The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution.

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity1. In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool2, we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

Loss of N-Acetylgalactosaminyltransferase-4 Orchestrates Oncogenic MicroRNA-9 in Hepatocellular Carcinoma.

Deregulated expression of N-acetylgalactosaminyltransferases (GALNTs), which is responsible for the initial step of mucin-type O-glycosylation, could produce abnormal truncated O-glycans and thereby exert pivotal functions during malignant transformation. GALNT4 is one of the few isoforms preferring to catalyze partial GalNAc-glycosylated substrates and modify the sites not utilized by other known GALNTs. This study aims to evaluate the impact of GALNT4 expression on malignant transformation of hepatocellular carcinoma (HCC). Immunohistochemistry and in situ hybridization analysis were performed to assess GALNT4 and miR-9 level in clinical specimens, respectively. GALNT4 expression is markedly repressed in primary HCC tissues, and reduced expression of GALNT4 is significantly associated with adverse survival of patients with HCC. Functional investigations demonstrate that repressed GALNT4 could promote migration, invasion, anoikis resistance, and stemness of HCC cells in vitro as well as tumor growth in vivo The wild-type GALNT4 could modify O-linked glycosylation on EGFR and thus modulate the activity of EGFR. A luciferase activity assay further identified microRNA-9 (miR-9) as the crucial specific arbitrator for GALNT4 expression in HCC cells. Furthermore, restoring GALNT4 expression attenuates miR-9-mediated oncogenic functions. Kaplan-Meier survival analysis indicates that the miR-9/GALNT4 expression signature yields promising prognostic significance to refine the risk stratification of patients with HCC. In conclusion, this study establishes the miR-9/GALNT4 axis as a potential adverse prognostic factor and therapeutic target for HCC patients.

Tumor Suppressive Function of p21-activated Kinase 6 in Hepatocellular Carcinoma.

Our previous studies identified the oncogenic role of p21-activated kinase 1 (PAK1) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Contrarily, PAK6 was found to predict a favorable prognosis in RCC patients. Nevertheless, the ambiguous tumor suppressive function of PAK6 in hepatocarcinogenesis remains obscure. Herein, decreased PAK6 expression was found to be associated with tumor node metastasis stage progression and unfavorable overall survival in HCC patients. Additionally, overexpression and silence of PAK6 experiments showed that PAK6 inhibited xenografted tumor growth in vivo, and restricted cell proliferation, colony formation, migration, and invasion and promoted cell apoptosis and anoikis in vitro. Moreover, overexpression of kinase dead and nuclear localization signal deletion mutants of PAK6 experiments indicated the tumor suppressive function of PAK6 was partially dependent on its kinase activity and nuclear translocation. Furthermore, gain or loss of function in polycomb repressive complex 2 (PRC2) components, including EZH2, SUZ12, and EED, elucidated epigenetic control of H3K27me3-arbitrated PAK6 down-regulation in hepatoma cells. More importantly, negative correlation between PAK6 and EZH2 expression was observed in hepatoma tissues from HCC patients. These data identified the tumor suppressive role and potential underlying mechanism of PAK6 in hepatocarcinogenesis.

Decreased expression of hepatocyte nuclear factor 4α (Hnf4α)/microRNA-122 (miR-122) axis in hepatitis B virus-associated hepatocellular carcinoma enhances potential oncogenic GALNT10 protein activity.

