NOP14 as a Potential Predictor of Adult-Type Diffuse Glioma Prognosis and Immunotherapy, is Related to Cell Migration, Proliferation, and CD8+T Cell Infiltration.

BACKGROUND: World Health Organization (WHO) grade 4 adult-type diffuse glioma is the most malignant primary tumor of the brain. Nucleolar protein 14 (NOP14) is recognized to contribute significantly to the assembly of small ribosomal subunits. However, the specific involvement of NOP14 in diverse cancers remains poorly understood, particularly its role in adult-type diffuse glioma, which has yet to be elucidated. METHODS: A total of 20 adult-type diffuse glioma samples with varying WHO stages were collected. The protein level of NOP14 was detected using immunohistochemistry. Additionally, NOP14 expression in LN229 and U251 cell lines and collected clinical tissue samples was quantified using the Western blot technique. Furthermore, the correlation between NOP14 and clinicopathological features, survival rates, matrix and immune scores, and immune components was investigated using data from the Cancer Gene Atlas database. RESULTS: NOP14 exhibited high expression in adult-type diffuse glioma patients, with the highest expression observed in the LN229 cell line. Moreover, elevated NOP14 expression was significantly correlated with poorer overall survival and demonstrated an association with unfavorable pathological features in a cohort of 703 glioblastoma (GBM) patients. Evidence of a connection between NOP14 and the tumor microenvironment was presented. Elevated NOP14 was linked to the infiltration of CD8+T cell and factors related to epithelial-mesenchymal transition. In in vitro assay, NOP14 was capable of suppressing adult-type diffuse glioma cell invasion and metastasis. CONCLUSIONS: NOP14 holds great promise as a candidate biomarker for detecting prognostic, molecular, and immune signatures of adult-type diffuse glioma.

Bioorthogonal "Click and Release" Reaction-Triggered Aggregation of Gold Nanoparticles Combined with Released Lonidamine for Enhanced Cancer Photothermal Therapy.

Cancer has been the most deadly disease, and 13 million cancer casualties are estimated to occur each year by 2030. Gold nanoparticles (AuNPs)-based photothermal therapy (PTT) has attracted great interest due to its high spatiotemporal controllability and noninvasiveness. Due to the trade-off between particle size and photothermal efficiency of AuNPs, rational design is needed to realize aggregation of AuNPs into larger particles with desirable NIR adsorption in tumor site. Exploiting the bioorthogonal "Click and Release" (BCR) reaction between iminosydnone and cycloalkyne, aggregation of AuNPs can be achieved and attractively accompanied by the release of chemotherapeutic drug purposed to photothermal synergizing. We synthesize iminosydnone-lonidamine (ImLND) as a prodrug and choose dibenzocyclooctyne (DBCO) as the trigger of BCR reaction. A PEGylated AuNPs-based two-component nanoplatform consisting of prodrug-loaded AuNPs-ImLND and tumor-targeting peptide RGD-conjugated AuNPs-DBCO-RGD is designed. In the therapeutic regimen, AuNPs-DBCO-RGD are intravenously injected first for tumor-specific enrichment and retention. Once the arrival of AuNPs-ImLND injected later at tumor site, highly photothermally active nanoaggregates of AuNPs are formed via the BCR reaction between ImLND and DBCO. The simultaneous release of lonidamine further enhanced the therapeutic performance by sensitizing cancer cells to PTT.

MCM10 as a novel prognostic biomarker and its relevance to immune infiltration in gliomas.

