Hepatitis B Virus-mediated m6A demethylation increases hepatocellular carcinoma stemness and immune escape.

Hepatitis B viral (HBV) persistent infection plays a significant role in hepatocellular carcinoma (HCC) tumorigenesis. Many studies have revealed the pivotal roles of N6-methyladenosine (m6A) in multiple cancers, while the regulatory mechanism in stemness maintenance of HBV persistent infection-related HCC remains elusive. Here, we demonstrated that the level of m6A modification was downregulated by HBV in HBV-positive HCC, through enhanced stability of ALKBH5 mRNA. More specifically, we also identified that ALKBH5 mRNA was functionally required for the stemness maintenance and self-renewal in the HBV-positive HCC, but dispensable in HBV-negative HCC. Mechanistically, ALKBH5 demethylated the m6A modification in the 3'UTR region of the oncogenic gene SNAI2 to prevent the recognition of YTHDF2 therewith stabilize SNAI2 transcripts, contributing to cancer stem cell traits in HBV-positive HCC. Moreover, the expression of SNAI2 reversed the suppression of stemness properties by knocking down ALKBH5. Additionally, ALKBH5/SNAI2 axis accelerates tumor immune evasion through activated ligand of immune checkpoint CD155. Our study unveiled that the ALKBH5 induces m6A demethylation of the SNAI2 as a key regulator in HBV-related HCC, and identifies the function of ALKBH5/SNAI2/YTHDF2 axis in promoting the stem-like cells phenotype and immune escape during HBV infection. Implications: HBV promotes hepatocellular carcinoma stemness maintenance through elevate m6A modification of SNAI2 in an ALKBH5-YTHDF2 dependent manner and increases the expression of the ligand of immune checkpoint CD155.

Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease.

Liver disease, a major health concern worldwide, is a serious and progressive disorder. Herein, we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut mycobiome. As liver disease advanced, gut integrity was disrupted, and the mycobiota was disturbed in the mouse models. The metabolites associated with hepatocellular carcinoma (HCC) differed from those associated with the cirrhotic phase as follows: levels of stercobilin and aflatoxin B1 dialcohol were reduced, while levels of triterpenoids, bafilomycin A1, and DHEA were increased in the HCC group. The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in HCC. Based on the results from clinical human samples, the genus Candida (Ascomycota) (in humans) and the genus Kazachstania (Ascomycota) (in mice) occupied a dominant position in the HCC group, while other fungi were depleted. The increased abundance of C. albicans and depletion of S. cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC. Moreover, the administration of C. albicans and S. cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC. Therefore, gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.

Possibility of PD-1/PD-L1 Inhibitors for the Treatment of Patients with Chronic Hepatitis B Infection.

BACKGROUND: Chronic hepatitis B (CHB) infection is still a major global public health problem, with nearly two billion patients. Although current antiviral drugs can inhibit viral replication and reduce hepatitis B virus (HBV) related complications, it is difficult to achieve clinical endpoints due to drug resistance. SUMMARY: Immune checkpoint inhibitors (ICIs) are an important strategy to reverse T-cell exhaustion, and rebuilding an effective functional T-cell response is a promising immunomodulatory approach for CHB patients. However, ICIs may lead to viral reactivation or immune-related adverse effects. There are still many controversies in the application of ICIs in treating patients with CHB. KEY MESSAGES: This article reviews the research progress of ICIs in CHB infection and related issues. The goal of this paper was to summarize the possible impact of new therapies for CHB with the aim of reducing potential clinical risks.

Sacubitril/Valsartan Can Reduce Atrial Fibrillation Recurrence After Catheter Ablation in Patients with Persistent Atrial Fibrillation.

PURPOSE: This study compared the effectiveness of sacubitril/valsartan (SV) vs. valsartan (V) for treating persistent atrial fibrillation (AF) after radio-frequency catheter ablation (RFCA). METHODS: Patients with persistent AF who received RFCA were randomly assigned to the SV or V treatment group with the intervention lasting for 12 months. The primary outcome included any atrial arrhythmia episode lasting ≥ 30 s after a 3-month blanking period. The secondary outcome included any atrial arrhythmia episode lasting ≥ 24 h or requiring cardioversion after a 3-month blanking period. The H2FPEF score was used to assess the possibility of patients suffering from heart failure with preserved ejection fraction. RESULTS: A total of 143 patients with persistent AF who received RFCA were randomized for the study, with 5 patients failing to follow-up. Among them, 29 (42%) out of 69 patients receiving V and 15 (21.7%) out of 69 patients receiving SV reached the primary endpoint (P < 0.001). A total of 26 (37.7%) out of 69 patients receiving V and 7 (10.1%) out of 69 patients receiving SV reached the secondary endpoint (P < 0.001). A decrease in the H2FPEF score after a 1-year follow-up seemed to be related to the recurrence of AF (OR, 0.065; 95% CI: 0.018-0.238, P < 0.001). CONCLUSIONS: SV can decrease AF recurrence after catheter ablation in patients with persistent AF at the 1-year follow-up. The mechanism for this process may be related to the reduction in the H2FPEF score in patients with preserved ejection fraction heart failure.

Critical role of peroxisome proliferator-activated receptor α in promoting platelet hyperreactivity and thrombosis under hyperlipidemia.

