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1. Oncogenic RAS mutations are present in 15-30% of thyroid carcinomas. Pubmed Oncogenic RAS mutations are present in 15-30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with HrasG12V in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in Tpo-Cre/homozygous FR-HrasG12V mice. The thyroid tumors closely phenocopied the histological features of human RAS-driven, poorly differentiated thyroid cancers. Characterization of transposon insertion sites in the SB-induced tumors identified 45 recurrently mutated candidate cancer genes. These mutation profiles were remarkably concordant with mutated cancer genes identified in a large series of human poorly differentiated and anaplastic thyroid cancers screened by next-generation sequencing using the MSK-IMPACT panel of cancer genes, which we modified to include all SB candidates. The disrupted genes primarily clustered in chromatin remodeling functional nodes and in the PI3K pathway. ATXN7, a component of a multiprotein complex with histone acetylase activity, scored as a significant SB hit. It was recurrently mutated in advanced human cancers and significantly co-occurred with RAS or NF1 mutations. Expression of ATXN7 mutants cooperated with oncogenic RAS to induce thyroid cell proliferation, pointing to ATXN7 as a previously unrecognized cancer gene. Pten; Ras; Sleeping Beauty; Swi/Snf; thyroid cancer genomics
2. Purpose: Evans Blue (EB) is an azo dye that binds quantitatively with serum albumin. Pubmed Purpose: Evans Blue (EB) is an azo dye that binds quantitatively with serum albumin. With an albumin binding, NOTA conjugated truncated Evan's blue (NEB) dye derived PET tracer, we aimed to establish a strategy for evaluating vascular permeability in malignant tumors via non-invasive PET. Experimental design: Sixty-minute dynamic PET using [18F]FAl-NEB was performed in three xenograft tumor models including INS-1 rat insulinoma, UM-SCC-22B human head and neck carcinoma and U-87 MG human glioblastoma. Tumor vascular permeability was quantified by the difference of the slopes between tumor and blood time-activity curve (TACs, expressed as Ps ). The method was further substantiated by EB extraction and colorimetric assay and correlates with that calculated from dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The changes in tumor vasculature at different time points were assessed with NEB PET in U-87 MG and UM-SCC-22B tumor models after treatment with bevacizumab or doxorubicin. Result: The Ps values calculated from tumor and blood TACs from multiple time-point static images are consistent with those from dynamic images. Moreover, the Ps showed a positive and significant correlation with extracted EB concentration and KPS-MRI generated from DCE-MRI, which further confirmed the soundness of this methodology. The antiangiogenic effect of bevacizumab could be revealed by NEB PET in U-87 MG tumors as early as 8 hrs after therapy, demonstrated by a substantial decrease of Ps. On the contrary, there was no significant change of Ps in bevacizumab treated UM-SCC-22B tumors, compared with control group. However, the significant changes of Ps were overestimated in doxorubicin treated UM-SCC-22B tumors. Conclusions: We successfully developed a relatively convenient and novel strategy to evaluate vascular permeability and blood volume using NEB PET. This method will be advantageous in evaluating vascular permeability, promoting drug delivery, and monitoring tumor response to therapeutics that affect tumor angiogenesis. Evans blue; positron emission tomography; therapy response; tumor vasculature; vascular permeability.
3. FKBP3 is a member of FK506-binding proteins (FKBPs). Pubmed FKBP3 is a member of FK506-binding proteins (FKBPs). Little is known about the expression and functional role(s) of FKBP3 in non-small cell lung cancer (NSCLC). In the present study, we demonstrated up-regulation of FKBP3 expression, both at mRNA and protein levels, in NSCLC samples which closely correlated with poor survival in NSCLC patients. In vitro and in vivo experiments revealed that FKBP3 could promote NSCLC cell proliferation. Furthermore, knockdown of FKBP3 significantly decreased histone deacetylase 2 (HDAC2) expression and increased p27 (a cell cycle inhibitor) expression. HDAC2 modulated the acetylation of histone H3K4 by directly binding to the p27 promoter. The proliferation-promoting effect of FKBP3 was dependent on HDAC2 and inhibited by p27. Also, FKBP3 induced HDAC2 promoter activity via inhibiting the ubiquitination of transcription factor Sp1. Additionally, we identified miR-145-5p as a regulator of FKBP3. miR-145-5p overexpression suppressed cell proliferation of NSCLC cells which was abrogated by FKBP3 overexpression. Taken together, our data clearly show that FKBP3/Sp1/HDAC2/p27 control cell proliferation during NSCLC development. FKBP3; NSCLC.; cell proliferation; miR-145; p27
4. We would like to submit the following correction to the published paper [1], the reason for this action is that the data in Table 3 were reanalyzed by one more accurate statistic method: On page 12, the sentence of paragraph three "OR and 95% CI were calculated by limited backward-LR (likelihood ratio) logistic regression analysis with adjustment by clinical variables" should be corrected into "OR and 95% CI were calculated by limited enter logistic regression analysis with adjustment by clinical variables". Pubmed We would like to submit the following correction to the published paper [1], the reason for this action is that the data in Table 3 were reanalyzed by one more accurate statistic method: On page 12, the sentence of paragraph three "OR and 95% CI were calculated by limited backward-LR (likelihood ratio) logistic regression analysis with adjustment by clinical variables" should be corrected into "OR and 95% CI were calculated by limited enter logistic regression analysis with adjustment by clinical variables".[...].
