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关键词： Adjuvant therapy   Clear cell ependymoma   Gross total resection   Overall survival   Progression-free survival   CENTRAL-NERVOUS-SYSTEM   INTRACRANIAL EPENDYMOMAS   PRIMARY BRAIN   TUMORS   OLIGODENDROGLIOMA   MANAGEMENT   FEATURES   HEMANGIOBLASTOMA   CLASSIFICATION   EPIDEMIOLOGY  

摘要： BACKGROUND: The survival outcomes of clear cell ependymomas are poorly understood. This study clarifies the role of surgery and adjuvant therapy when this morphologically distinct tumor is encountered. METHODS: A systematic search for studies relating to clear cell ependymomas was conducted. Primary outcomes were progression-free survival and overall survival. Prognostic variables were age, sex, tumor consistency, extent of resection, and postoperative adjuvant therapy. Kaplan-Meier survival curves were generated and compared by the log-rank test. Multivariate Cox regression models were constructed, interrogated with Schoenfeld residuals, and used to identify independent prognostic factors. RESULTS: Of the 384 articles retrieved, 8 articles comprising 77 cases of clear cell ependymoma were included. Five-year overall survival and progression-free survival were 581% (95% confidence interval [CI], 46.3%-72.9%) and 46.3% (95% CI, 34.2%-62.8%), respectively. Kaplan-Meier analysis with the log-rank test showed that gross total resection was superior to subtotal resection in prolonging survival (P = 0.047) and delayed time to recurrence (P < 0.01). Multivariate analysis confirmed gross total resection as an independent protective factor against relapse (odds ratio, 0.39; 95% CI, 017-019; P = 0.03). Age <50 years predicted longer overall survival (odds ratio, 0.16; 95% CI, 0.05-0.49; P < 0.01). Postoperative adjuvant therapy after gross total resection did not affect overall survival (P = 0.98) or progression-free survival (P = 0.93). Adjuvant therapy after subtotal resection favored improved overall survival (P = 0.052). CONCLUSIONS: Clear cell ependymomas are particularly aggressive in those aged >50 years. Gross total resection remains the cornerstone of management. Postoperative adjuvant therapy is likely to be of survival benefit only after subtotal resection.

关键词： Non-small cell lung cancer   Brain metastases   Immunotherapy   Human leukocyte antigen (HLA) class 1   SURVIVAL   ESCAPE  

摘要： Loss of human leukocyte antigen (HLA) class 1 expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. Patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors can have discordant responses between brain metastases and extracranial sites of disease. We sought to evaluate whether HLA class 1 expression was retained in metastatic NSCLC. Patients with paired primary NSCLC and brain metastases were identified from our institution's tissue registry. HLA class 1 cell membrane expression on tumor cells was determined by immunohistochemistry. Tumors with greater than the median of 10% HLA expression were considered positive. Agreement statistics (kappa) were used to assess the congruence of HLA expression. 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA class 1 expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%) (kappa = 0.57, 95% CI 0.35-0.79) (p = 0.0001). None of the patients received checkpoint inhibitors for treatment of these lesions. The results show that while there is moderate agreement in HLA class 1 expression between primary lung tumor and brain metastasis pairs, HLA expression is incongruent in nearly one quarter of patients. Loss of antigen presentation may represent one of the many potential mechanisms of discordant responses to checkpoint inhibitor therapy.

关键词： Epithelial kidney cells   SV40 T antigen   Transfection   Cell immortalization   LARGE T-ANTIGEN   HUMAN-DIPLOID FIBROBLASTS   IN-VIVO   LINE   REPLICATION   DNA   TRANSFORMATION   PROPAGATION   INSTABILITY   EXPRESSION  