BACKGROUND: Gliomas are one of the most common malignancies in the central nervous system (CNS). Members of the minichromosomal maintenance protein (MCM) family play an essential role in diagnosing and prognosis of malignant tumors. MCM10 is found in gliomas, but the prognosis and immune infiltration of gliomas has not been elucidated. OBJECTIVE: To explore the biological function and immune infiltration of MCM10 in gliomas and provide a reference for the diagnosis, treatment, and prognostic evaluation. METHODS: The MCM10 expression profile and the clinical information database of glioma patients were obtained from the China Glioma Genome Atlas (CGGA) and Cancer Genome Atlas (TCGA) glioma data. We analyzed the MCM10 expression levels in various cancers from The TCGA.RNA sequencing data were analyzed using the R packages to determine differentially expressed genes (DEGs) between high- and low MCM10 expressing GBM tissues from the TCGA-GBM database. The Wilcoxon rank sum test was used to compare MCM10 expression levels in glioma and normal brain tissue. To evaluate the value of MCM10 expressions in the prognosis of glioma patients by the Kaplan-Meier survival analysis, a univariate Cox analysis, multivariate Cox analysis, and a ROC curve analysis were used to analyze the correlation of MCM10 expression and the clinicopathological features of glioma patients using the TCGA database data. Subsequently, a functional enrichment analysis was performed to explore its potential signaling pathways and biological functions. Moreover, a single-sample gene set enrichment analysis was used to assess the extent of immune cell infiltration. Lastly, the authors constructed a nomogram to predict the overall survival rate (OS) of gliomas at 1, 3 and 5 years after diagnosis. RESULTS: MCM10 is highly expressed in 20 cancer types including gliomas, and MCM10 expression was an independent adverse prognostic factor in glioma patients. Similarly, high expression of MCM10 was associated with advanced age (60 years), increased tumor grade, tumor recurrence or development of a secondary tumor, IDH wild-type, and non-codeletion of 1p19q (p< 0.01). The OS nomogram generated a consistency index of 0.821. The results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) functional analysis showed that the cell-cycle-related and tumor-related signaling pathways were significantly enriched in the MCM10 high expression phenotype. Moreover, signaling pathways were significantly enriched in Gene Set Enrichment Analysis (GSEA), including Rho GTPases, M phase, DNA repair, extracellular matrix organization, and nuclear receptors. Furthermore, MCM10 over expression was negatively correlated with the level of immune cell infiltration in natural killer CD56 bright cells, follicular helper T cells, plasmacytoma dendritic cells, and dendritic cells. CONCLUSION: MCM10 is an independent prognostic index of glioma patients, and the high expression of MCM10 suggests a poor prognosis; MCM10 expression is closely related to the immune cell infiltration of gliomas, and MCM10 may be related to drug resistance and development of gliomas.

Application of Tranexamic Acid in Shoulder Arthroscopic Surgery: A Randomised Controlled Trial.

Objective To explore the optimal administration route of tranexamic acid (TXA) in shoulder arthroscopic surgery. Methods Patients undergoing arthroscopic rotator cuff repair were randomly divided into four groups: control group (without TXA treatment), intravenous group (TXA was intravenously administered 10 minutes before surgery), irrigation group (TXA was added to the irrigation fluid during subacromial decompression and acromioplasty), and intravenous plus irrigation group (TXA was applied both intravenously and via intra-articular irrigation). The primary outcome was visual clarity assessed with visual analog scale (VAS) score, and the secondary outcomes included irrigation fluid consumption and time to subacromial decompression and acromioplasty procedure. Results There were 134 patients enrolled in the study, including 33 in the control group, 35 in the intravenous group, 32 in the irrigation group, and 34 in the intravenous plus irrigation group. The median and interquartile range of VAS scores for the intravenous, irrigation, and intravenous plus irrigation groups were 2.70 (2.50, 2.86) (Z = -3.677, P = 0.002), 2.67 (2.50, 2.77) (Z = -3.058, P < 0.001), and 2.91 (2.75, 3.00) (Z = -6.634, P < 0.001), respectively, significantly higher than that of the control group [2.44 (2.37, 2.53)]. Moreover, the control group consumed more irrigation fluid than the intravenous group, irrigation group, and intravenous plus irrigation group (all P < 0.05). The intravenous plus irrigation group consumed less irrigation fluid than either the intravenous group or the irrigation group (both P < 0.001). There was no difference in subacromial decompression and acromioplasty operative time among the four groups. Conclusion TXA applied both topically and systematically can improve intraoperative visual clarity, and the combined application is more effective.