MicroRNA-122 (miR-122), a mammalian liver-specific miRNA, has been reported to play crucial roles in the control of diverse aspects of hepatic function and dysfunction, including viral infection and hepatocarcinogenesis. In this study, we explored the clinical significance, transcriptional regulation, and direct target of miR-122 in hepatitis B virus (HBV)-associated hepatocellular carcinoma. Reduced expression of miR-122 in patients with HBV-associated hepatocellular carcinoma was correlated with venous invasion and poor prognosis. Furthermore, UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase-10 (GALNT10) was identified as a bona fide target of miR-122 in hepatoma cells. Ectopic expression and knockdown studies showed that GALNT10 indeed promotes proliferation and apoptosis resistance of hepatoma cells in a glycosyltransferase-dependent manner. Critically, adverse correlation between miR-122 and GALNT10, a poor prognosticator of clinical outcome, was demonstrated in hepatoma patients. Hepatocyte nuclear factor 4α (Hnf4α), a liver-enriched transcription factor that activates miR-122 gene transcription, was suppressed in HBV-infected hepatoma cells. Chromatin immunoprecipitation assay showed significantly reduced association of Hnf4α with the miR-122 promoter in HBV-infected hepatoma cells. Moreover, GALNT10 was found to intensify O-glycosylation following signal activation of the epidermal growth factor receptor. In addition, in a therapeutic perspective, we proved that GALNT10 silencing increases sensitivity to sorafenib and doxorubicin challenge. In summary, our results reveal a novel Hnf4α/miR-122/GALNT10 regulatory pathway that facilitates EGF miR-122 activation and hepatoma growth in HBV-associated hepatocarcinogenesis.

Increased expression of interleukin-8 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma.

On the basis of aberrant interleukin-8 (IL-8) expression, a crucial angiogenesis factor and potential therapeutic target, in clear-cell renal cell carcinoma (ccRCC), this study aims to assess the prognostic significance of IL-8 in ccRCC. This retrospective study enrolled 271 patients who underwent nephrectomy for ccRCC in a single institution. The associations of IL-8 expression with clinical and pathological features were assessed using chi-squared tests. The impact on cancer-specific survival (CSS) and relapse-free survival (RFS) was analyzed using univariable and multivariable Cox regression models. The area under the receiver operating characteristic (ROC) curve (AUC) was used as an index of prognostic performance. Intratumoral IL-8 was found to be significantly elevated in ccRCC tissues compared with peritumor tissue and be predominately localized in the cytoplasm. Moreover, high IL-8 expression was positively correlated with Fuhrman grade (P < 0.001). Multivariate Cox regression analysis identified IL-8 as an independent adverse prognostic factor of CSS (P < 0.001) and RFS (P < 0.001), which could be incorporated into the traditional TNM staging system to improve the prognostic value for CSS and RFS in ccRCC patients. The predictive accuracy of traditional TNM stage model was significantly improved when IL-8 expression was added. Increased expression of IL-8 is a potential independent adverse prognostic biomarker for CSS and RFS in patients with ccRCC after nephrectomy.

High expression of interleukin-11 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma.

Interleukin-11 (IL-11), a member of the IL-6 family of cytokines, exerts pleiotropic oncogenic activities by stimulating angiogenesis and metastasis in many cancer types. The present study aims to evaluate the impact of IL-11 expression on recurrence and mortality of patients with clear-cell renal cell carcinoma (ccRCC). We retrospectively enrolled 193 ccRCC patients undergoing nephrectomy at a single center. Clinicopathologic features, recurrence-free survival (RFS) and overall survival (OS) were recorded. IL-11 intensity was assessed by immunohistochemistry in tumor specimens. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on RFS and OS. The concordance index (C-index) was calculated to assess predictive accuracy. High IL-11 expression is associated with increased risk of recurrence and poor survival for ccRCC patients (P < 0.001 and P < 0.001, respectively), especially those with early-stage disease (TNM stage I + II). Multivariate analyses confirmed that IL-11 expression was an independent prognostic factor for RFS and OS (P = 0.006 and P = 0.008, respectively). The predictive accuracy of well-established prognostic models was improved when IL-11 expression was integrated. In conclusion, high IL-11 expression is an independent predictor of poor prognosis in ccRCC patients. It may help identify patients who could benefit from additional treatments and closer follow up.

Galectin-9 predicts postoperative recurrence and survival of patients with clear-cell renal cell carcinoma.