5. Upregulation of the heat shock transcription factor 1 (HSF1) has been described as a frequent event in many cancer types, but its oncogenic role in hepatocellular carcinoma (HCC) remains poorly delineated. Pubmed Upregulation of the heat shock transcription factor 1 (HSF1) has been described as a frequent event in many cancer types, but its oncogenic role in hepatocellular carcinoma (HCC) remains poorly delineated. In the present study, we assessed the function(s) of HSF1 in hepatocarcinogenesis via in vitro and in vivo approaches. In particular, we determined the importance of HSF1 on v-Akt murine thymoma viral oncogene homolog (AKT)-induced liver cancer development in mice. We found that knockdown of HSF1 activity via specific siRNA triggered growth restraint by suppressing cell proliferation and inducing massive cell apoptosis in human HCC cell lines. At the molecular level, HSF1 inhibition was accompanied by downregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade and related metabolic pathways. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery led to the inhibition of mouse hepatocarcinogenesis driven by overexpression of AKT. In human liver cancer specimens, we detected that HSF1 is progressively induced from human non-tumorous surrounding livers to HCC, reaching the highest expression in the tumors characterized by the poorest outcome (as defined by the length of patients' survival). In conclusion, HSF1 is an independent prognostic factor in liver cancer and might represent an innovative therapeutic target in HCC subsets characterized by activation of the AKT/mTOR pathway. HSF1; hepatocellular carcinoma; signaling pathways
6. Lung cancer is one of the most fatal cancers in the world. Pubmed Lung cancer is one of the most fatal cancers in the world. To early distinguish benign and malignant pulmonary nodule is critical for disease prognosis. Confocal laser endomicroscopy (CLE) can be used to explore bronchus mucous membrane, alveolar elastic fiber structures and microvessels, and could be helpful for the diagnostic imaging and for the localization guidance. In this report, we presented two cases of peripheral pulmonary nodule. Under the guidance of X-ray and endobronchial ultrasound, needle-based confocal laser endomicroscopy (nCLE) could directly approach the peripheral pulmonary nodule via an exploratory puncture needle. The results indicated that the utility of the nCLE is helpful to precise positioning and characterize the peripheral pulmonary nodule. This report presents for the first time the application of nCLE for positioning the peripheral extraluminal nodule and describe the different confocal imaging features between adenocarcinoma and tuberculosis. Needle-based confocal laser endomicroscopy (nCLE); bronchoscopy; diagnosis; lung cancer; peripheral pulmonary nodule
7. Histone acetylation adds an acetyl group on the lysine residue commonly found within the N-terminal tail protruding from the histone core of the nucleosome, and is important for chromosome structure and function in gene transcription and chromatin remodeling. Pubmed Histone acetylation adds an acetyl group on the lysine residue commonly found within the N-terminal tail protruding from the histone core of the nucleosome, and is important for chromosome structure and function in gene transcription and chromatin remodeling. Acetylation may also occur on other residues additional to lysine, but have not been thoroughly investigated at the proteomics level. Here we report a wide tolerance acetylation study mimicking the addition of 42 ± 0.5 Da delta mass modification on undefined amino acid residues of histones by shotgun proteomics using liquid chromatography-tandem mass spectrometry. A multi-blind spectral alignment algorithm with a wide peptide tolerance revealed frequent occurrence of 42 ± 0.5 Da modifications at lysine (K), serine (S) and threonine (T) residues in human histones from kidney tissues. Precision delta mass analysis identified acetylation (42.011 ± 0.004 Da) and trimethylation (42.047 ± 0.002 Da) modifications within the delta mass range. A specific antibody was produced to validate the acetylated T22 of human histone H3 (H3T22ac) by immune assays. Thus, we demonstrated that the wide tolerance acetylation approach identified histone acetylation as well as modification variants commonly associated with acetylation at undefined residues additional to lysine. acetylation; human histones; mass spectrometry; post-translational modifications; proteomics
8. Lung cancer (LC) screening will be more efficient if it is applied to a well-defined high-risk population. Pubmed Lung cancer (LC) screening will be more efficient if it is applied to a well-defined high-risk population. Characteristics including metabolic byproducts may be taken into account to access LC risk more precisely. Breath examination provides a non-invasive method to monitor metabolic byproducts. However, the association between volatile organic compounds (VOCs) in exhaled breath and LC risk or LC risk factors is not studied. Exhaled breath samples from 122 healthy persons, who were given routine annual exam from December 2015 to December 2016, were analyzed using thermal desorption coupled with gas chromatography mass spectrometry (TD-GC-MS). Smoking characteristics, air quality, and other risk factors for lung cancer were collected. Univariate and multivariate analyses were used to evaluate the relationship between VOCs and LC risk factors. 7, 7, 11, and 27 VOCs were correlated with smoking status, smoking intensity, years of smoking, and depth of inhalation, respectively. Exhaled VOCs are related to smoking and might have a potential to evaluate LC risk more precisely. Both an assessment of temporal stability and testing in a prospective study are needed to establish the performance of VOCs such as 2,5-dimethylfuranm and 4-methyloctane as lung cancer risk biomarkers. breath test; lung cancer; smoking; volatile organic compounds
9. WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Pubmed WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of Ninj1-deficient mice and found that Ninj1+/- mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1-p53 loop may be targeted to manage inflammatory diseases and cancer. Ninjurin 1; cell adhesion; inflammation; mutant p53; p53
10. While chemotherapy related cognitive disorder has been described in many studies, but we still lack relatively reliable and objective diagnostic tools, and there are few similar studies in Asian patients. Pubmed While chemotherapy related cognitive disorder has been described in many studies, but we still lack relatively reliable and objective diagnostic tools, and there are few similar studies in Asian patients. We recruited Asian breast cancer patients to perform a cohort study to uncover chemotherapy related cognitive disorder by using resting-state functioning magnetic resonance imaging (RS-fMRI) and magnetic resonance diffusion tensor imaging (DTI) combined with neuropsychologic assessments. This is the first prospective study which combines RS-fMRI and DTI to detect chemotherapy related cognitive disorder. The neuropsychologic tests and MRI were performed before and after the chemotherapy. The healthy controls were tested at matched times. The chemotherapy-treated group performed worse on memory and we found significant changes in the cerebellum, right orbitofrontal area, right middle and superior temporal gyrus, right subcentral area, left dorsolateral prefrontal cortex, and precentral gyrus in RS-fMRI after chemotherapy. We found changes in the fornix and superior fronto-occipital fasciculus with DTI. There was a correlation between some cognitive function and MRI measurements in the correlation analysis, but it was not significant after false discovery rate (FDR) multiple testing corrections. The results indicate that RS-fMRI and DTI may be a prospective application for assessing chemotherapy related cognitive disorder. breast cancer; chemotherapy; cognitive disorder; diffusion tensor imaging; resting-state functional magnetic resonance imaging
11. Glycolysis was reported to have a positive correlation with radioresistance. Pubmed Glycolysis was reported to have a positive correlation with radioresistance. Our previous study found that the miR-33a functioned as a tumor suppressor in malignant melanoma by targeting hypoxia-inducible factor1-alpha (HIF-1α), a gene known to promote glycolysis. However, the role of miR-33a-5p in radiosensitivity remains to be elucidated. We found that miR-33a-5p was downregulated in melanoma tissues and cells. Cell proliferation was downregulated after overexpression of miR-33a-5p in WM451 cells, accompanied by a decreased level of glycolysis. In contrast, cell proliferation was upregulated after inhibition of miR-33a-5p in WM35 cells, accompanied by increased glycolysis. Overexpression of miR-33a-5p enhanced the sensitivity of melanoma cells to X-radiation by MTT assay, while downregulation of miR-33a-5p had the opposite effects. Finally, in vivo experiments with xenografts in nude mice confirmed that high expression of miR-33a-5p in tumor cells increased radiosensitivity via inhibiting glycolysis. In conclusions, miR-33a-5p promotes radiosensitivity by negatively regulating glycolysis in melanoma. HIF-1α; glucose; lactate dehydrogenase A; microRNA; radiation
12. Integrin, beta-like 1 (ITGBL1), a β-integrin-related extracellular matrix protein, was found more commonly up-regulated in gastric cancer (GC) by screening and analyzing Gene Expression Omnibus (GEO) and Oncomine databases, reminding us to explore its prognostic significance in GC. Pubmed Integrin, beta-like 1 (ITGBL1), a β-integrin-related extracellular matrix protein, was found more commonly up-regulated in gastric cancer (GC) by screening and analyzing Gene Expression Omnibus (GEO) and Oncomine databases, reminding us to explore its prognostic significance in GC. In our current study, we observed that ITGBL1 expression was significantly up-regulated in GC compared with normal controls in clinical specimens. In addition, elevated ITGBL1 expression was positively correlated with patients' tumor-node-metastasis (TNM) stage and distant metastasis. Kaplan-Meier analysis indicated that high ITGBL1 expression was significantly associated with shorter survival times in GC patients. Multivariate Cox regression analysis confirmed ITGBL1 expression as an independent prognostic factor in GC. Gene set enrichment analysis (GSEA) of multiple GEO datasets revealed a close relationship between ITGBL1 expression and the KRAS/epithelial-mesenchymal transition (EMT) signaling pathway. In conclusion, these data provide evidences that ITGBL1 is a potential predictor and may be involved in cancer cell invasion and metastasis via inducing EMT, and the ITGBL1-related pathways may represent a novel therapeutic strategy for treatment of GC. EMT; ITGBL1; gastric cancer.; metastasis; prognosis
