits a better antitumor therapeutic effect than therapies using CMSN-GOx or PD-1 alone. Additionally, we used the positron emission tomography imaging to measuring the level of glucose metabolism in tumor tissues, for which we investigate the effect with the cancer therapy in vivo.


Assuntos
Antineoplásicos/farmacologia , Membrana Celular/química , Imunoterapia , Melanoma Experimental/terapia , Nanopartículas/química , Dióxido de Silício/química , Animais , Membrana Celular/imunologia , Glucose Oxidase/química , Glucose Oxidase/imunologia , Glucose Oxidase/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Tamanho da Partícula , Porosidade , Dióxido de Silício/imunologia , Propriedades de Superfície , Células Tumorais Cultivadas
15.
Pathol Res Pract ; 215(4): 772-778, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30683473

RESUMO

Expression of the family with sequence similarity 3 member C (FAM3C) is necessary for the epithelial-mesenchymal transition (EMT). However, the expression level and clinicopathological significance of FAM3C in oral squamous cell carcinoma (OSCC) has not been thoroughly elucidated to date. We performed immunohistochemical staining on human OSCC specimens with FAM3C, co-inhibitory immune checkpoints, EMT markers, and cancer stem cells (CSCs) markers to analyze the expression levels and clinicopathological features of FAM3C in OSCC. There were 210 primary OSCC specimens, 69 oral epithelial dysplasia and 42 normal oral mucosae in our human OSCC tissue microarrays cohort. We observed that FAM3C expression was upregulated in OSCC compared with normal mucosa and epithelial dysplasia (P < 0.001). Moreover, patients with higher FAM3C expression levels had a worse prognosis than those with lower expression levels (P < 0.05). Also, FAM3C expression was positively correlated with the immune checkpoints PD-L1, VISTA, and B7-H4, the EMT marker Slug and the CSC markers SOX2 and ALDH1. In conclusion, these findings suggested that overexpression of FAM3C in human OSCC may predict a poor prognosis for OSCC patients.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Citocinas/metabolismo , Neoplasias Bucais/metabolismo , Proteínas de Neoplasias/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Prognóstico , Taxa de Sobrevida , Análise Serial de Tecidos
16.
Histol Histopathol ; 34(7): 803-810, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30632601

RESUMO

Glycoprotein non-metastatic protein B (GPNMB) is a transmembrane glycoprotein that is highly expressed in several malignancies compared with its expression in matched healthy tissues. The aim of this study was to investigate the clinical characteristics and prognostic value of GPNMB expression in tumor tissue derived from a cohort of patients with head and neck squamous cell carcinoma (HNSCC). GPNMB expression in human HNSCC, oral dysplasia and normal mucosal tissue was evaluated by immunohistochemistry (IHC). The correlations of GPNMB expression with the clinical characteristics of HNSCC were assessed by one-way ANOVA and t test analyses. Survival data were analyzed using Kaplan-Meier analysis and the Cox proportional hazards model. GPNMB was highly expressed in HNSCC tissue compared with dysplasia and normal mucosal tissue. Additionally, a high level of GPNMB expression in HNSCC was associated with poor prognosis (P<0.01). In the analysis of tumor-node-metastasis (TNM) staging, a high GPNMB expression level in HNSCC tissue, as well as metastatic lymph node tissue, correlated with an advanced N stage. In conclusion, GPNMB was overexpressed in human HNSCC tissue and predicted poor prognosis in human HNSCC tissue. In addition, GPNMB expression was closely correlated with N stage in patients with HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/mortalidade , Glicoproteínas de Membrana/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Biomarcadores Tumorais , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Membrana Mucosa/metabolismo , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
17.
Oncogene ; 38(14): 2516-2532, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30531834

