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Background The centromere proteins (CENPs) are the key regulators in mitosis-related protein complexes and involved in kinetochore assembly and chromosome segregation during mitosis, yet they remain largely unexplored in hepatocellular carcinoma (HCC). Methods In our study, we analyzed the potential role of CENPs family numbers by bioinformatic analysis. We detected the expression level of Centromere protein A (CENPA) in HCC tissues and cells by qRT-PCR, IHC and western blotting. Furthermore, CCK-8, colony formation, EdU and flow cytometry assays were used to evaluated the potential function of CENPA in HCC cells. Subcutaneous and orthotopically mouse model were used to explored the oncogenic role of CENPA. Besides, we demonstrated the interaction between CENPA and YY1 by silver staining and co-immunoprecipitation (co-IP) assays. Dual luciferase reporter and ChIP-sequencing (ChIP-seq) assays were used to identify the potential binding sites of CENPA and YY1 on CCND1 and NRP2 promoter regions. Results In this study, CENPA was identified significantly up-regulated in HCC, and the CENPA overexpression was linked to the poor prognosis of HCC patients. CENPA knockdown inhibited the HCC cell proliferation and tumor growth. Mechanistically, CENPA activated YY1 transcription and cooperatively interacted with YY1 to bind at cyclin D1 (CCND1) and neuropilin 2 (NRP2) promoter regions for transcriptional activation. Moreover, we identified a lactylation modification site (K124) of CENPA, which is essential for CENPA to activate its target genes transcriptionally. Conclusions These findings indicate the synergistic mechanism between CENPA and YY1 that promotes CCND1 and NRP2 expression, which leads to HCC progression.

Background and Aims The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. Methods This large retrospective cohort study included 2073 patients with COVID-19 having definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted and determined their associated factors and death risk by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19 with and without hepatitis B were compared after 1:3 propensity score matching. Results Of the 2073 patients, 1282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of AST and D-Bil increased early after symptom onset in deceased patients and showed disparity compared with that in discharged patients throughout the clinical course of the disease. Abnormal admission AST (adjusted hazard ratio [HR]: 1.39, 95%CI: 1.04-1.86, P=0.027) and D-Bil (adjusted HR: 1.66, 95%CI: 1.22-2.26, P=0.001) levels were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of COVID-19-associated poor outcomes. Conclusions Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19 mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, in hospitalized patients with COVID-19, is necessary., Graphical abstract, Highlights 1. Levels of AST and D-Bil elevated early after the symptom onset in deceased patients and showed disparity compared with that in discharged patients throughout the clinical course of COVID-19. 2. Abnormal admission AST and D-Bil levels at admission were independent predictors of COVID-19 mortality. 3. A novel nomogram was built based on admission AST and D-Bil levels as well as other baseline characteristics to predict the in-hospital mortality of COVID-19. 4. Hepatitis B infection was not found to be associated with the risk of lethal outcome in patients with COVID-19., Lay Summary The AST and D-Bil levels increased early after symptom initiation in deceased patients of COVID-19 and showed disparity compared with that in discharged patients throughout the clinical course of the disease. Abnormal AST and D-Bil levels at admission were independent predictors for COVID-19 mortality. HBV infection in patients did not increase the risk of COVID-19-associated poor outcomes.

The differential expression of chromosome 12 open reading frame 75 (C12orf75) is closely related with cancer progression. Here, we studied the expression levels of C12orf75 and investigated its prognostic value in various cancers across distinct datasets including ONCOMINE, PrognoScan, GEPIA, and TCGA. The correlation between genetic alteration of C12orf75 and immune infiltration was investigated using the cBioPortal and TIMER databases. RNA interference was used to verify the influence of C12orf75 knockdown on the biological phenotype of hepatocellular carcinoma cells. C12orf75 showed increased expression in most tested human cancers. The increased expression of C12orf75 was related with a poor prognosis in urothelial bladder carcinoma and hepatocellular liver carcinoma, but it was surprisingly converse in renal papillary cell carcinoma. In urothelial bladder carcinoma and hepatocellular liver carcinoma, we observed positive correlations between the expression of C12orf75 and the infiltration of immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The knockdown of C12orf75 in hepatocellular carcinoma cells suppressed the proliferation, migration, and invasion and arrested the cell cycle. This is the first report C12orf75 has potential as a prognostic biomarker and therapeutic target for molecularly targeted drugs in urothelial bladder carcinoma, hepatocellular liver carcinoma, and renal papillary cell carcinoma.