Galectin-9 (Gal-9), a member of animal lectin family with evolutionary conserved carbohydrate recognition domains, has been reported to exert a large variety of functional roles in tumorigenesis due to its ß-galactoside-binding affinity. The aim of this study is to evaluate the expression and prognostic significance of Gal-9 in patients with clear-cell renal cell carcinoma (ccRCC). The expression of Gal-9 was assessed by immunohistochemistry in 196 patients with ccRCC who underwent nephrectomy. In the cohort, 48 patients died and 61 patients suffered recurrence. Kaplan-Meier method with log-rank test was applied to compare survival curves. The authors employed univariate and multivariate Cox regression models to evaluate the prognostic value of Gal-9 expression in overall survival (OS) and recurrence-free survival (RFS). In patients with ccRCC, Gal-9 expression, which was positively associated with tumor size (P = 0.014), Fuhrman grade (P = 0.010), and necrosis (P = 0.025), was determined to be an independent prognostic indicator for OS (hazard ratio [HR] 2.394; P = 0.005) and RFS (HR 2.096; P = 0.006). High expression of Gal-9 was associated with poor survival (P = 0.001) and early recurrence (P = 0.006). Furthermore, Gal-9 expression could significantly stratify the patients in early (grades I + II) tumor, node, and metastasis (TNM) stage (OS: P = 0.005; RFS: P = 0.041) and low (grades 1 + 2) Fuhrman grade (OS: P = 0.004; RFS: P = 0.006). The prognostic accuracy of TNM, SSIGN, and UISS prognostic models was improved when Gal-9 expression was added. Gal-9 expression is a potential independent prognostic factor for OS and RFS in patients with ccRCC.

Prognostic value of purinergic P2X7 receptor expression in patients with hepatocellular carcinoma after curative resection.

The family of type 2 purinergic (P2) receptors, especially P2X7, is responsible for the direct tumor-killing functions of extracellular adenosine triphosphate (ATP), but the precise role of P2X7 in the progression of hepatocellular carcinoma (HCC) remains elusive. This study aims to evaluate prognostic value of P2X7 expression in HCC patients after surgical resection. Expression of P2X7 was assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissues from 273 patients with HCC who had undergone hepatectomy between 2006 and 2007. Prognostic value of P2X7 expression and clinical outcomes were evaluated. Peritumoral P2X7 expression was significantly higher than intratumoral P2X7 expression. No significant prognostic difference was observed for overall survival for intratumoral P2X7 density, whereas peritumoral P2X7 density indicates unfavorable overall survival in training set and BCLC stage 0-A subset. Besides, peritumoral P2X7 density, which correlated with tumor size, venous invasion, and BCLC stage, was identified as an independent poor prognosticator for overall survival and recurrence-free survival. The association was further validated in validation set. Peritumoral P2X7 is a potential unfavorable prognosticator for overall survival and recurrence free survival in HCC patients after surgical resection. Further external validation and functional analysis should be pursued to evaluate its potential prognostic value and therapeutic significance for HCC patients.

ß1,6-N-acetylglucosaminyltransferase V predicts recurrence and survival of patients with clear-cell renal cell carcinoma after surgical resection.

PURPOSE: ß1,6-N-acetylglucosaminyltransferase V (MGAT5), which is required for the biosynthesis of ß1,6GlcNAc-branched N-linked glycans attached to cell surface and secreted glycoproteins, accounts for oncogenic growth signal transduction during the development and progression of various malignancies. Our present study aimed to evaluate the impact of MGAT5 expression on recurrence and survival of patients with clear-cell renal cell carcinoma (ccRCC) following surgery. METHODS: We retrospectively enrolled 265 patients (196 in the training cohort and 69 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, overall survival (OS) and recurrence-free survival (RFS) were recorded. MGAT5 intensities were assessed by immunohistochemistry in specimens of patients. Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on OS and RFS. Concordance index (C-index) was calculated to assess predictive accuracy. RESULTS: In both cohorts, MGAT5 expression positively correlated with metastatic and advanced TNM stage. High MGAT5 expression indicated poor survival (P < 0.001 in training set and P < 0.001 in validation set) and early recurrence (P < 0.001 in training set and P = 0.004 in validation set) of patients with ccRCC. After multivariate Cox regression analysis, MGAT5 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of TNM, UISS and SSIGN prognostic models was improved when MGAT5 expression was added. CONCLUSIONS: MGAT5 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.