An analysis report on the application of immune checkpoint inhibitors after liver transplantation.

Up to now, a variety of immune checkpoint inhibitors (ICIs) have been proved to have good therapeutic effects in the treatment of hepatocellular carcinoma (HCC). However, the effects of their applications in liver transplant (LT) recipients are still unclear. In this analysis report, the clinical applications and therapeutic effects of ICIs on LT recipients with hepatic tumor recurrence or de novo carcinoma based on eight databases, including PubMed, EMBASE, Web of Science, Google Scholar, China National Knowledge Infrastructure, Wanfang Data, and CQVIP, were investigated. And the prior treatment, disease response, adverse reactions, and prognosis of patients with malignant tumors after LT and receiving ICI treatments were analyzed. After screening, a total of 28 articles with 47 recipients on the application of ICIs after LT were included. In these patients, their median age was 57 (14-71) years and the main type of tumor after LT was HCC (59.6%). The overall remission rate following ICI treatment was 29.8% (14/47) and the disease progression rate was 68.1% (32/47). Among all these patients, 31.9% (15/47) of patients had immune rejection; the median survival time was 6.5 (0.3-48) months, and the fatality rate was 61.7% (29/47). Considering that the therapeutic effect of ICIs in LT recipients with HCC recurrence or de novo carcinoma is not ideal, ICI treatment should be carefully considered for LT patients, and further research is needed.

Association of C-reactive Protein with Cardiovascular Outcomes: A Mendelian Randomization Study in the Japanese Population.

OBJECTIVE: Traditional epidemiological studies have shown that C-reactive protein (CRP) is associated with the risk of cardiovascular diseases (CVDs). However, whether this association is causal remains unclear. Therefore, Mendelian randomization (MR) was used to explore the causal relationship of CRP with cardiovascular outcomes including ischemic stroke, atrial fibrillation, arrhythmia and congestive heart failure. METHODS: We performed two-sample MR by using summary-level data obtained from Japanese Encyclopedia of Genetic association by Riken (JENGER), and we selected four single-nucleotide polymorphisms associated with CRP level as instrumental variables. MR estimates were calculated with the inverse-variance weighted (IVW), penalized weighted median and weighted median. MR-Egger regression was used to explore pleiotropy. RESULTS: No significant causal association of genetically determined CRP level with ischemic stroke, atrial fibrillation or arrhythmia was found with all four MR methods (all Ps > 0.05). The IVW method indicated suggestive evidence of a causal association between CRP and congestive heart failure ( OR: 1.337, 95% CI: 1.005-1.780, P = 0.046), whereas the other three methods did not. No clear pleiotropy or heterogeneity were observed. CONCLUSIONS: Suggestive evidence was found only in analysis of congestive heart failure; therefore, further studies are necessary. Furthermore, no causal association was found between CRP and the other three cardiovascular outcomes.

[Prognostic Factors and Predictive Value of MRD before Consolidation Therapy in Middle-risk Newly Diagnosed Young and Middle-aged Patients with AML].