摘要： Sheep primary epithelial cells are short-lived in cell culture systems. For long-term in vitro studies, primary cells need to be immortalized. This study aims to establish and characterize T immortalized sheep embryo kidney cells (TISEKC). In this study, we used fetal lamb kidneys to derive primary cultures of epithelial cells. We subsequently immortalized these cells using the large T SV40 antigen to generate crude TISEKC and isolate TISEKC clones. Among numerous clones of immortalized cells, the selected TISEKC-5 maintained active division and cell growth over 20 passages but lacked expression of the oncogenic large T SV40 antigen. Morphologically, TISEKC-5 maintained their epithelial aspect similar to the parental primary epithelial cells. However, their growth properties showed quite different patterns. Crude TISEKC, as well as the clones of TISEKC proliferated highly in culture compared to the parental primary cells. In the early passages, immortalized cells showed heterogeneous polyploidy but in the late passages the karyotype of immortalized cells became progressively stable, identical to that of the primary cells, because the TISEKC-5 cell line has lost the large SV40 T antigen expression, this cell line is a valuable tool for veterinary sciences and biotechnological productions.

关键词： CRISPR interference   knockdown   inducible Tet-on system   multiplicity of infection   sgRNA  

摘要： To determine how nuclease deactivated Cas9 (dCas9) or single-guide RNA (sgRNA) expression levels affect the knockdown efficiency of CRISPRi, we created K562 cell clones expressing KRAB-dCas9 protein either with the inducible Tet-on system or with the constitutive SFFV promotor. Single clones were selected by fluorescence-activated cell sorting (FACS) for further study. Six genes with various expression levels were targeted using lentiviral sgRNA from two libraries in four cell clones with various KRAB-dCas9 expression levels. The expression level of dCas9 protein/sgRNA levels and the knockdown efficiency were determined by flow cytometry. The cell clone with the highest KRAB-dCas9 expression level achieved effective CRISPRi knockdown. The data describing this clone were statistically different from that on other clones, indicating the strong KRAB-dCas9 expression might be a prerequisite for CRISPRi. By adopting different multiplicity of infection (MOI) in lentiviral transduction of this clone, we modified the expression level of sgRNA and found that the knockdown efficiency was neither affected by the target gene expression level nor correlated with KRAB-dCas9 levels, which remained relatively constant across all knockdown experiments (coefficient of variation = 2.2%). As an example, the following levels of the knockdowns: 74.72, 72.28 and 39.08% for mmadhc, rpia and znf148 genes, respectively, were achieved. These knockdown efficiencies correlated well with the respective sgRNA expression levels. Linear regression models built using this data indicate that the knockdown efficiency may be significantly affected by the levels of both KRAB-dCas9 and sgRNA. Notably, the sgRNA levels have greater impact, being a major factor affecting CRISPRi efficiency.

关键词： cfDNA   Apoptosis   Necrosis   Active secretion   Liquid biopsy   DOUBLE-STRANDED DNA   FREE NUCLEIC-ACIDS   LIQUID BIOPSIES   MOLECULAR-MECHANISMS   MEDIATED TRANSFER   BLOOD-PLASMA   GENOMIC DNA   CANCER   EXOSOMES   CLEAVAGE  

摘要： Cell-free DNA (cfDNA) as an emerging biomarker with huge potential for clinical application, especially in the field of liquid biopsy. The field is now in a critical transitional period in which cfDNA-based analysis is developing rapidly. No doubt learning more about the biological knowledge of cfDNA is beneficial to catalyze this transformation process. Therefore, in this review we have summarized the characteristics of cfDNA, including its structure and origin of tissues, in order to provide researchers with a more holistic insight of cfDNA. Subsequently, we focused on the pathways that cfDNA releases from cells, such as apoptosis, necrosis, and active secretion. Additionally, the clearance of cfDNA derived from both cellular death and active secretion in the physiological environment is also discussed. Finally, we have mentioned the link between cfDNA active secretion and tumor microenvironment.

关键词： Non-small cell lung cancer   PET/MRI   Prognostic markers   POSITRON-EMISSION-TOMOGRAPHY   COMPUTED TOMOGRAPHY   PROGNOSTIC VALUE   18F-FDG PET/CT   WEIGHTED MRI   LESIONS   REPEATABILITY   PARAMETERS   TISSUES   HYBRID  