Prognostic significance of ß1,6-N-acetylglucosaminyltransferase V expression in patients with hepatocellular carcinoma.

OBJECTIVE: Alterations to the N-glycans in glycoproteins have been suggested to play important roles in the proliferation, differentiation, invasion and metastasis of hepatocellular carcinoma (HCC). This study aims to evaluate the potential prognostic value of ß1,6-N-acetylglucosaminyltransferase V (Mgat5) in hepatocellular carcinoma patients after surgical resection. METHODS: We retrospectively enrolled 300 patients (156 in the training cohort and 144 in the validation cohort) with hepatocellular carcinoma undergoing hepatectomy at a single institution. Mgat5 intensities were assessed by immunohistochemistry in the specimens of patients. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on overall survival and recurrence-free survival. The concordance index was calculated to assess predictive accuracy. RESULTS: Intratumoral Mgat5 expression was significantly higher than non-tumoral tissues (P < 0.001). In both cohorts, elevated Mgat5 expression in tumor tissues positively correlated with vascular invasion and advanced tumor-node-metastasis stage. High Mgat5 expression indicated poor survival (P < 0.001 in the training cohort and P < 0.001 in the validation cohort) and recurrence (P < 0.001 in both cohorts, respectively) in patients with hepatocellular carcinoma, particularly with early-stage disease. Mgat5 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of tumor-node-metastasis and Barcelona Clinic Liver Cancer prognostic models was improved when Mgat5 expression was added. CONCLUSION: Mgat5 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with hepatocellular carcinoma after hepatectomy.

p21-activated kinase 1 predicts recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma.

OBJECTIVES: To estimate the impact of p21-activated kinase 1 expression on recurrence and survival of patients with non-metastatic clear cell renal cell carcinoma after surgical resection. METHODS: We retrospectively enrolled 254 patients (187 in the training cohort and 67 in the validation cohort) with non-metastatic clear cell renal cell carcinoma undergoing nephrectomy at a single institution. Clinicopathological features, overall survival and recurrence-free survival were recorded. p21-activated kinase 1 intensities were assessed by immunohistochemistry of patients' specimens. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on overall survival and recurrence-free survival. The concordance index was calculated to assess predictive accuracy. RESULTS: In both cohorts, elevated p21-activated kinase 1 expression in tumor tissues positively correlated with advanced T stage and Fuhrman grade. High p21-activated kinase 1 expression indicated poor survival and early recurrence of patients with non-metastatic clear cell renal cell carcinoma, especially with early T1-2 stage disease. After backward elimination, p21-activated kinase 1 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of the traditional University of California Integrated Staging System and Mayo Clinic stage, size, grade and necrosis prognostic models was improved when p21-activated kinase 1 expression was added. CONCLUSIONS: Elevated expression of p21-activated kinase 1 seems to be an independent adverse prognostic biomarker for recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma after nephrectomy.

GALNT4 predicts clinical outcome in patients with clear cell renal cell carcinoma.