Patients with cancer are at increased risk of severe infections. From a cohort including 3060 patients with confirmed COVID-19, 109 (3.4%) cancer patients were included in this study. Among them, 23 (21.1%) patients died in the hospital. Cancer patients, especially those with hematological malignancies (41.6%), urinary carcinoma (35.7%), malignancies of the digestive system (33.3%), gynecological malignancies (20%), and lung cancer (14.3%), had a much higher mortality than patients without cancer. A total of 19 (17.4%) cancer patients were infected in the hospital. The clinical characteristics of deceased cancer patients were compared with those of recovered cancer patients. Multivariate Cox regression analysis indicated that a Nutritional Risk Screening (NRS2002) score ⩾ 3 (adjusted hazard ratio (HR) 11.00; 95% confidence interval (CI) 4.60–26.32; P < 0.001), high-risk type (adjusted HR 18.81; 95% CI 4.21–83.93; P < 0.001), tumor stage IV (adjusted HR 4.26; 95% CI 2.34–7.75; P < 0.001), and recent adjuvant therapy (< 1 month) (adjusted HR 3.16; 95% CI 1.75–5.70; P < 0.01) were independent risk factors for in-hospital death after adjusting for age, comorbidities, D-dimer, and lymphocyte count. In conclusion, cancer patients showed a higher risk of COVID-19 infection with a poorer prognosis than patients without cancer. Cancer patients with high-risk tumor, NRS2002 score ⩾ 3, advanced tumor stage, and recent adjuvant therapy (< 1 month) may have high risk of mortality. Electronic Supplementary Material Supplementary material is available in the online version of this article at 10.1007/s11684-021-0845-6 and is accessible for authorized users.

Context Although the incidence of papillary thyroid carcinoma (PTC) is significantly higher in females than in males, the prognosis of male PTC is more unfavorable. However, the cause of higher malignancy of PTC in male patients remains unclear. Objective We conducted our analysis on microarrays datasets, tissue samples from PTC patients and the RNAseq datasets from TCGA with survival data. Methods We searched all publicly available microarray datasets and performed a genome-wide meta-analysis comparing PTC and normal samples. Gene Ontology analysis was then conducted. The candidate genes were tested by quantitative real-time polymerase chain reaction. The analysis of prognostic value of genes was performed with datasets from The Cancer Genome Atlas. Results After meta-analyses, 150 significantly differentially expressed genes (DEGs) were specifically found in male subjects. Gene Ontology analysis of these 150 genes revealed that the viral process was activated. Seven genes involved in the viral process in male patients showed a significantly differential expression between PTC and normal tissue. Survival analysis exhibited that the 7 genes, used in combination, were prognostically valuable and, of them, PSMB1 possessed a conspicuous prognostic value, especially in males. Conclusion In this study, we searched all publicly available microarray datasets and conducted a comprehensive analysis to understand the male propensity for higher malignancy. We found that markers of viral infection showed significantly differential expression only in male patients compared with their female counterparts and had a sex-sensitive prognostic value in PTC.