13. BACKGROUND: Although the significance of D-dimer in cancer patients has been extensively studied and plasma D-dimer levels have been reported to be abnormally high in certain types of lung cancer patients, its prognostic value for small cell lung cancer (SCLC) remains largely unknown. Pubmed BACKGROUND: Although the significance of D-dimer in cancer patients has been extensively studied and plasma D-dimer levels have been reported to be abnormally high in certain types of lung cancer patients, its prognostic value for small cell lung cancer (SCLC) remains largely unknown. METHODS: One hundred and seven newly diagnosed SCLC patients were enrolled in this study. Variables including the clinical features, pre-treatment levels of D-dimer, serum neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were extracted. The correlations between D-dimer levels and prognosis of the patient were analysed with Kaplan-Meier survival analysis. RESULTS: Plasma D-dimer levels were elevated in 57.01% of patients. Patients with extensive stage disease had higher D-dimer levels compared with those at limited stage. D-dimer levels were positively correlated with NSE and CEA levels. The elevated D-dimer levels were significantly associated with the SCLC-related mortality. Patients with elevated D-dimer levels had a shorter median survival time than those with normal levels, and a significant difference existed between the two groups. CONCLUSIONS: Increased D-dimer levels suggested a shorter survival time in SCLC patients. Pre-treatment D-dimer level is useful in estimating the prognosis of patients with SCLC. D-dimer; prognosis; small cell lung cancer (SCLC)
14. Growing evidence indicates that inflammation plays an important role in cancer progression and prognosis; however, the prognostic role of platelet to lymphocyte ratio (PLR) in colorectal cancer (CRC) is unknown. Pubmed Growing evidence indicates that inflammation plays an important role in cancer progression and prognosis; however, the prognostic role of platelet to lymphocyte ratio (PLR) in colorectal cancer (CRC) is unknown. A cohort of 1845 CRC patients from the Department of Surgical Oncology at The First Hospital of China Medical University (CMU-SO) was retrospectively analyzed. Harrell's concordance index (c-index) was used to determine the optimal cut-off value of PLR and evaluate its predictive ability. Our results from CMU-SO indicated that the overall survival (OS) rate was significantly lower in the high-PLR group compared with the low-PLR group (P = 0.001). A similar result was observed for the cancer-specific survival (CSS) rate between these two groups (P = 0.001). The multivariate analysis indicated that high PLR was an independent prognostic indicator of poor OS (hazard ratio [HR] = 1.356, 95% confidence interval [CI] = 1.117-1.647, P = 0.002) and CSS (HR = 1.364, 95% CI = 1.111-1.675, P = 0.003). In addition, the c-indexes of TNM staging combined with PLR were greater than those of TNM staging alone (OS: 0.768 vs. 0.732; CSS: 0.785 vs. 0.746). In conclusion, elevated PLR is a negative prognostic indicator of CRC and may serve as an additional index of the current TNM staging system for predicting CRC. TNM staging; colorectal cancer; meta-analysis; platelet to lymphocyte ratio; prognosis
15. Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis and rapid progression. Pubmed Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis and rapid progression. MicroRNAs (miRNAs) play important roles in carcinogenesis and tumor progression. Insulin-like growth factor 1 receptor (IGF1R) is a transmembrane heterotetrameric protein that has been reported to promote transformation to malignancy and cancer cell proliferation and survival. In this study, we found that the expression of miR-29a-3p was downregulated in HCC patients, resulting in poor survival rates. Contrastingly, the overexpression of miR-29a-3p significantly inhibited proliferation and migration in HepG2 cells. miR-29a-3p directly targeted IGF1R and down-regulated its expression. Moreover, knockdown of IGF1R led to the increased production of chemokine ligand 5 (CCL5). In tumor lesions, the local expression of CCL5 negatively affected the expression of IGF1R. Transwell analysis showed that CCL5 was important for the chemotactic movement of CD8+ T lymphocytes. The expression of CCL5 in HCC tissues positively correlated with the expression of CD8+ T lymphocyte surface marker, CD8. Patients with high CCL5 expression exhibited better survival. Our results revealed that miR-29a-3p is a tumor suppressor gene that acts by directly repressing the oncogene IGF1R, which takes part in immunoregulation in tumor microenvironments in HCC, implying that miR-29a-3p could be a potential target for HCC treatment. CCL5; IGF1R; hepatocellular carcinoma; miR-29a-3p; proliferation
16. Combination cancer treatment has emerged as a critical approach to achieve remarkable anticancer effect. Pubmed Combination cancer treatment has emerged as a critical approach to achieve remarkable anticancer effect. In this study, we prepared a theranostic nanoformulation that allows for photoacoustic imaging as well as combination gene and photothermal therapy. Gold nanorods (GNR) were coated with dipicolyl amine (DPA), which forms stable complexes with Zn2+ cations. The resulting nanoparticles, Zn(II)/DPA-GNR, recognize phosphate-containing molecules, including siRNA, because of the specific interaction between Zn(II) and the phosphates. We chose anti-polo-like kinase 1 siRNA (siPLK) as our example for gene silencing. The strong complexation between Zn(II)/DPA-GNR and siPLK provided high stability to the nano-complexes, which efficiently delivered siRNA into the targeted cancer cells in vitro and in vivo. The particle served as a theranostic agent because the GNRs of nano-complexes permitted effective photothermal therapy as well as photoacoustic imaging upon laser irradiation. This gene/photothermal combination therapy using siPLK/Zn(II)DPA-GNRs exhibited significant antitumor activity in a PC-3 tumor mouse model. The concept described in this work may be extended to the development of efficient delivery strategies for other polynucleotides as well as advanced anticancer therapy. combination therapy; dipicolylamine; gold nanorod; metal-organic complexes; photoacoustic imaging; photothermal therapy; siRNA; theranostics.