PURPOSE: We investigated the clinical significance of GALNT4 expression in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: Enrolled in this study were 104 patients treated with curative nephrectomy at Zhongshan Hospital, Shanghai during 2004. Of the cohort 23 patients died of disease, 33 experienced recurrence and 3 died of another cause. GALNT4 density was assessed by immunohistochemistry in patient specimens. Univariate and multivariate Cox models, and ROC analysis were used to analyze the impact of prognostic factors on overall and relapse-free survival. Kaplan-Meier analysis with the log rank test was done to compare clinical outcomes between subgroups. RESULTS: Intratumor GALNT4 expression was significantly lower than peritumor expression. Low GALNT4 expression was associated with poor overall and relapse-free survival (p = 0.001 and 0.004, respectively). Intratumor GALNT4 expression, which negatively correlated with tumor size (p = 0.032), necrosis (p = 0.013) and TNM stage (p = 0.017), was an independent prognostic indicator for overall and relapse-free survival (HR 3.088, p = 0.020 and 2.173, p = 0.047, respectively). Extending the TNM staging system according to GALNT4 expression showed a better prognostic value for overall and relapse-free survival (AUC 0.786, p = 0.029 and 0.761, p = 0.040, respectively). CONCLUSIONS: Intratumor GALNT4 expression is a potential independent prognostic factor for overall and relapse-free survival in patients with clear cell renal cell carcinoma. Further external validation and functional analysis should be performed to assess its potential prognostic and therapeutic value in patients with clear cell renal cell carcinoma.

Prognostic significance of p21-activated kinase 6 expression in patients with clear cell renal cell carcinoma.

PURPOSE: To investigate prognostic values of intratumoral p21-activated kinase 6 (PAK6) expression in patients with clear cell renal cell carcinoma (ccRCC). METHODS: Immunohistochemistry in tissue microarray was used to evaluate the expression of PAK6 in 104 patients who had undergone nephrectomy at Zhongshan Hospital of Fudan University. Prognostic value and clinical outcomes were evaluated. RESULTS: Intratumoral PAK6 expression was significantly lower than nontumoral tissues (P < 0.001). Moreover, low expression of PAK6 was associated with unfavorable overall survival (OS) (P = 0.001) and recurrence-free survival (RFS) (P = 0.001). In the subgroup of patients with tumor, node, metastasis classification system (TNM) stage I + II disease, those with low expression of PAK6 were prone to have poor OS (P = 0.014) and RFS (P = 0.037). Intratumoral PAK6 low expression was correlated with tumor size (P = 0.001) and TNM stage (P = 0.006), and was identified as an independent prognostic factor for OS (hazard ratio 4.109, P = 0.002) and RFS (hazard ratio 3.175, P = 0.002). Use of an extended TNM staging system with intratumoral PAK6 expression showed a better prognostic value for OS [area under the receiver operating characteristic curve (AUC) 0.790, P = 0.022] and RFS (AUC 0.769, P = 0.040). The c-index of a Cox-based model combined with Eastern Cooperative Oncology Group performance status, TNM stage, Fuhrman grade, and PAK6 was 0.83 for OS and 0.80 for RFS. CONCLUSIONS: Intratumoral PAK6 could be a potential prognosticator for OS and RFS in ccRCC patients after nephrectomy. Further external validation and functional analysis should be pursued to assess its potential prognostic and therapeutic values for ccRCC patients.

Attitudes, practices and information needs regarding novel influenza A (H7N9) among employees of food production and operation in Guangzhou, Southern China: a cross-sectional study.