RESUMO

p53, circRNAs and miRNAs are important components of the regulatory network that activates the EMT program in cancer metastasis. In prostate cancer (PCa), however, it has not been investigated whether and how p53 regulates EMT by circRNAs and miRNAs. Here we show that a Amotl1-derived circRNA, termed circAMOTL1L, is downregulated in human PCa, and that decreased circAMOTL1L facilitates PCa cell migration and invasion through downregulating E-cadherin and upregulating vimentin, thus leading to EMT and PCa progression. Mechanistically, we demonstrate that circAMOTL1L serves as a sponge for binding miR-193a-5p in PCa cells, relieving miR-193a-5p repression of Pcdha gene cluster (a subset of the cadherin superfamily members). Accordingly, dysregulation of the circAMOTL1L-miR-193a-5p-Pcdha8 regulatory pathway mediated by circAMOTL1L downregulation contributes to PCa growth in vivo. Further, we show that RBM25 binds directly to circAMOTL1L and induces its biogenesis, whereas p53 regulates EMT via direct activation of RBM25 gene. These findings have linked p53/RBM25-mediated circAMOTL1L-miR-193a-5p-Pcdha regulatory axis to EMT in metastatic progression of PCa. Targeting this newly identified regulatory axis provides a potential therapeutic strategy for aggressive PCa.


Assuntos
Proteínas de Membrana/genética , MicroRNAs/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas de Ligação a RNA/genética , Proteína Supressora de Tumor p53/genética , Idoso , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Células PC-3 , Transdução de Sinais/genética , Regulação para Cima/genética , Vimentina/genética
18.
Head Neck ; 41(4): 1080-1086, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30549148

RESUMO

BACKGROUND: This study aims to investigate the characteristic role of inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) in oral squamous cell carcinoma (OSCC). METHODS: The expressions of LAIR-1 and other immune-related molecules were detected in a human OSCC tissue microarray. LAIR-1 expression difference among different clinicopathological parameters was analyzed. The correlations of LAIR-1 with several immune-related markers were assessed. RESULTS: Compared with dysplasia and oral mucosa, the expression of LAIR-1 was significantly upregulated in the stroma of OSCC, and its overexpression was correlated with advanced pathological grade. Overexpression of LAIR-1 was significantly associated with tumor-associated macrophage and myeloid-derived suppressor cell markers (CD68, CD163; CD33, CD11b), indoleamine 2,3-dioxygenase (IDO) and two immune checkpoints (B7-H3 and VISTA). CONCLUSIONS: Overexpression of LAIR-1 was associated with advanced pathological grade and correlated with immune suppressive features in OSCC. Further studies are required to identify the specific immunological role of LAIR-1.


Assuntos
Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica , Hospedeiro Imunocomprometido/genética , Neoplasias Bucais/patologia , Receptores Imunológicos/genética , Adulto , Biópsia por Agulha , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Neoplasias Bucais/genética , Neoplasias Bucais/imunologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Estatísticas não Paramétricas , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Regulação para Cima
19.
Cell Mol Life Sci ; 75(22): 4223-4234, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29955905

RESUMO

The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs' inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8+ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/terapia , Dasatinibe/uso terapêutico , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Quimioterapia Combinada , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genética , Fator de Transcrição STAT3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral , Quinases da Família src/antagonistas & inibidores
20.
J Mol Histol ; 49(4): 389-398, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29846864

RESUMO

IQ-domain GTPase-activating protein 1 (IQGAP1) is associated with the development and progression of many human cancers. We aimed to investigate the expression and clinicopathological significances of IQGAP1 in head and neck squamous cell carcinoma (HNSCC). In this study, immunohistochemical staining of IQGAP1, co-inhibitory immune checkpoint molecules and macrophage markers were performed in human HNSCC samples to analyze the expression and correlation with clinicopathological characteristics. Immunoreactivity of IQGAP1 was also detected in immunocompetent mouse HNSCC tissue. We found that IQGAP1 expression level was significantly increased in human HNSCC compared with dysplasia and normal mucosa, and the expression of IQGAP1 in HNSCC was positively associated with advanced lymph node status. Besides, our data indicated that patients with higher IQGAP1 expression exhibited poor overall survival compared with patients with lower IQGAP1 expression. Furthermore, this study demonstrated that IQGAP1 expression was positively associated with TIM3, Galectin-9 (TIM3 ligand), B7H4, macrophage markers CD68 and CD163. In conclusion, these findings suggest that over-expression of IQGAP1 in human HNSCC may indicate poor prognosis.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Carcinoma de Células Escamosas/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Linfonodos/patologia , Masculino , Camundongos Knockout , Análise Multivariada , Proteínas de Neoplasias/metabolismo , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de Sobrevida
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