OBJECTIVE: To explore the prognostic factors of young and middle-aged patients with acute myeloid leukemia (AML) and the predictive value of minimal residual disease (MRD) before consolidation therapy. METHODS: The clinical data of 262 middle-risk young and middle-aged patients with AML treated in our hospital from January 2010 to December 2018 were selected retrospectively. All the patients were reached morphological leukemia-free state (MLFS) after induction chemotherapy, the overall and subgroup clinical data of the selected patients were analyzed. Cox regression model was used to evaluate the independent prognostic factors of middle-risk newly diagnosed young and middle-aged patients. RESULTS: Among the patients less than 40 years old treated by consolidation therapy with PR-CT and allo-HSCT regimens, the 5-year cumulative leukemia-free survival(LFS) rates were 40.92% and 63.51%（P=0.01）respectively, while those over 40 years old were 23.61% and 49.14%（P=0.00）, respectively. The 5-year cumulative LFS rates of the patients treated by chemotherapy and achieved early remission and late remission were 63.51% and 41.33% （P=0.01）, respectively. The 5-year cumulative overall survival(OS) rates of the patients treated by PR-CT and allo-HSCT regimens were 23.65% and 69.32% (P=0.00), respectively, and the 5-year cumulative LFS rates were 26.44% and 52.30% (P=0.01). Among the patients treated by PR-CT consolidation treatment, the MRD-negative and MRD-positive cases were 74 and 60 cases, respectively. The 5-year cumulative incidence of relapse rate in the MRD-negative subgroup was significantly lower than those in the MRD-positive subgroup (P<0.05), the 5-year LFS rate and OS rate of the patients in MRD-negative subgroup were significantly higher than those in MRD-positive subgroup (P<0.05). For the patients treated by allo-HSCT consolidation treatment, the MRD-negative and MRD-positive cases were 66 and 62 cases, respectively. The 5-year cumulative incidence of relapse rate of the patients in MRD-negative subgroup was significantly lower than those in MRD-positive subgroup（P<0.05）, and the 5-year LFS and OS rates of the patients in MRD-negative subgroup were significantly higher than those in MRD-positive subgroup (P<0.05). The univariate analysis results showed that age, chromosome karyotype, MRD status after reaching MLFS, and consolidation treatment regime were all related to the prognosis of patients (P<0.05). The multivariate analysis results showed that age, MRD status after reaching MLFS, and consolidation therapy were the independent factors affecting the cumulative OS rate of the patients (P<0.05). Chromosome karyotype was an independent factor affecting the cumulative LFS rate of the patients (P<0.05). MRD status and consolidation treatment plan after reaching MLFS were the independent factors affecting the cumulative recurrence rate of the patients (P<0.05). CONCLUSION: The OS rate of middle-risk young and middle-aged patients with newly diagnosed AML is independently related to age, MRD status after MLFS and consolidation therapy, while chromosome karyotype is independently related to cumulative LFS, and allo-HSCT consolidation therapy is recommended for middle-risk young and middle-aged AML patients after induction chemotherapy for MLFS, especially for those less than 40 years old and MRD positive before consolidation therapy.

Preliminary single-center experience of Helicobacter pylori eradication among the liver transplant recipients.

OBJECTIVE: To investigate the prevalence of Helicobacter pylori infection among orthotopic liver transplant (LT) recipients and explore the efficacy and safety of H. pylori eradication therapy. METHODS: Liver transplant recipients receiving regular follow-up in our center were assessed by 13C-urea breath test between February 2018 and July 2020. A group of healthy tested patients were selected as control group at a rate of 1:3. All LT recipients with H. pylori were recommended to receive eradication therapy with bismuth-containing quadruple therapy (BQT), which included esomeprazole 20 mg + clarithromycin 500 mg + amoxicillin 1 g + bismuth 220 mg, twice daily for 14 days. RESULTS: The prevalence of H. pylori infection among the LT recipients was 19.6% (30/153), which was significantly lower than the control group (30/153 [19.6%] vs. 200/459 [43.6%], p < 0.001). In LT recipients who received transplantation at <1 year, 1-3 years, and >3 years, the prevalence of H. pylori infection was 10.6% (5/47), 17.5% (10/57), and 30.6% (15/49), respectively, which increased with the time after transplantation (p = 0.04). With BQT, the eradication rate of H. pylori was 91.3% (21/23). During the process of eradication, the blood trough concentration of immunosuppressants increased from 1.7 to 3.6 times, and reducing the dose of the drugs to one-third of what they were before the eradication therapy could avoid excessively elevated concentration of immunosuppressants. Adverse effects occurred in 55.2% (11/23), of the LT recipients and 21.0% (42/200) of the control group (p < 0.01), which was probably caused by the increased blood concentration of immunosuppressants. Normal liver function was observed, while transient abnormal kidney function was occurred in one recipient. CONCLUSION: The prevalence of H. pylori infection was 19.6% among the LT recipients, which increased with the postoperative time. With BQT, H. pylori eradication was safe and effective in LT recipients.