Resistance to anoikis, cell death due to matrix detachment, is acquired during tumor progression. The 14-3-3σ protein is implicated in the development of chemo- and radiation resistance, indicating a poor prognosis in multiple human cancers. However, its function in anoikis resistance and metastasis in hepatocellular carcinoma (HCC) is currently unknown. Methods: Protein expression levels of 14-3-3σ were measured in paired HCC and normal tissue samples using western blot and immunohistochemical (IHC) staining. Statistical analysis was performed to evaluate the clinical correlation between 14-3-3σ expression, clinicopathological features, and overall survival. Artificial modulation of 14-3-3σ (downregulation and overexpression) was performed to explore the role of 14-3-3σ in HCC anoikis resistance and tumor metastasis in vitro and in vivo. Association of 14-3-3σ with epidermal growth factor receptor (EGFR) was assayed by co-immunoprecipitation. Effects of ectopic 14-3-3σ expression or knockdown on EGFR signaling, ligand-induced EGFR degradation and ubiquitination were examined using immunoblotting and co-immunoprecipitation, immunofluorescence staining, and flow cytometry analysis. The levels of EGFR ubiquitination, the interaction between EGFR and 14-3-3σ, and the association of EGFR with c-Cbl after EGF stimulation, in 14-3-3σ overexpressing or knockdown cells were examined to elucidate the mechanism by which 14-3-3σ inhibits EGFR degradation. Using gain-of-function or loss-of-function strategies, we further investigated the role of the EGFR signaling pathway and its downstream target machinery in 14-3-3σ-mediated anoikis resistance of HCC cells. Results: We demonstrated that 14-3-3σ was upregulated in HCC tissues, whereby its overexpression was correlated with aggressive clinicopathological features and a poor prognosis. In vitro and in vivo experiments indicated that 14-3-3σ promoted anoikis resistance and metastasis of HCC cells. Mechanistically, we show that 14-3-3σ can interact with EGFR and significantly inhibit EGF-induced degradation of EGFR, stabilizing the activated receptor, and therefore prolong the activation of EGFR signaling. We demonstrated that 14-3-3σ downregulated ligand-induced EGFR degradation by inhibiting EGFR-c-Cbl association and subsequent c-Cbl-mediated EGFR ubiquitination. We further verified that activation of the ERK1/2 pathway was responsible for 14-3-3σ-mediated anoikis resistance of HCC cells. Moreover, EGFR inactivation could reverse the 14-3-3σ-mediated effects on ERK1/2 phosphorylation and anoikis resistance. Expression of 14-3-3σ and EGFR were found to be positively correlated in human HCC tissues. Conclusions: Our results indicate that 14-3-3σ plays a pivotal role in the anoikis resistance and metastasis of HCC cells, presumably by inhibiting EGFR degradation and regulating the activation of the EGFR-dependent ERK1/2 pathway. To our best knowledge, this is the first report of the role of 14-3-3σ in the anoikis resistance of HCC cells, offering new research directions for the treatment of metastatic cancer by targeting 14-3-3σ.

Coronavirus Disease 2019 (COVID-19) emerges as a global pandemic and there is a lack of evidence about the clinical course and outcome of patients on maintenance hemodialysis (MHD). Here we conducted a retrospective longitudinal study aimed to analyze the clinical features and outcome of MHD patients hospitalized with COVID-19. Of 3126 inpatients with COVID-19 at 3 Branches of Wuhan Tongji Hospital from Jan 18th to Mar 9th, 2020, 19 patients were undergoing maintenance hemodialysis. Among the 19 MHD patients with COVID-19, 6 patients (31.6%) died, and 13 patients (68.4%) were able to be discharged. Baseline characteristics, clinical courses, laboratory findings, and dynamic trajectories of major laboratory markers were compared between survivors and nonsurvivors. According to our findings, MHD patients with COVID-19 who experienced non-surviving outcome had more elevated CRP, IL6 and procalcitonin as well as fibrinogen levels at various points compared to survivors. Thus the dysregulation of immune response as well as coagulation abnormalities might be highly involved in the pathological process of COVID-19, contributing to the poor prognosis in MHD patients.

