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The pathological diagnosis of intracranial germinoma (IG), oligodendroglioma, and low-grade astrocytoma on intraoperative frozen section (IFS) and hematoxylin-eosin (HE)-staining section directly determines patients' treatment options, but it is a difficult task for pathologists. We aimed to investigate whether whole-slide imaging (WSI)-based deep learning can contribute new precision to the diagnosis of IG, oligodendroglioma, and low-grade astrocytoma. Two types of WSIs (500 IFSs and 832 HE-staining sections) were collected from 379 patients at multiple medical centers. Patients at Center 1 were split into the training, testing, and internal validation sets (3:1:1), while the other centers were the external validation sets. First, we subdivided WSIs into small tiles and selected tissue tiles using a tissue tile selection model. Then a tile-level classification model was established, and the majority voting method was used to determine the final diagnoses. Color jitter was applied to the tiles so that the deep learning (DL) models could adapt to the variations in the staining. Last, we investigated the effectiveness of model assistance. The internal validation accuracies of the IFS and HE models were 93.9% and 95.3%, respectively. The external validation accuracies of the IFS and HE models were 82.0% and 76.9%, respectively. Furthermore, the IFS and HE models can predict Ki-67 positive cell areas with R2 of 0.81 and 0.86, respectively. With model assistance, the IFS and HE diagnosis accuracy of pathologists improved from 54.6%-69.7% and 53.5%-83.7% to 87.9%-93.9% and 86.0%-90.7%, respectively. Both the IFS model and the HE model can differentiate the three tumors, predict the expression of Ki-67, and improve the diagnostic accuracy of pathologists. The use of our model can assist clinicians in providing patients with optimal and timely treatment options.
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Astrocitoma , Neoplasias Encefálicas , Aprendizaje Profundo , Oligodendroglioma , Humanos , Oligodendroglioma/diagnóstico por imagen , Oligodendroglioma/cirugía , Antígeno Ki-67 , Neuropatología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugíaRESUMEN
[This retracts the article DOI: 10.3892/etm.2017.4593.].
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Objective: The Wnt/ß-catenin pathway is involved in the development of hepatocellular carcinoma (HCC) and malignant events such as the epithelial-mesenchymal transition (EMT), metastasis, and invasion. Studies have illustrated that the inhibition of tankyrases (TNKS) antagonizes Wnt/ß-catenin signaling in many cancer cells. Methods: The expression levels of proteins related to the Wnt/ß-catenin pathway and EMT were analyzed by immunohistochemistry in HCC tissue and paired adjacent normal tissue (n = 10), and in an analysis of The Cancer Genome Atlas (TCGA) data. Additionally, after treatment of HCC cell lines with TNKS1/2 small interfering RNA (siRNA) and a novel TNKS inhibitor (NVP-TNKS656), cell viability, cell clone formation, wound-healing, and cell invasion assays were performed. Results: Higher expression of ß-catenin, TNKS, vimentin, and N-cadherin was observed in HCC tissue compared to adjacent normal tissue, but lower expression of E-cadherin was found in HCC tissue. These findings were also observed in the TCGA analysis. In addition, TNKS inhibition (using TNKS1/2 siRNA and NVP-TNKS656) not only abrogated the proliferation of the HCC cell lines but also suppressed metastasis, invasion, and EMT phenotypic features. Moreover, the mechanisms related to TNKS inhibition in HCC probably involved the stabilization of AXIN levels and the downregulation of ß-catenin, which mediates EMT marker expression. Conclusion: The TNKS/ß-catenin signaling pathway is a potential anti-proliferation and anti-metastatic target in HCC.