A dual-functional nanovehicle with fluorescent tracking and its targeted killing effects on hepatocellular carcinoma cells.

All-in-one drug delivery nanovehicles with low cytotoxicity, high clinical imaging tracking capability, and targeted- and controlled-releasing performances are regarded as promising nanoplatforms for tumor theranostics. Recently, the design of these novel nanovehicles by low molecular weight amphiphilic chitosan (CS) was proposed. Based on fluorescent gold nanoclusters (AuNCs), a tumor-targeting nanovehicle (i.e. AuNCs-CS-AS1411) was prepared via electrostatic attraction between AuNC-conjugated chitosan (i.e. AuNCs-CS) and the anti-nucleolin aptamer, AS1411. After that, the anticancer drug methotrexate (MTX) was encapsulated into the nanovehicles and then the dual-functional nano-drug (i.e. MTX@AuNCs-CS-AS1411) was comparatively supplied to the human hepatocellular carcinoma cell line HepG2 and the human normal liver cell line LO2, to exhibit its "all in one" behavior. Under the conditions of the same concentration of MTX, MTX@AuNCs-CS-AS1411 demonstrates more intensive cytotoxicity and apoptosis-inducing activity against HepG2 cells than those against normal LO2 cells, mainly due to the targeting effect of AS1411 on the nucleolins that were found at high levels on the surface of tumor cells, but are at low levels or absent on normal cells. On the other hand, the MTX release from the MTX@AuNCs-CS-AS1411 was much faster in mildly acidic solution than that in neutral pH. Thus, it may provide a possibility to more significantly release MTX in intracellular lysosome of tumor cells, rather than let loose MTX during transport of the drug from blood vessels to tumor tissue. In conclusion, our dual-functional nanovehicle possesses high fluorescence efficiency and photostability, low cytotoxicity, pH-dependent controlled release, high sensitivity and target-specificity to cancer cells which allowed concurrent targeted imaging and delivery in cancer chemotherapies.

Prebiotics-Encapsulated Probiotic Spores Regulate Gut Microbiota and Suppress Colon Cancer.

While microbial-based therapy has been considered as an effective strategy for treating diseases such as colon cancer, its safety remains the biggest challenge. Here, probiotics and prebiotics, which possess ideal biocompatibility and are extensively used as additives in food and pharmaceutical products, are combined to construct a safe microbiota-modulating material. Through the host-guest chemistry between commercial Clostridium butyricum and chemically modified prebiotic dextran, prebiotics-encapsulated probiotic spores (spores-dex) are prepared. It is found that spores-dex can specifically enrich in colon cancers after oral administration. In the lesion, dextran is fermented by C. butyricum, and thereby produces anti-cancer short-chain fatty acids (SCFAs). Additionally, spores-dex regulate the gut microbiota, augment the abundance of SCFA-producing bacteria (e.g., Eubacterium and Roseburia), and markedly increase the overall richness of microbiota. In subcutaneous and orthotopic tumor models, drug-loaded spores-dex inhibit tumor growth up to 89% and 65%, respectively. Importantly, no obvious adverse effect is found. The work sheds light on the possibility of using a highly safe strategy to regulate gut microbiota, and provides a promising avenue for treating various gastrointestinal diseases.

Recurrent epithelioid malignant peripheral nerve sheath tumor with neurofibromatosis type 1: A case report and literature review.

Malignant peripheral nerve sheath tumors (MPNSTs) are unusual and aggressive malignant soft-tissue tumors that comprise 5-10% of all soft-tissue sarcomas. Approximately 50% of MPNST cases are associated with neurofibromatosis type-1 (NF-1). As a rare MPNST subset, the epithelioid variant of MPNST (eMPNST) is histologically characterized by the predominant presence of epithelioid tumor cells, and accounts for <5% of all MPNSTs. In addition, eMPNST is rarely associated with NF-1 when compared with conventional MPNST. Although extensive clinicopathological studies have been conducted on eMPNST, clinicians face difficulty when attempting to make an accurate diagnosis. Subsequently, the biological consequences, including recurrence, metastasis and mortality rate in patients with eMPNST remain unclear. The current study presents the case of a 71-year-old woman with eMPNST and a family history of NF-1 in whom tumors had recurred twice on the lower back. A literature search for eMPNSTs was conducted by browsing PubMed and MEDLINE for English-language articles, as well as references from review articles, and revealed 129 published cases. Only 5 cases of eMPNST were associated with NF-1. The studies were retrospectively reviewed and the clinicopathological data of the patients, including tumor site, treatment, follow-up, prognosis, and immunohistochemical positivity were collected.

METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN.

RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention. KEY MESSAGES: METTL1 is upregulated in HCC and correlated with poor outcomes. METTL1 promotes cell proliferation and migration in HCC. METTL1 exerts oncogenic activities via suppression of PTEN signaling.

Long-term follow-up of auditory performance and speech perception and effects of age on cochlear implantation in children with pre-lingual deafness.

BACKGROUND: The development of auditory and speech perception ability of children with hearing loss is affected by many factors after they undergo cochlear implantation (CI). Age at CI (CI age) appears to play an important role among these factors. This study aimed to evaluate the development of auditory and speech perception ability and explore the impact of CI age on children with pre-lingual deafness present before 3 years of age. METHODS: Two hundred and seventy-eight children with pre-lingual deafness (176 boys and 102 girls) were included in this study, and the CI age ranged from 6 to 36 months (mean age, 19 months). Categorical auditory performance (CAP) was assessed to evaluate auditory ability, and the speech intelligibility rating was used to evaluate speech intelligibility. The evaluations were performed before CI and 1, 3, 6, 12, 18, 24, 36, 48, and 60 months after CI. RESULTS: The auditory ability of the pre-lingually hearing-impaired children showed the fastest development within 6 months after CI (k = 0.524, t = 30.992, P < 0.05); then, the progress started to decelerate (k = 0.14, t = 3.704, P < 0.05) and entered a plateau at the 24th month (k = 0.03, t = 1.908, P < 0.05). Speech intelligibility showed the fastest improvement between the 12th and 24th months after CI (k = 0.138, t = 5.365, P < 0.05); then, the progress started to decelerate (k = 0.026, t = 1.465, P < 0.05) and entered a plateau at the 48th month (k = 0.012, t = 1.542, P < 0.05). The CI age had no statistical significant effect on the auditory and speech abilities starting at 2 years after CI (P > 0.05). The optimal cutoff age for CI was 15 months. CONCLUSIONS: Within 5 years after CI, the auditory and speech ability of young hearing-impaired children continuously improved, although speech development lagged behind that of hearing. An earlier CI age is recommended; the optimal cutoff age for CI is at 15 months.

Histologic pattern is better correlated with clinical outcomes than biochemical classification in patients with drug-induced liver injury.

Histologically, drug-induced liver injury could be classified into acute hepatitis, chronic hepatitis, acute cholestasis, chronic cholestasis, and cholestatic hepatitis. The correlation between these histologic patterns and long-term clinical outcomes has not been well established. Therefore, we conducted a retrospective cohort study to investigate the association of histologic patterns and long-term clinical outcomes defined as biochemical normalization, persistent abnormal liver biochemistry or death at designated time points. In this study, biochemical classification was determined by R-values; histologic injury pattern was determined by morphological features. Predictive ability of clinical outcomes by these two classifications was assessed using Receiver Operating Characteristic Curves. Logistic regression was performed to identify histologic factors associated with outcomes. Totally, 88 patients with drug-induced liver injury were included for final analysis. Biochemical and histologic classification were consistent in 50 (57%) cases. 53 (60%) cases showed biochemical normalization within 6 months, and a further 11 (13%), 16 (18%), and 6 (7%) cases within 1, 2, and 3 years, respectively. Compared with biochemical classification, histologic injury pattern had better predictive ability for abnormal biochemistry at 6 months (Areas under Receiver Operating Characteristic Curves 0.92 versus 0.60, P < 0.001) and 1 year (Areas under Receiver Operating Characteristic Curves 0.94 versus 0.69, P < 0.001). Interlobular bile duct loss in >25% portal areas was independently associated with abnormal biochemistry at 6 months, 1 year, and 2 years. In conclusion, histologic injury pattern is better correlated with clinical outcome at 6 months and 1 year than biochemical classification. Moderate bile duct loss is an important histologic feature associated with persistent biochemical abnormality at 6 months, 1 year, and 2 years.