Objective: APBB1IP is a Rap1-binding protein that mainly acts as a regulator of leukocyte recruitment and pathogen clearance through complement-mediated phagocytosis. However, the role of APBB1IP in tumor immunity remains unclear. This study was carried out to evaluate the prognostic landscape of APBB1IP in pan-cancer analysis and investigate the relationship between APBB1IP expression and immune infiltration. Methods: We explored the expression pattern and prognostic value of APBB1IP in pan-cancer analysis through Kaplan-Meier Plotter and multiple databases, including TCGA, Oncomine. We then assessed the correlation between APBB1IP expression and immune cell infiltration using the TIMER database. Furthermore, we identified the proteins that interact with APBB1IP and performed epigenetic and transcriptional analyses. Multivariate Cox regression analyses were applied to construct a prognostic model, which consisted of APBB1IP and its interacting proteins, based on the lung cancer cohorts from the Gene Expression Omnibus (GEO) database. Results: The expression of APBB1IP was correlated with the prognosis of several types of cancer. APBB1IP upregulation was found to be associated with increased immune cell infiltration, especially for CD8+ T cells, natural killer (NK) cells, and immune regulators. A link was found between APBB1IP and immune-related proteins including RAP1A/B, TLN1/2 and VCL in the interaction network. Conclusion: APBB1IP can serve as a prognostic biomarker in pan-cancer analysis. APBB1IP upregulation was correlated with increased immune-cell infiltration, and the expression APBB1IP in different tumors might be related to the tumor immune microenvironment.

Transforming growth factor β (TGF-β) is a potent inducer of epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), and plays a critical role in its tumorigenesis and progression. Accumulating evidence indicates that protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), may play key roles in the tumorigenesis and progression of HCC. In this study, we first report on the differential expression of lncRNAs, mRNAs, miRNAs, and circRNAs in Huh7 cells treated with TGF-β or DMSO for 7 days. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for significantly differentially expressed RNAs (DE RNAs). Then the competing endogenous RNA (ceRNA) network based on these DE RNAs was predicted and constructed. Among them, we identified that lncRNA SLC7A11-AS1 and hsa_circ_0006123 are involved in the EMT process induced by TGF-β and may promotes the metastasis of HCC. This knowledge may pave the way to develop novel clinical diagnostics and therapeutic approaches. Our study might open a new avenue for future investigations of the molecular mechanisms driving the EMT process induced by TGF-β in HCC.

Cholangiocarcinoma (CCA) still has a very unfavorable prognosis with a very high mortality, which is complicated by a lack of prognostic biomarkers. In this study, CCA patients in the Gene Expression Omnibus (GEO) cohort were categorized into two subtypes. Differentially expressed and methylated genes were identified, and the impact of DNA methylation in the trans-regulation of gene expression was investigated. Finally, a CIMP-related methylation signature specific for CCA (CMSC) was trained in GEO and validated in the Tongji cohort. A subset of patients with CIMP-H was identified, which was correlated with an unfavorable prognosis. Gene enrichment analysis implied the potential mechanism of CIMP as a promoter of carcinogenesis by regulating proliferation. The trans-regulation among differentially methylated CpG sites and genes with the same change trends was positively correlated, while the converse situation showed a negative correlation. Notably, CMSC based on four genes could significantly classify CCA patients into low- and high-risk groups in the GEO cohort, and the robustness of CMSC was validated in the Tongji cohort. The results of receiver operating characteristic analysis further indicated that CMSC was capable of highly sensitive and specific prediction of the patient outcomes in CCA. In conclusion, our work highlights the clinical significance of CMSC in the prognosis of CCA.