17. Chemoresistance represents a major obstacle to effective therapy for breast cancer. Pubmed Chemoresistance represents a major obstacle to effective therapy for breast cancer. Emerging evidences associated aberrantly expressed miRNAs with tumor development and chemoresistance. MiR-1268b has never been studied in any cancers before, and its roles in mediating tumor progression and drug resistance are still unclear. Selected from miRNA microarray and confirmed by real-time quantitative PCR (RT-qPCR), miR-1268b was found to be significantly upregulated in drug sensitive and ERBB2 negative tissues, as well as in breast cancer patients with low clinical stage. And miR-1268b had a higher expression in chemosensitive breast cancer cell lines, compared with the chemoresistant cell line. Moreover, the results revealed that miR-1268b induced breast cancer cell apoptosis and increased cell chemosensitivity. ERBB2 was demonstrated to be the target gene of miR-1268b by dual-luciferase reporter assays, western blot, and immunocytochemistry. Furthermore, PI3KCA, AKT, BCL2 in the ERBB2-PI3K-AKT signaling pathway were found to be downstream effectors of miR-1268b. In conclusion, miR-1268b increased chemosensitivity, at least in part, via modulation of PI3K-AKT pathway by targeting ERBB2. MiR-1268b may serve as a potential therapeutic target for patients with breast cancers. ERBB2; MiR-1268b; PI3K-AKT; breast cancer; chemoresistance
18. Many studies have investigated the diagnostic role of circulating microRNAs (miRNAs) in patients with lung cancer; however, the results still remain inconclusive. Pubmed Many studies have investigated the diagnostic role of circulating microRNAs (miRNAs) in patients with lung cancer; however, the results still remain inconclusive. An updated system review and meta-analysis was necessary to give a comprehensive evaluation of diagnostic role of circulating miRNAs in lung cancer. Eligible studies were searched in electronical databases. The sensitivity and specificity were used to plot the summary receiver operator characteristic (SROC) curve and calculate the area under the curve (AUC). The between-study heterogeneity was evaluated by Q test and I2 statistics. Subgroup analyses and meta-regression were further performed to explore the potential sources of heterogeneity. A total of 134 studies from 65 articles (6,919 patients with lung cancer and 7,064 controls) were included for analysis. Overall analysis showed that circulating miRNAs had a good diagnostic performance in lung cancers, with a sensitivity of 0.83, a specificity of 0.84, and an AUC of 0.90. Subgroup analysis suggested that combined miRNAs and Caucasian populations may yield relatively higher diagnostic performance. In addition, we found serum might serve as an ideal material to detecting miRNA as good diagnostic performance. We also found the diagnostic role of miRNAs in early stage lung cancer was still relatively high (the sensitivity, specificity and an AUC of stage I/II was 0.81, 0.82 and 0.88; and for stage I, it was 0.80, 0.81, and 0.88). We also identified a panel of miRNAs such as miR-21-5p, miR-223-3p, miR-155-5p and miR-126-3p might serve as potential biomarkers for lung cancer. As a result, circulating miRNAs, particularly the combination of multiple miRNAs, may serve as promising biomarkers for the diagnosis of lung cancer. circulating microRNAs; diagnostic value; lung cancer; meta-analysis
19. BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the expression of cytomembranic programmed death-ligand 1 (PD-L1) and its clinical significance in locoregionally advanced nasopharyngeal carcinoma (NPC). Pubmed BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the expression of cytomembranic programmed death-ligand 1 (PD-L1) and its clinical significance in locoregionally advanced nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded tissue biopsies from 85 patients with histological diagnosis of locoregionally advanced NPC treated with radical intensity-modulated radiotherapy and concurrent cisplatin-based chemotherapy were studied. By using immunohistochemistry staining, expressions of cytomembranic PD-L1 on tumor cells were detected. RESULTS: After a median follow-up duration of 65.8 months, 7 (8.2%), 5 (5.9%), and 5 (5.9%) patients suffered from local failure, regional failure, and distant metastases, respectively. The 5-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival (OS) rates were 90.9%, 94.8%, 94.0%, and 92.2%, respectively. Our results revealed that a high expression of cytomembranic PD-L1 was correlated with shorter OS (5y-OS: 82.5% vs 97.6%, P=0.022). In the multivariate analysis, only the cytomembranic PD-L1 was an independent prognostic factor for OS (hazard ratio: 6.176, 95% confidence interval, 1.166-32.710, P=0.032). CONCLUSION: Cytomembranic PD-L1 expression levels correlated with OS in locoregionally advanced NPC. Agreement between different methods is needed for further application of PD-L1 biomarker assays in NPC. PD-L1; nasopharyngeal carcinoma; overall survival; prognosis; programmed death-ligand 1
20. In traditional Chinese medicine, Fuzi is widely used as an antitumor agent or an adjuvant medication combined with radiotherapy and chemotherapy, but its mechanism remains unclear. Pubmed In traditional Chinese medicine, Fuzi is widely used as an antitumor agent or an adjuvant medication combined with radiotherapy and chemotherapy, but its mechanism remains unclear. In this study, we investigated anti-tumor and immunoregulation efficacy of Fuzi combined with radiotherapy in mice with Lewis lung cancer (LLC). We found that Fuzi combined with radiotherapy significantly inhibited the growth of LLC, promoted the apoptosis of cancer cells, and prolonged the survival of mice with LLC. Mechanistically, we found that Fuzi decreased the proportion of Treg cells, reduced serum levels of cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β, and downregulated the expression of programmed death ligand-1 in mice with LLC subjected to radiotherapy. This study suggests that Fuzi has immunomodulation function to act as radiosensitizer and improve radiotherapy against lung cancer. Fuzi; Lung cancer.; PD-L1; Radiotherapy; TGF-β; Treg cells