BACKGROUND: As of 30 May 2013, 132 human infections with avian influenza A (H7N9) had been reported in 10 Chinese cities. On 17 May 2013, because a chicken infection with H7 subtype avian influenza virus was detected in Guanzhou, Guangzhou became the 11th city to conduct emergency response operations. The goal of this study was to identify attitudes, practices and information needs among employees of food production and operation in Guangzhou. METHODS: A cross-sectional survey of face-to-face interviews was used during 17-24 June 2013. All adults seeking health examination in Guangzhou Center for Disease Control and Prevention who had lived in Guangzhou for at least 3 months, were engaged in food production and operation, and agreed to participate were interviewed. RESULTS: Of 1,450 participants, 69.72% worried about being infected with the A/H7N9 and 74.41% stated that they had searched for information about A/H7N9. The internet (76.92%), television (67.56%), and newspapers (56.26%) were the main methods of obtaining information; the use of these methods differed significantly by various demographic variables (P < 0.05). More than one-fifth of participants complained that the information was not timely enough (20.28%) and was intentionally concealed by the government (20.76%). Nearly one-third (32.35%) did not believe that the government could control the A/H7N9 epidemic. Most participants (80.76%) reported washing hands more frequently than before, while over one-third (37.17%) stated no longer buying poultry. A total of 84.00% indicated a willingness to receive an A/H7N9 vaccine, and the primary reason for not being willing was concern about safety (58.19%). A history of influenza vaccination and worry about being infected with the A/H7N9 were significantly associated with intention to receive an A/H7N9 vaccine (P < 0.05). CONCLUSIONS: Our findings provide insight into the attitudes and practices of employees of food production and operation 3 months after the first human A/H7N9 case reported in China, and 1 month after infected chickens were identified in Guangzhou. Distrust in the health department should be addressed, and more effort should be made to improve compliance of proper preventive measures to reduce panic among the public. The information needs should be taken into account in the next step of health education.

N-acetylglucosaminyltransferase V confers hepatoma cells with resistance to anoikis through EGFR/PAK1 activation.

Elevated expression and activity of N-acetylglucosaminyltransferase V (Mgat5) in hepatocellular carcinoma (HCC) is a common early event involved in tumor invasion during hepatocarcinogenesis. A better understanding of the functional role and the molecular mechanism for Mgat5-targeted protein and downstream signaling pathway behind hepatoma invasion and metastasis is urgently needed. Here, we show that Mgat5 overexpression promoted anchorage-independent growth and inhibited anoikis in hepatoma cells. This effect was reversed by glycosyltransferase inactive mutant Mgat5 L188R transfection, α-mannosidase II inhibitor swainsonine treatment and N-acetyl glucosamine (GlcNAc) phosphotransferase (GPT) inhibitor tunicamycin administration. Mgat5 overexpression increased p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase inactivation with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor P21-activated kinase inhibitor III (IPA3) treatment reversed anoikis resistance in Mgat5-overexpressed hepatoma cells. Furthermore, Mgat5 overexpression upregulated ß-1-6-GlcNAc branched N-glycosylation and following phosphorylation of epidermal growth factor receptor (EGFR) in hepatoma cells. EGFR tyrosine kinase inhibitors AG1478 and Iressa treatment declined anchorage-independent growth and anoikis resistance, which could be rescued by constitutive active mutant PAK1 T423E coexpression in Mgat5-overexpressed hepatoma cells. Conversely, knockdown of Mgat5 reduced EGFR/PAK1-dependent anoikis resistance, which could be reversed by PAK1 T423E. These results identified Mgat5-mediated ß-1-6-GlcNAc branched N-glycosylation and following activation of EGFR as a potential novel upstream molecular event for PAK1-induced anoikis resistance in hepatoma cells, implicating that molecular targeted therapeutics against Mgat5/EGFR/PAK1 might open a new avenue for personalized medicine in advanced-stage HCC patients.

Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2.

Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes that regulate cancer cell growth and survival. It is overexpressed in hepatocellular carcinoma (HCC) with a clinical significance that remains obscure. Sorafenib, a multikinase inhibitor, has been used as a first-line therapeutic drug and shown clinical efficiency for advanced-stage HCC patients. In the present study, we found that sorafenib lowered the protein level of EZH2 through accelerating proteasome-mediated EZH2 degradation in hepatoma cells. Overexpression of EZH2 reversed sorafenib-induced cell growth arrest, cell cycle arrest, and cell apoptosis dependent on histone methyltransferase activity in hepatoma cells. More importantly, shRNA-mediated EZH2 knockdown or EZH2 inhibition with 3-deazaneplanocin A treatment promoted sorafenib-induced hepatoma cell growth arrest and apoptosis. Sorafenib altered the hepatoma epigenome by reducing EZH2 and H3K27 trimethylation. These results revealed a novel therapeutic mechanism underlying sorafenib treatment in suppressing hepatoma growth and survival by accelerating EZH2 degradation. Genetic deletion or pharmacological ablation of EZH2 made hepatoma cells more sensitive to sorafenib, which helps provide a strong framework for exploring innovative combined therapies for advanced-stage HCC patients.