Recent evidence suggests that small nucleolar RNAs (snoRNAs) are involved in the progression of various cancers, but their precise roles in hepatocellular carcinoma (HCC) remain largely unclear. Here, we report that SNORD17 promotes the progression of HCC through a positive feedback loop with p53. HCC-related microarray datasets from the Gene Expression Omnibus (GEO) database and clinical HCC samples were used to identify clinically relevant snoRNAs in HCC. SNORD17 was found upregulated in HCC tissues compared with normal liver tissues, and the higher expression of SNORD17 predicted poor outcomes in patients with HCC, especially in those with wild-type p53. SNORD17 promoted the growth and tumorigenicity of HCC cells in vitro and in vivo by inhibiting p53-mediated cell cycle arrest and apoptosis. Mechanistically, SNORD17 anchored nucleophosmin 1 (NPM1) and MYB binding protein 1a (MYBBP1A) in the nucleolus by binding them simultaneously. Loss of SNORD17 promoted the translocation of NPM1 and MYBBP1A into the nucleoplasm, leading to NPM1/MDM2-mediated stability and MYBBP1A/p300-mediated activation of p53. Interestingly, p300-mediated acetylation of p53 inhibited SNORD17 expression by binding to the promoter of SNORD17 in turn, forming a positive feedback loop between SNORD17 and p53. Administration of SNORD17 antisense oligonucleotides (ASOs) significantly suppressed the growth of xenograft tumors in mice. In summary, this study suggests that SNORD17 drives cancer progression by constitutively inhibiting p53 signaling in HCC and may represent a potential therapeutic target for HCC.

Summary: Background/Objective: Previous studies have proposed several objective means for liver function assessment in hepatocellular carcinoma (HCC) patients; however, their efficiency in predicting survival of HCC rupture is unknown. Our study aims to confirm which is a better liver function model for ruptured HCC. Methods: A total of 230 patients with HCC ruptures at our center were included. Kaplan–Meier and Cox regression analyses were performed to compare long-term survival and short-term mortality. The 90-day mortality was compared with the area under the receiver characteristic curve. Logistic regression was used to determine the risk factors for 90-day deaths, and the discriminant ability of the model was measured. Results: There were significant differences in predicting OS of the Child-Pugh (CP) score in all patients, the non-surgical subgroup, and the surgical subgroup (all P

Objective: Spontaneous hepatocellular carcinoma (HCC) rupture can be fatal, and hepatic resection could achieve a favorable long-term survival among all strategies of tumor rupture. However, there is no available prognostic scoring system for patients with ruptured HCC who underwent partial hepatectomy.Methods: From January 2005 to May 2015, 129 patients with spontaneous HCC rupture underwent partial hepatectomy. Preoperative clinical data were collected and analyzed. Independent risk factors affecting overall survival (OS) were used to develop the new scoring system. Harrell’s C statistics, Akaike information criterion (AIC), the relative likelihood, and the log likelihood ratio were calculated to measure the homogeneity and discriminatory ability of a prognostic system.Results: In the multivariable Cox regression analysis, three factors, including tumor size, preoperative α-fetoprotein level, and alkaline phosphatase level, were chosen for the new tumor-associated antigen (TAA) prognostic scoring system. The 1-year OS rates were 88.1%, 43.2%, and 30.2% for TAA scores of 0–5 points (low-risk group), 6–9 points (moderate-risk group), and 10–13 points (high-risk group), respectively. The TAA scoring system had superior homogeneity and discriminatory ability (Harrell’s C statistics, 0.693 vs. 0.627 and 0.634; AIC, 794.79 vs. 817.23 and 820.16; relative likelihood, both < 0.001; and log likelihood ratio, 45.21 vs. 22.77 and 21.84) than the Barcelona Clinic Liver Cancer staging system and the Cancer of the Liver Italian Program in predicting OS. Similar results were found while predicting disease-free survival (DFS).Conclusions: The new prognostic scoring system is simple and effective in predicting both OS and DFS of patients with spontaneous ruptured HCC.