摘要： Objectives: To investigate if the combined analysis of the apparent diffusion coefficient (ADC) and standardized uptake values (SUV) measured in F-18-fluoro-deoxy-glucose-positron emission tomography/magnetic resonance imaging (F-18-FDG PET/MRI) examinations correlates with overall survival in non-small cell lung cancer (NSCLC). Material and methods: A total of 92 patients with newly diagnosed, histopathologically proven NSCLC (44 women and 48 men, mean age 63.1 +/- 9.9y) underwent a dedicated thoracic F-18-FDG PET/MRI examination. A manually drawn polygonal region of interest (ROI), encompassing the entire primary tumor mass, was placed over the primary tumor on fused PET/MR images to determine the maximum and mean standardized uptake values (SUVmax; SDVmean) as well as on the ADC maps to quantify the mean and minimum ADC values (ADC(mean), ADC(min)). The impact of these parameters to predict patient's overall survival was tested using hazard ratios (HR). Pearson's correlation coefficients were calculated to assess dependencies between the different values. A p-value < 0.05 indicated statistical significance. Results: In all 92 patients (n = 59 dead at time of retrospective data collection, mean time till death: 19 +/- 16 month, n = 33 alive, mean time to last follow-up: 56 +/- 22 month) the Hazard ratios (HR) as independent predictors for overall survival (OS) of SUVmax were 2.37 (95 % CI: 1.23-4.59, p = 0.008) and for SUVmean 1.85 (95 % CI: 1.05-3.26, p = 0.03) while ADC(min) showed a HR of 0.95 (95 % CI: 0.57-1.59, p = 0.842) and ADC(mean) a HR of 2.01 (95 % CI: 1.2-3.38, p = 0.007). Furthermore, a combined analysis for SUVmax/ADC(mean), SUVmax/ ADC(min) and SUVmean/ADC(mean) revealed a HR of 2.01 (95 % CI: 1.10-3.67, p = 0.02), 1.75 (95 % CI: 0.97-3.15, p = 0.058) and 1.78 (95 % CI: 1.02-3.10, p = 0.04). Conclusion: SUVmax and SDVmean of the primary tumor are predictors for OS in therapy-naive NSCLC patients, whereas the combined analysis of SUV and ADC values

关键词： Spindle cell sarcoma   Malignant tumors of heart   LA myxoma  

摘要： Primary spindle cell sarcoma of the heart is a rare malignant tumor of the heart. A 65-year-old woman was admitted under our care with complaints of shortness of breath. Echocardiogram showed pedunculated mass in the left atrium. Cardiac magnetic resonance imaging done elsewhere had confirmed a left atrial tumor. No further investigations were considered with a diagnosis of left atrial myxoma. She underwent total excision of the tumor: mitral valve involvement necessitated a repair all of which was done under cardiopulmonary bypass. Histopathology showed a primary spindle cell sarcoma. In view of histology, chemotherapy was planned and initiated. A month after surgery, she presented again with a recurrence.

关键词： TLR4   MYD88 L265P mutation   P-STAT3   PCNSL   POOR-PROGNOSIS   STAT3   ACTIVATION   CONTRIBUTE   IBRUTINIB   PATHWAY  

摘要： Patients with primary central nervous system lymphoma (PCNSL) have a prognosis poorer than that of systemic lymphoma patients. In patients with this condition, TLR4/STAT3 pathway alterations and the MYD88 L265P mutation may be viable targets for therapeutic intervention. The present study was, therefore, designed to identify clinicopathologic correlates of MYD88 mutations and TLR4/STAT3 pathway alterations in PCNSL. We detected TLR4 and p-STAT3 in 41.5% (22/53) and 43.4% (23/53) of PCNSL patients, respectively, while 60.4% of these patients (32/53) were found to harbor the MYD88 L265P mutation. TLR4 expression was found to be significantly associated with the presence of multiple brain lesions, while p-STAT3 expression was significantly linked to advanced age, the presence of multiple brain lesions, non-GCB histological findings, and non-CR status. The presence of the MYD88 L265P mutation was significantly linked to advanced age, the presence of multiple brain lesions, and DLBCL molecular subtype. Multivariate analyses additionally confirmed that elevated TLR4 and p-STAT3 expression levels are associated with a poorer PCNSL patient prognosis. Based on these findings, we hypothesize that signaling through the TLR4/MYD88/STAT3 pathway plays a key role in the pathogenesis of PCNSL.