21. Rationale To investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Pubmed Rationale To investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods Eligible patients were included and blood samples were collected from a phase III trial. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment in a 1.15M size panel covering exon regions of 1,086 genes. Molecular mutational burden (MMB) was calculated to investigate the relationship between molecular features of cfDNA and response to chemotherapy. Results In total, 52 eligible cases were enrolled and their blood samples were prospectively collected at baseline, every cycle of chemotherapy and time of disease progression. At baseline, alterations of 17 genes were found. Patients with partial response (PR) had significantly lower baseline MMB of these genes than those patients with either stable disease (SD) (P = 0.0006) or progression disease (PD) (P = 0.0074). Further analysis revealed that the mutational landscape of cfDNA from pretreatment blood samples were distinctly different among patients with PR vs. SD/PD. For patients with baseline TP53 mutation, those with PR experienced a significant reduction in MMB whereas patients with SD or PD experienced an increase after two, three or four cycles of chemotherapy. Furthermore, patients with low MMB had superior response rate and significantly longer progression-free survival than those with high MMB. Conclusion This study indicated that the mutational landscape of cfDNA has potential clinical value to predict the therapeutic response to first-line platinum-based doublet chemotherapy in NSCLC patients. At the single gene level, dynamic change of molecular mutational burden of TP53 is valuable to monitor efficacy (and, therefore, might aid in early recognition of resistance and relapse) in patients harboring this mutation at baseline. Non-small-cell lung cancer; chemotherapy; circulating cell-free DNA; molecular mutational burden
22. We aimed to characterize the trends and projections of cancer mortalities in Yangpu, an industry restructuring district of Shanghai, China. Pubmed We aimed to characterize the trends and projections of cancer mortalities in Yangpu, an industry restructuring district of Shanghai, China. With high-quality data from the death registration system, the authors analyzed the trends in cancer mortalities during 1974-2014 and their relationship with pollution control and socioeconomic improvements. Cancer burden was projected into 2029. During 1974-2014, cancer death accounted for 28.80% of all-cause death. The 5 leading causes of cancer death were cancers of the lung & bronchus, stomach, liver, colon & rectum, and esophagus. Age-standardized mortality of all cancers was higher in men than in women (153.1/105vs. 88.8/105, p<0.001) and increased from 1974 to 1991 and decreased thereafter. The mortalities of cancers of the larynx, bladder, liver, nasopharynx, lung & bronchus, esophagus, lip oral & pharynx, stomach, kidney, and lymphoma were significantly higher in men than in women. Age-standardized mortalities of cancers of the esophagus, stomach, leukemia, female nasopharynx, female bladder, liver, and bone decreased especially after the 1990s, those of the colon & rectum, kidney, prostate, pancreas, breast, gallbladder, and ovary increased significantly. Lung cancer, breast cancer, colorectal cancer, and pancreas cancer in women and lung cancer, colorectal cancer, prostate cancer, and stomach cancer in men will be the leading causes of cancer death in 2025-2029. Cancer-caused life loss kept increasing since 2000. Conclusively, cancers associated with pollutions and infection decreased, especially after the 1990s, while those related to metabolic syndrome increased. These trends are related to closedown of polluted industries in the 1980s and lifestyle changes. age-standardized mortality; cancer-caused life loss; lifestyle; pollution
23. Deregulated activity of the c-Myc protooncogene is a frequent molecular event underlying mouse and human hepatocarcinogenesis. Pubmed Deregulated activity of the c-Myc protooncogene is a frequent molecular event underlying mouse and human hepatocarcinogenesis. Nonetheless, the mechanisms sustaining c-Myc oncogenic activity in liver cancer remain scarcely delineated. Recently, we showed that the mammalian target of rapamycin complex 1 (mTORC1) cascade is induced and necessary for c-Myc dependent liver tumor development and progression. Since the heat shock factor 1 (HSF1) transcription factor is a major positive regulator of mTORC1 in the cell, we investigated the functional interaction between HSF1 and c-Myc using in vitro and in vivo approaches. We found that ablation of HSF1 restrains the growth of c-Myc-derived mouse hepatocellular carcinoma (HCC) cell lines, where it induces downregulation of c-Myc levels. Conversely, silencing of c-Myc gene in human and mouse HCC cells led to downregulation of HSF1 expression. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery resulted in the complete inhibition of mouse hepatocarcinogenesis driven by overexpression of c-Myc. Altogether, the present results indicate that a functional HSF1 is necessary for c-Myc-driven hepatocarcinogenesis. Consequently, targeting HSF1 might represent a novel and effective therapeutic strategy for the treatment of HCC subsets with activated c-Myc signaling. HSF1; c-Myc; hepatocellular carcinoma; liver cancer; signalling pathways