Objective Hyperamylasemia was found in a group of patients with COVID-19 during hospitalization. However, the evolution and the clinical significance of hyperamylasemia in COVID-19, is not well characterized. Design In this retrospective cohort study, the epidemiological, demographic, laboratory, treatment and outcome information of 1,515 COVID-19 patients with available longitudinal amylase records collected from electronic medical system were analyzed to assess the prevalence and clinical significance of hyperamylasemia in this infection. Associated variables with hyperamylasemia in COVID-19 were also analyzed. Results Of 1,515 patients, 196 (12.9%) developed hyperamylasemia, among whom 19 (1.3%) greater than 3 times upper limit of normal (ULN) and no clinical acute pancreatitis was seen. Multivariable ordered logistic regression implied older age, male, chronic kidney disease, several medications (immunoglobin, systemic corticosteroids, and antifungals), increased creatinine might be associated with hyperamylasemia during hospitalization. Restricted cubic spline analysis indicated hyperamylasemia had a J-shaped association with all-cause mortality and the estimated hazard ratio per standard deviation was 2.85 (2.03-4.00) above ULN. Based on the multivariable mixed-effect cox or logistic regression model taking hospital sites as random effects, elevated serum amylase during hospitalization was identified as an independent risk factor associated with in-hospital death and intensive complications, including sepsis, cardiac injury, acute respiratory distress syndrome, and acute kidney injury. Conclusions Elevated serum amylase was independently associated with adverse clinical outcomes in COVID-19 patients. Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.

Background: The coronavirus disease 2019 (COVID-19) has swept through the world at a tremendous speed, and there is still limited data available on the treatment for COVID-19. The mortality of severely and critically ill COVID-19 patients in the Optical Valley Branch of Tongji Hospital was low. We aimed to analyze the available treatment strategies to reduce mortality.Methods: In this retrospective, single-center study, we included 1,106 COVID-19 patients admitted to the Optical Valley Branch of Tongji Hospital from February 9 to March 9, 2020. Cases were analyzed for demographic and clinical features, laboratory data, and treatment methods. Outcomes were followed up until March 29, 2020.Results: Inflammation-related indices (hs-CRP, ESR, serum ferritin, and procalcitonin) were significantly higher in severe and critically ill patients than those in moderate patients. The levels of cytokines, including IL-6, IL2R, IL-8, and TNF-α, were also higher in the critical patients. Incidence of acute respiratory distress syndrome (ARDS) in the severely and critically ill group was 23.0% (99/431). Sixty-one patients underwent invasive mechanical ventilation. The correlation between SpO2/FiO2 and PaO2/FiO2 was confirmed, and the cut-off value of SpO2/FiO2 related to survival was 134.43. The mortality of patients with low SpO2/FiO2 (2/FiO2 (>134.43) (72.7 vs. 33.3%). Among critical patients, the application rates of glucocorticoid therapy, continuous renal replacement therapy (CRRT), and anticoagulation treatment reached 55.2% (238/431), 7.2% (31/431), and 37.1% (160/431), respectively. Among the intubated patients, the application rates of glucocorticoid therapy, CRRT, and anticoagulation treatment were respectively 77.0% (47/61), 54.1% (33/61), and 98.4% (60/61).Conclusion: No vaccines or specific antiviral drugs for COVID-19 have been shown to be sufficiently safe and effective to date. Comprehensive treatment including ventilatory support, multiple organ function preservation, glucocorticoid use, renal replacement therapy, anticoagulation, and restrictive fluid management was the main treatment strategy. Early recognition and intervention, multidisciplinary collaboration, multi-organ function support, and personalized treatment might be the key for reducing mortality.