SPAG5 interacts with CEP55 and exerts oncogenic activities via PI3K/AKT pathway in hepatocellular carcinoma.

BACKGROUND: Deregulation of microtubules and centrosome integrity is response for the initiation and progression of human cancers. Sperm-associated antigen 5 (SPAG5) is essential for the spindle apparatus organization and chromosome segregation, but its role in hepatocellular carcinoma (HCC) remains undefined. METHODS: The expression of SPAG5 in HCC were examined in a large cohort of patients by RT-PCR, western blot and IHC. The clinical significance of SPAG5 was next determined by statistical analyses. The biological function of SPAG5 in HCC and the underlying mechanisms were investigated, using in vitro and in vivo models. RESULTS: Here, we demonstrated that SPAG5 exhibited pro-HCC activities via the activation of PI3K/AKT signaling pathway. SPAG5 expression was increased in HCC and correlated with poor outcomes in two independent cohorts containing 670 patients. High SPAG5 expression was associated with poor tumor differentiation, larger tumor size, advanced TNM stage, tumor vascular invasion and lymph node metastasis. In vitro and in vivo data showed that SPAG5 overexpression promoted tumor growth and metastasis, whereas SPAG5 knockdown led to the opposite phenotypes. SPAG5 interacted with centrosomal protein CEP55 to trigger the phosphorylation of AKT at Ser473. Inhibition of PI3K/AKT signaling markedly attenuated SPAG5-mediated cell growth. Furthermore, SPAG5 expression was suppressed by miR-363-3p which inhibited the activity of SPAG5 mRNA 3'UTR. Ectopic expression of SPAG5 partly abolished the miR-363-3p-caused cell cycle arrest and suppression of cell proliferation and migration. CONCLUSIONS: Collectively, these findings indicate that SPAG5 serves a promising prognostic factor in HCC and functions as an oncogene via CEP55-mediated PI3K/AKT pathway. The newly identified miR-363-3p/SPAG5/CEP55 axis may represent a potential therapeutic target for the clinical intervention of HCC.

CBX1 Indicates Poor Outcomes and Exerts Oncogenic Activity in Hepatocellular Carcinoma.

Dysregulation of chromobox proteins contributes to the progression of human diseases. CBX1 has been implicated in epigenetic control of chromatin structure and gene expression, but its role in human cancers remains largely unknown. Here we show that CBX1 exhibits oncogenic activities in hepatocellular carcinoma (HCC) and indicates poor outcomes. The expression of CBX1 was noticeably increased, at both mRNA and protein levels, in HCC tissues and cell lines, compared with the nontumorous ones. High CBX1 expression was significantly associated with larger tumor size, poor tumor differentiation and tumor vascular invasion. Patients with elevated expression of CBX1 were frequently accompanied with unfavorable overall and disease-free survivals in two independent cohorts consisting of 648 HCC cases. The prognostic value of CBX1 was further confirmed by stratified survival analyses. Multivariate cox regression model suggested CBX1 as an independent factor for overall survival (hazard ratio = 1.735, 95% confident interval: 1.342-2.244, P < .001). In vitro data demonstrated that CBX1 overexpression promoted cell proliferation and migration, whereas the knockdown of CBX1 resulted in the opposite phenotypes. Mechanistically, CBX1 interacted with transcription factor HMGA2 to activate the Wnt/ß-Catenin signaling pathway. Suppression of ß-Catenin by siRNA or specific inhibitor XAV-939 markedly attenuated CBX1-mediated cell growth. Collectively, our findings indicate that CBX1 functions as an oncogene and may serve as a potential prognostic biomarker in HCC.