24. AIM: To conduct a meta-analysis to determine the relative merits between robotic video-assisted thoracoscopic surgery (R-VATS) and conventional video-assisted thoracoscopic surgery (VATS) for lung cancer. Pubmed AIM: To conduct a meta-analysis to determine the relative merits between robotic video-assisted thoracoscopic surgery (R-VATS) and conventional video-assisted thoracoscopic surgery (VATS) for lung cancer. RESULTS: Fifteen studies matched the selection criterion, which reported 8827 subjects, of whom 1704 underwent R-VATS and 7123 underwent VATS. Compared the perioperative outcomes with VATS, reports of R-VATS indicated unfavorable outcomes considering the operative time (SMD = 0.48, 95% CI 0.15 to 0.81). Meanwhile, the number of dissected lymph nodes (SMD = 0.12, 95% CI -0.27 to 0.51) and hospital stay following surgery (SMD = -0.1; 95% CI -0.27 to 0.07), conversion (RR = 0.68; 95% CI 0.42 to 1.11), morbidity (RR = 0.99, 95% CI 0.92 to 1.07) and mortality (RR = 0.33, 95% CI 0.1 to 1.09) were similar for both procedures. MATERIALS AND METHODS: A literature search was performed to identify comparative studies reporting perioperative outcomes for R-VATS and VATS for lung cancer. Pooled risk ratio (RR) and standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated using either the fixed effects model or the random effects model. CONCLUSIONS: There is no difference in terms of perioperative outcomes between R-VATS and VATS except for the operative time which is significantly high for R-VATS. Further studies are required to confirm these results. da Vinci robotic system; lung cancer; meta-analysis; robotic; video-assisted thoracoscopic surgery
25. Tumor recurrence in gliomas is partly attributed to increased epithelial-mesenchymal transition (EMT) and enhanced tumor cell dissemination in the adjacent brain parenchyma. Pubmed Tumor recurrence in gliomas is partly attributed to increased epithelial-mesenchymal transition (EMT) and enhanced tumor cell dissemination in the adjacent brain parenchyma. Thus, exploring effective strategies for against EMT-like changes in glioma invasion and recurrence will be important for glioma treatment. In this study, we investigated the roles of melatonin in hypoxia-induced EMT suppression, and found that melatonin could significantly suppress the release of the cytokine, CCL20, from cancer cells and antagonize glioma cell metastasis and invasion under hypoxic stress in glioma cells. Furthermore, our findings show that melatonin deregulates Smad7 expression to suppress TGFβ/Smad-mediated increase in CCL20 transcript levels and CCL20-induced EMT occurrence, suggesting a potential anti-EMT therapeutic role for melatonin in malignant transformation in gliomas. CCL20; epithelial–mesenchymal transition (EMT); glioma; melatonin
26. Drug resistance is becoming an obstacle in anti-cancer therapies. Pubmed Drug resistance is becoming an obstacle in anti-cancer therapies. For target-based therapy of lung cancer, gefitinib, as the first generation of tyrosine kinase inhibitors (TKIs), demonstrated good initial response to the non-small cell lung cancer (NSCLC) patients whom harbors epidermal growth factor receptor (EGFR) mutation. However, within one year, additional EGFR mutation occurred, leading to eventual gefitinib-resistance. Therefore, it is urgently to discover novel effective small molecule inhibitors for those patients. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5'-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have identified a novel direct AMPK agonist, D561-0775 from a compound library by using molecular docking screening technique. We demonstrated that D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but less cytotoxicity on normal cells. Furthermore, D561-0775 demonstrated a remarkable in vitro AMPK enzyme activation effect. Taken together, D561-0775 showed potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells. D561-0775 has provided a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly. NSCLC; gefitinib-resistant; lipid metabolism; novel AMPK activator
27. BACKGROUND: Aimed to identify the benefit population from continuation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), this study investigated the efficacy of continuation of EGFR-TKIs plus chemotherapy beyond the response evaluation criteria in solid tumors-progressive disease (RECIST-PD) according to different progression modes and T790M mutational status. Pubmed BACKGROUND: Aimed to identify the benefit population from continuation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), this study investigated the efficacy of continuation of EGFR-TKIs plus chemotherapy beyond the response evaluation criteria in solid tumors-progressive disease (RECIST-PD) according to different progression modes and T790M mutational status. METHODS: From November 2009 to July 2015, 630 patients with advanced non-small cell lung cancer (NSCLC) receiving gefitinib as initial EGFR-TKI treatment were screened in Shanghai Pulmonary Hospital. A total of 170 patients with documented gradual or dramatic progression after gefitinib treatment who received chemotherapy alone or in combination with gefitinib were included. Post-RECIST-PD progression-free survival (PPFS) between continuation of gefitinib plus chemotherapy and chemotherapy alone was assessed. RESULTS: The incidence of T790M mutation was 42.9% (63/147) in patients who got acquired resistance in this study. Median PPFS was 4.0 months [95% confidence interval (CI), 3.1-4.9 months] in the chemotherapy group and 5.0 months (95% CI, 3.6-6.4 months) in the combination group with a borderline statistical significance (P=0.071). Continuation of gefitinib plus chemotherapy resulted in a significant improvement in PPFS compared with chemotherapy alone in patients with EGFRT790M-negative tumors [median PPFS: 6.6 vs. 3.5 months, hazard ratio (HR) 0.50, 95% CI, 0.29-0.88; P=0.011], especially in pemetrexed-based chemotherapy (HR 0.45, 95% CI, 0.24-0.86; P=0.011). PPFS was similar in patients with EGFRT790M-positive tumors (median PPFS: 5.0 vs. 5.5 months, HR 0.80, 95% CI, 0.40-1.61; P=0.520) or EGFRT790M-unknown tumors (median PPFS: 2.0 vs. 3.0 months, HR 1.40, 95% CI, 0.69-2.81; P=0.323). CONCLUSIONS: Our study showed that continuous gefitinib plus chemotherapy, especially pemetrexed-based therapy, significantly improved PPFS in patients with EGFRT790M-negative tumors as compared with chemotherapy alone, suggesting that this subtype of patients may derive clinical benefit from continuation of gefitinib treatment beyond progression. EGFR tyrosine kinase inhibitor (EGFR-TKI); Non-small-cell lung cancer (NSCLC); acquired resistance; continuation; epidermal growth factor receptor (EGFR)