Introduction: The prognosis for recurrent intrahepatic cholangiocarcinoma with bone metastasis remains dismal and its treatment poses a challenge for oncologists. To date, only 2 cases were reported in which pembrolizumab, an agent against programmed cell death protein-1 (PD-1), combined with chemotherapy led to a complete response.[1] The safety and efficacy of nivolumab-based immunotherapy combined with lenvatinibin intrahepatic cholangiocarcinoma is unknown. Patient concerns: A 40-year-old female was identified as having a lesion of 7.0 cm in diameter in the right lobe of the liver. In addition, calculi in the main and left hepatic bile ducts as well as the gallbladder were found. Diagnosis: Based on the results of imaging studies and tumor biomarker level, the patient was initially diagnosed as having intrahepatic cholangiocellular carcinoma and cholelithiasis, after which surgery was performed. The pathological examination confirmed that the tumor was cholangiocarcinoma. Adjuvant chemotherapy was administered after surgery. However, the patient developed recurrent lesions at the 5th month after surgery, and the cholangiocarcinoma expanded to the right thoracic vertebral pedicle (T7–8) at the 6th month. Interventions: The patient underwent percutaneous microwave ablation after recurrence in the liver was identified. After that, the patient received nivolumab plus lenvatinib. Outcomes: The lesions in the liver decreased in size and disappeared after treatment with nivolumab plus lenvatinib. Additionally, the metastases in the right thoracic vertebral pedicle were stable after 9 months of therapy. Lessons: Immunotherapy has revolutionized the treatment of non-small-cell lung cancer, melanoma, and advanced renal cell carcinoma. In this case, the patient achieved an excellent radiological and symptomatic response after receiving nivolumab plus lenvatinib combination therapy. Patients suffering from cholangiocarcinoma with dMMR status and a high tumor mutation burden (TMB) may have a consistent eutherapeutic effect with anti-PD-1-directed treatment.

Background CpG island methylator phenotype (CIMP), a common biological phenomenon characterized by a subset of concurrently methylated genes, can have an influence on the progression of multiple cancers. However, the potential mechanism of CIMP in hepatocarcinogenesis and its clinical relevance remains only partially understood. Methods: We used a methylation array from the cancer genome atlas (TCGA) to stratify HCC patients into different CIMP subtypes, and evaluated their correlation with clinical characteristics. In addition, mutation, CNV, and transcriptome profiles were also utilized to evaluate the distinctive genomic patterns correlated with CIMP. Finally, a CIMP-associated prognostic model (CPM) was trained and validated using four independent datasets. Findings A subgroup of patients was identified as having CIMP-H, which was associated with worse OS and DFS. Gene enrichment analysis indicated that the terms “liver cancer with EPCAM up”, “tumor invasiveness up”, “methyltransferase complex”, and “translational initiation” were enriched in CIMP-H subgroup. Notably, somatic mutation analysis indicated that CIMP-H patients presented with a higher mutation burden of BRD4, DDIAS and NOX1. Moreover, four CPM associated genes could significantly categorize patients into low- and high-risk groups in the training dataset and another 3 independent validation datasets. Finally, a nomogram incorporating a classifier based on four mRNAs, pathological M stage and CIMP status was established, which showed a favorable discriminating ability and might contribute to clinical decision-making for HCC. Interpretation Our work highlights the potential clinical application value of CPM in predicting the overall survival of HCC patients and the mechanisms underlying the role of CIMP in hepatocarcinogenesis. Fund This work was supported by the State Key Project on Infectious Diseases of China (2018ZX10723204-003), the National Nature Science Foundation of China (Nos. 81874065, 81500565, 81874149, 81572427, and 81401997), the Hepato-Biliary-Pancreatic Malignant Tumor Investigation Fund of Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province (CXPJJH11800001-2018356).

Cholangiocarcinoma (CCA) is the second widespread liver tumor with relatively poor survival. Increasing evidence in recent studies showed long noncoding RNAs (lncRNAs) exert a crucial impact on the development and progression of CCA based on the mechanism of competing endogenous RNAs (ceRNAs). However, functional roles and regulatory mechanisms of lncRNA‐regulated ceRNA in CCA, are only partially understood. The expression profile of messenger RNAs (mRNAs), lncRNAs, and microRNAs (miRNAs) downloaded from The Cancer Genome Atlas were comprehensively investigated. Differential expression of these three types of RNA between CCA and corresponding precancerous tissues were screened out for further analysis. On the basis of interactive information generated from miRDB, miRTarBase, TargetScan, and miRcode public databases, we then constructed an mRNA‐miRNA‐lncRNA regulatory network. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses were conducted to identify the biological function of the ceRNA network involved in CCA. As a result, 2883 mRNAs, 136 miRNAs, and 993 lncRNAs were screened out as differentially expressed RNAs in CCA. In addition, a ceRNA network in CCA was constructed, composing of 50 up and 27 downregulated lncRNAs, 14 up and 7 downregulated miRNAs, 29 up and 25 downregulated mRNAs. Finally, gene set enrichment and pathway analysis indicated our CCA‐specific ceRNA network was related with cancer‐related pathway and molecular function. In conclusion, our research identified a novel lncRNA‐related ceRNA network in CCA, which might act as a potential therapeutic target for patients with CCA.