The effects of distractors on brightness perception based on a spiking network.

Visual perception can be modified by the surrounding context. Particularly, experimental observations have demonstrated that visual perception and primary visual cortical responses could be modified by properties of surrounding distractors. However, the underlying mechanism remains unclear. To simulate primary visual cortical activities in this paper, we design a k-winner-take-all (k-WTA) spiking network whose responses are generated through probabilistic inference. In simulations, images with the same target and various surrounding distractors perform as stimuli. Distractors are designed with multiple varying properties, including the luminance, the sizes and the distances to the target. Simulations for each varying property are performed with other properties fixed. Each property could modify second-layer neural responses and interactions in the network. To the same target in the designed images, the modified network responses could simulate distinguishing brightness perception consistent with experimental observations. Our model provides a possible explanation of how the surrounding distractors modify primary visual cortical responses to induce various brightness perception of the given target.

The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer.

Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we showed that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increased the clonal diversity of bladder cancer, driving divergent cancer evolution. Characterization of the single-base substitution signature induced by APOBEC3G in vivo established the induction of a mutational signature distinct from those caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers revealed the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Overall, this study dissects the mutagenic impact of APOBEC3G on the bladder cancer genome, identifying that it contributes to genomic instability, tumor mutational burden, copy-number loss events, and clonal diversity. SIGNIFICANCE: APOBEC3G plays a role in cancer mutagenesis and clonal heterogeneity, which can potentially inform future therapeutic efforts that restrict tumor evolution. See related commentary by Caswell and Swanton, p. 487.

Loss of function mutations in CDKN1A are permissive for APOBEC3-induced mutagenesis in urothelial carcinoma.

Mutagenic mechanisms that shape the genomic landscape and dysfunction of DNA repair converge to promote bladder tumorigenesis. A recent study by Arnoff and El-Deiry highlights the unique interactions between CDKN1A loss of function mutations, which play a key role in cell cycle regulation, modulating DNA repair, and inducing cell apoptosis and senescence, and APOBEC3-induced mutagenesis, the predominant contributor of mutations in urothelial carcinoma.

Knowledge of Emerging and Reemerging Infectious Diseases in the Public of Guangzhou, Southern China.

OBJECTIVE: The objective of this study is to get the overall picture about the knowledge of emerging and reemerging infectious diseases in public in Guangzhou and provide a scientific basis for developing health information strategies. METHODS: We used the structured questionnaire to interview 1,000 Guangzhou residents by health enquiry hotline. Descriptive analysis was presented to evaluate the knowledge of the participants. Multiple logistic regression model was performed to determine the influence factors for knowledge of emerging and reemerging infectious diseases. RESULTS: A total of 801 individuals completed the survey. About one-third had heard of Middle East respiratory syndrome (MERS) and Zika, whereas Ebola and plague about 50%. A total of 32.08% participants had never heard of any of the four diseases. Only 2.08% knew the sexual transmission of Zika and 90.17% had no idea about the epidemic region of plague. No more than 15% knew they should check their health status after returning from the epidemic region. Education level and income were the key factors that influenced knowledge rate. CONCLUSIONS: The low-level knowledge called for the improvement in health information to the public, especially those with low level of education and income. Effective and precise health information was urged to carry out to improve the prevention for the emerging and reemerging infectious diseases.