28. Chemotherapeutic insensitivity remains one of the major obstacles in clinical treatment of lung squamous cell carcinoma (LSCC). Pubmed Chemotherapeutic insensitivity remains one of the major obstacles in clinical treatment of lung squamous cell carcinoma (LSCC). Recently, increasing evidence has suggested that long non-coding RNAs (lncRNAs) promote tumorigenesis in many cancer types. However, the potential biological roles and regulatory mechanisms of lncRNAs in response to cisplatin treatment are poorly understood. Here, we found that lncRNA SFTA1P (surfactant associated 1, pseudogene), highly expressed in lung, was down-regulated in LSCC tissues and could be induced upon cisplatin treatment in LSCC cells. Elevated SFTA1P induced apoptosis and enhanced the sensitivity to cisplatin of LSCC cells. We further identified that hnRNP-U (heterogeneous nuclear ribonucleoprotein U) was down-regulated in LSCCs and positively correlated with patients' poor prognosis as well as SFTA1P. Mechanistic studies revealed that SFTA1P could up-regulate hnRNP-U expression. In addition, we identified that hnRNP-U enhanced cisplatin-induced apoptosis through up-regulation of GADD45A, high expression of which was correlated with good prognosis in LSCC patients. Our findings demonstrated that SFTA1P might serve as a useful biomarker for LSCC diagnosis and a predictor for cisplatin chemotherapy response in patients with LSCC. apoptosis; cisplatin chemosensitivity; hnRNP-U- GADD45A; long noncoding RNA SFTA1P; lung squamous cell carcinoma
29. A biodegradable drug delivery system (DDS) is one the most promising therapeutic strategies for cancer therapy. Pubmed A biodegradable drug delivery system (DDS) is one the most promising therapeutic strategies for cancer therapy. Here, we propose a unique concept of light activation of black phosphorus (BP) at hydrogel nanostructures for cancer therapy. A photosensitizer converts light into heat that softens and melts drug-loaded hydrogel-based nanostructures. Drug release rates can be accurately controlled by light intensity, exposure duration, BP concentration, and hydrogel composition. Owing to sufficiently deep penetration of near-infrared (NIR) light through tissues, our BP-based system shows high therapeutic efficacy for treatment of s.c. cancers. Importantly, our drug delivery system is completely harmless and degradable in vivo. Together, our work proposes a unique concept for precision cancer therapy by external light excitation to release cancer drugs. If these findings are successfully translated into the clinic, millions of patients with cancer will benefit from our work. NIR-light responsive; black phosphorus; cancer therapy; drug delivery; hydrogel
30. Cancer is still a global public health problem, which is the leading cause of death in most countries. Pubmed Cancer is still a global public health problem, which is the leading cause of death in most countries. Ginseng has been used for centuries all over the world as a panacea that promotes longevity. As the king of herb plants, ginseng holds great promise as a new treatment option which is used either by itself or in combination with other medicinal ingredients that is widely accepted as complementary and alternative medicine in cancer therapy. Ginsenosides, the major pharmacologically active ingredients of ginseng, have been shown to have multiple medicinal effects including prominent anticancer activity. The purpose of this review is to give our perspective about the roles of ginsenosides in reactive oxygen species (ROS)-mediated anticancer therapy. Additionally, to provide new sheds light for further improvement and carry out pre-clinical and clinical trials to develop it successfully into a potential anticancer agent. Panax herbs and their derivate/metabolites ginsenosides exert beneficial effects for treating various types of cancers. The mechanism of ROS-mediated anticancer activities of ginsenosides varies depending on the specific type of cancer cells involved. Ginsenosides may suppress cancer cell proliferation through anti-oxidation on tumor initiation and induce apoptosis, paraptosis or autophagy via generation of ROS on tumor progression, promotion, angiogenesis, invasion and metastasis by various signaling pathways e.g., activation of AMPK, MEK, ASK-1/JNK, ESR2-NCF1-ROS, ER-dependent PI3K/Akt/Nrf2, P53-CHOP, ROS-JNK-autophagy, and/or inhibition of PI3K/Akt signaling pathways. These multiple effects rather than a single may play a crucial role in emerging ginsenosides as a successful anticancer drug. ROS; anticancer therapy; cancer; ginsenosides; mechanism
31. cMet signaling pathway is involved in the resistance to anti-VEGF therapy and cMet overexpression is associated with tumor progression and poor prognosis. Pubmed cMet signaling pathway is involved in the resistance to anti-VEGF therapy and cMet overexpression is associated with tumor progression and poor prognosis. In this study, the expression of cMet in 146 Chinese colorectal cancer (CRC) patients was examined by immunohistochemistry staining. Our data demonstrated that cMet overexpression rate was 42.5% (62/146) and cMet overexpression was closely correlated with distant metastasis of CRC. Using CRC patient-derived xenograft (PDX) mouse models we investigated antitumor activity of a novel selective cMet inhibitor volitinib alone or in combination with anti-VEGF inhibitor apatinib in vivo. Our results showed that combination treatment significantly inhibited tumor growth in two PDX models. While volitinib treatment alone induced moderate improvement in tumor growth inhibition, combination treatment synergistically reduced microvessel density, suppressed proliferation, and increased apoptosis in PDX models. Further analysis showed synergistic inhibition of MAPK and PI3K/Akt pathways by volitinib and apatinib. Taken together, our data provide a rationale to targeting both cMet and VEGF in the treatment of cMet overexpressing CRC in clinical trials. Apatinib; Colorectal cancer; PDX; Volitinib; cMet


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