DNA methylation is a crucial regulator of gene transcription in the etiology and pathogenesis of hepatocellular carcinoma (HCC). Thus, it is reasonable to identify DNA methylation-related prognostic markers. Currently, we aimed to make an integrative epigenetic analysis of HCC to identify the effectiveness of epigenetic drivers in predicting prognosis for HCC patients. By the software pipeline TCGA-Assembler 2, RNA-seq, and methylation data were downloaded and processed from The Cancer Genome Atlas. A bioconductor package MethylMix was utilized to incorporate gene expression and methylation data on all 363 samples and identify 589 epigenetic drivers with transcriptionally predictive. By univariate survival analysis, 72 epigenetic drivers correlated with overall survival (OS) were selected for further analysis in our training cohort. By the robust likelihood-based survival model, six epi-drivers (doublecortin domain containing 2, flavin containing monooxygenase 3, G protein-coupled receptor 171, Lck interacting transmembrane adaptor 1, S100 calcium binding protein P, small nucleolar RNA host gene 6) serving as prognostic markers was identified and then a DNA methylation signature for HCC (MSH) predicting OS was identified to stratify patients into low-risk and high-risk groups in the training cohort (p < 0.001). The capability of MSH was also assessed in the validation cohort (p = 0.002). Furthermore, a receiver operating characteristic curve confirmed MSH as an effective prognostic model for predicting OS in HCC patients in training area under curve (AUC = 0.802) and validation (AUC = 0.691) cohorts. Finally, a nomogram comprising MSH and pathologic stage was generated to predict OS in the training cohort, and it also operated effectively in the validation cohort (concordance index: 0.674). In conclusion, MSH, a six epi-drivers based signature, is a potential model to predict prognosis for HCC patients.

Introduction: Hepatic paraganglioma (HPGL) originates from the sympathetic nervous tissue in the liver, and is an extremely rare type of the sympathetic paragangliomas. Till now, only 11 HPGL cases have been reported. Case presentation: A 49-year-old woman presented to our hospital with a lesion in the right lobe of the liver, which grew from 2 to 6 cm in 2 years. In addition, she had a 6-year history of diabetes. The patient was initially diagnosed as hepatocellular carcinoma and hepatectomy was performed. Surgical resection of the liver lesion was successful, but the blood pressure rose and fell sharply when the lesion was being removed. The pathological examination of the liver lesion showed that it was HPGL. After the operation, the patient recovered uneventfully. Follow-up examination showed the blood glucose level went back to the normal range in 20 days after the operation, and MRI and 131I-MIBG scan showed that there was no evidence of recurrence and metastasis in >2 years. Conclusion: By means of reporting this case and reviewing 11 reported cases, we conclude that the incidence of HPGLs is extremely low and the clinical and radiological characteristics of HPGLs are nonspecific; thus, it is hard to diagnose HPGLs correctly. Surgical resection is curative therapy for HPGLs, whereas the removing of HPGLs may cause the releasing of catecholamine, and then lead to hypertension crisis and arrhythmia. Thus, antihypertensive therapy is necessary during the operation. Follow-ups after the operation are important for HPGL patients, for pathological examinations are not sufficient to differ malignant HPGLs from benign ones, and follow-ups are helpful for HPGL patients to find the recurrent foci or metastases timely.