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BACKGROUND: Osteoarthritis (OA) is a metabolic disorder and able to be relieved by traditional Chinese medicines. However, the effect of Ligusticum wallichii on OA is unknown. METHODS: Cytokine IL-1ß and L. wallichii extracts were used to stimulate the primary mouse chondrocytes. MTT assay was used to measure the cell viability. The mRNA and protein level of each gene were test by qRT-PCR and western blotting, respectively. The rate of apoptotic cell was measured by flow cytometry. GC/MS-based metabolomics was utilized to characterize the variation of metabolome. RESULTS: Here, we found that L. wallichii attenuated the IL-1ß-induced apoptosis, inflammatory response, and extracellular matrix (ECM) degradation in mouse chondrocytes. Then we used GC/MS-based metabolomics to characterize the variation of metabolomes. The established metabolic profile of mouse chondrocytes showed that the abundance of most metabolites (n = 40) altered by IL-1ß stimulation could be repressed by L. wallichii treatment. Multivariate data analysis identified that cholesterol, linoleic acid, hexadecandioic acid, proline, l-valine, l-leucine, pyruvate, palmitic acid, and proline are the most key biomarkers for understanding the metabolic role of L. wallichii in IL-1ß-treated chondrocytes. Further pathway analysis using these metabolites enriched fourteen metabolic pathways, which were dramatically changed in IL-1ß-treated chondrocytes and capable of being reprogrammed by L. wallichii incubation. These enriched pathways were involved in carbon metabolisms, fatty acid biosynthesis, and amino acid metabolisms. CONCLUSIONS: These findings provide potential clues that metabolic strategies are linked to protective mechanisms of L. wallichii treatment in IL-1ß-stimulated chondrocytes and emphasize the importance of metabolic strategies against inflammatory responses in OA development.
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We conducted a meta-analysis to compare the efficacy of brachytherapy and penectomy in patients with penile cancer. We searched the published articles in the PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang databases up to March 20, 2017. Twenty-two studies entered the final analyses. We used five-year overall survival rate, five-year local control rate, disease-free progression and lymph node positive rate to assess the efficacy. The meta-analysis found that patients who received penectomy had higher five-year local control rate (85% vs 80%, odds ratio = 0.72, 95% confidence interval: 0.58-0.90), five-year disease-free progression rate (77% vs 72%, odds ratio = 0.77, 95% confidence interval: 0.63-0.93) and lymph node positive rates (24% vs 20%, odds ratio = 0.79, 95% confidence interval: 0.64-0.98) than brachytherapy. No significant difference was observed for two group in five-year overall survival rate (76% vs 74%, odds ratios = 1.11 with the 95% confidence interval: 0.91-1.36). Both of penectomy and brachytherapy can improve the survival status. Penectomy provided better control efficacy, and not improved the survival status compared with brachytherapy solely. However, further research was required because of retrospective nature and potential bias of the data.
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MicroRNAs (miRs) are a type of small non-coding RNA that serve crucial roles in the development and progression of breast cancer. However, the exact role and underlying molecular mechanism of miR-375 in mediating the growth and metastasis of breast cancer remains unknown. In the present study, reverse transcription-quantitative polymerase chain reaction and western blot analysis were conducted to examine RNA and protein expression. A luciferase reporter assay was performed to determine the association between miR-375 and paired box 6 (PAX6). The results of the current study indicate that the expression of miR-375 was reduced in breast cancer tissues compared with matched adjacent normal tissues. Transfection with miR-375 mimics led to a significant increase in levels of miR-375 in human breast cancer Michigan Cancer Foundation (MCF)-7 cells (P<0.05). The increase in miR-375 expression caused a significant decrease in the viability, migration and invasion of MCF-7 cells (P<0.05), accompanied by a reduced expression of matrix metalloproteinase (MMP) 2 and MMP9 proteins. Luciferase reporter assay identified PAX6 as a novel target of miR-375 and miR-375 in turn, negatively regulated the protein expression of PAX6 in MCF-7 cells. By contrast, overexpression of PAX6 led to a significant increase in MCF-7 cell viability (P<0.01) but did not affect the migration and invasion of MCF-7 cells, suggesting that the inhibitory effect of miR-375 on MCF-7 cell viability may be occurring, in part, via the direct targeting of PAX6.
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Although epithelial membrane protein 3 (EMP3) has been implicated as a candidate tumor suppressor gene for low grade glioma, its biological function in glioblastoma multiforme (GBM) still remains poorly understood. Herein, we showed that EMP3 was highly expressed in CD44-high primary GBMs. Depletion of EMP3 expression suppressed cell proliferation, impaired in vitro tumorigenic potential and induced apoptosis in CD44-high GBM cell lines. We also identified TGF-ß/Smad2/3 signaling pathway as a potential target of EMP3. EMP3 interacts with TGF-ß receptor type 2 (TGFBR2) upon TGF-ß stimulation in GBM cells. Consequently, the EMP3-TGFBR2 interaction regulates TGF-ß/Smad2/3 signaling activation and positively impacts on TGF-ß-stimulated gene expression and cell proliferation in vitro and in vivo. Highly correlated protein expression of EMP3 and TGF-ß/Smad2/3 signaling pathway components was also observed in GBM specimens, confirming the clinical relevancy of activated EMP3/TGF-ß/Smad2/3 signaling in GBM. In conclusion, our findings revealed that EMP3 might be a potential target for CD44-high GBMs and highlight the essential functions of EMP3 in TGF-ß/Smad2/3 signaling activation and tumor progression.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Receptores de Hialuranos/metabolismo , Glicoproteínas de Membrana/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferación Celular , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Ratones , Ratones Desnudos , Clasificación del Tumor , Pronóstico , Transducción de Señal , Proteína Smad2/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
CONCLUSION: In patients with nasopharyngeal carcinoma (NPC), PKCα is linked to local advancement and plays dual roles in tumorigenesis. Moreover, positive PKCα is associated with 2-year overall survival of NPC. OBJECTIVE: This study seeks to investigate the role of PKCα to identify different sub-types in NPC. METHODS: PKCα expression levels were detected in a collection of NPC samples. CT and MRI scans of the corresponding patients were used to assess adjacent tissue invasion and lymph node metastasis. The correlation of tumour invasion and PKCα levels was evaluated by statistical analysis. The correlation between expression level of PKCα and 2-year overall survival was analysed by the Kaplan-Meier curves. Moreover, a multivariate Cox proportional hazard regression analysis was used to identify the independent prognostic factors for NPC. RESULTS: PKCα is linked to the invasion of adjacent tissues, especially in the skull base. However, down-regulation of PKCα is a risk factor for regional lymph node metastasis. The 2-year overall survival of the PKCα negative group is better than that of the PKCα positive group (PKCα negative group 100%, PKCα positive group 88.5%, p = 0.034). Based on the multivariate Cox proportional hazard regression analysis, age was identified as a risk factor.
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Carcinoma/enzimología , Neoplasias Nasofaríngeas/enzimología , Proteína Quinasa C-alfa/metabolismo , Adulto , Anciano , Carcinoma/mortalidad , Carcinoma/patología , China/epidemiología , Humanos , Metástasis Linfática , Persona de Mediana Edad , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Invasividad Neoplásica , Adulto JovenRESUMEN
NIMA-related expressed kinase 2 (NEK2) participates in the carcinogenesis and progression of certain types of cancer, however, its expression and roles in the development of hepatocellular carcinoma (HCC) remains unknown. Here, we found that NEK2 expression was significantly upregulated in both human HCC tissues and cell lines, and increased NEK2 expression in HCC was significantly correlated with clinical progression of HCC in patients. Knockdown of NEK2 in HCC cells inhibited HCC progression, as determined by the suppressed cell proliferation, invasion and metastasis. Furthermore, knockdown of NEK2 inhibited drug resistance of HCC cells, as shown by the promoted suppression of cell viability in 5-fluorouracil (5FU)treated HCC cells. Mechanistically, protein phosphatase 1 (PP1)/Akt and Wnt signaling activation are significantly inhibited by NEK2 knockdown, which is responsible for the HCC progression and involved in NEK2induced cancer cell abnormal biological behavior. Thus, enhanced NEK2 expression in HCC promotes HCC progression and drug resistance by promoting PP1/Akt and Wnt pathway activation, which may represent a new therapeutic target for HCC.