Platelet hyperreactivity and increased atherothrombotic risk are specifically associated with dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARα) is an important regulator of lipid metabolism. It has been suggested to affect both thrombosis and hemostasis, yet the underlying mechanisms are not well understood. In this study, the role and mechanism of PPARα in platelet activation and thrombosis related to dyslipidemia were examined. Employing mice with deletion of PPARα (Pparα-/-), we demonstrated that PPARa is required for platelet activation and thrombus formation. The effect of PPARα is critically dependent on platelet dense granule secretion, and is contributed by p38MAPK/Akt, fatty acid b-oxidation, and NAD(P)H oxidase pathways. Importantly, PPARα and the associated pathways mediated a prothrombotic state induced by a high-fat diet and platelet hyperactivity provoked by oxidized low density lipoproteins. Platelet reactivity was positively correlated with the levels of expression of PPARα, as revealed by data from wild-type, chimeric (Pparα+/-), and Pparα-/- mice. This positive correlation was recapitulated in platelets from hyperlipidemic patients. In a lipid-treated megakaryocytic cell line, the lipid-induced reactive oxygen species-NF-kB pathway was revealed to upregulate platelet PPARα in hyperlipidemia. These data suggest that platelet PPARα critically mediates platelet activation and contributes to the prothrombotic status under hyperlipidemia.

Corrigendum: Identification and Analysis of the Blood lncRNA Signature for Liver Cirrhosis and Hepatocellular Carcinoma.

[This corrects the article DOI: 10.3389/fgene.2020.595699.].

High-Normal Thyroid Function and Recurrence of Atrial Fibrillation after Catheter Ablation: A Prospective Observational Study.

BACKGROUND: Thyroid function is increasingly recognized as an important modifiable factor for atrial fibrillation (AF); however, it is unclear if the changes in thyroid hormones, even within the normal range, are associated with AF recurrence after catheter ablation. METHODS: Consecutive paroxysmal AF patients who underwent catheter ablation were enrolled. Patients with abnormal thyroid hormones or previous thyroid illnesses were excluded. Patients were followed for 12 months or until they presented with the first episode of atrial tachyarrhythmia after a blanking period. RESULTS: The study included 448 patients with a mean age of 61 (14) years, and 46% were women. After a 1-year follow-up, 104 (23.2%) patients experienced atrial tachyarrhythmia recurrences after an ablation procedure. Recurrence was significantly different among quartile groups of thyroid function, with highest FT4 and FT3 levels associated with the greatest risk of recurrence (p < 0.001 and p = 0.024, respectively). FT4 and FT3 levels were independent predictors of atrial tachyarrhythmia recurrence (hazard ratio 1.07 per 1 pmol/L increase in FT4, 95% confidence interval [CI] 1.01-1.15, p = 0.036 and 1.31 per 1 pmol/L increase in FT3, 95% CI 1.01-1.71, p = 0.032). CONCLUSIONS: High-normal FT3 and FT4 levels are associated with AF recurrence after catheter ablation in this Chinese population. Attention to thyroid hormones could be valuable to assist in the management of AF.

MiR-9-5p promotes cell proliferation and migration of hepatocellular carcinoma by targeting CPEB3.

Objective: This study aimed to observe the effect of miR-9-5p and CPEB3 on hepatocellular carcinoma (HCC) cells, and investigate the underlying targeting regulatory mechanism. Materials & methods: Various experiments like CCK-8, colony formation assay, wound healing assay and Transwell were performed for cancer cell activities detection, including cell proliferation, growth activity, migration and invasion. Results: MiR-9-5p was found to be highly expressed in HCC cells, while CPEB3 was poorly expressed (p < 0.05). The overexpression of miR-9-5p and the silencing of CPEB3 both could significantly promote cell proliferation, migration and invasion (p < 0.05). In addition, miR-9-5p could target to downregulate CPEB3 expression, thus accelerating cell proliferation, migration, invasion and epithelial-mesenchymal transition process in HCC. Conclusion: MiR-9-5p can target CPEB3, thereby promoting cell proliferation, migration and invasion in HCC. The axis of miR-9-5p/CPEB3 is expected to become a potential therapeutic target beneficial for HCC patients.

Hepatitis B virus P protein initiates glycolytic bypass in HBV-related hepatocellular carcinoma via a FOXO3/miRNA-30b-5p/MINPP1 axis.

BACKGROUND: Hepatitis B virus (HBV) infection is a crucial risk factor for hepatocellular carcinoma (HCC). However, its underlying mechanism remains understudied. METHODS: Microarray analysis was conducted to compare the genes and miRNAs in liver tissue from HBV-positive and HBV-negative HCC patients. Biological functions of these biomarkers in HBV-related HCC were validated via in vitro and in vivo experiments. Furthermore, we investigated the effect of HBV on the proliferation and migration of tumor cells in HBV-positive HCC tissue. Bioinformatics analysis was then performed to validate the clinical value of the biomarkers in a large HCC cohort. RESULTS: We found that a gene, MINPP1 from the glycolytic bypass metabolic pathway, has an important biological function in the development of HBV-positive HCC. MINPP1 is down-regulated in HBV-positive HCC and could inhibit the proliferation and migration of the tumor cells. Meanwhile, miRNA-30b-5p was found to be a stimulator for the proliferation of tumor cell through glycolytic bypass in HBV-positive HCC. More importantly, miRNA-30b-5p could significantly downregulate MINPP1 expression. Metabolic experiments showed that the miRNA-30b-5p/MINPP1 axis is able to accelerate the conversion of glucose to lactate and 2,3-bisphosphoglycerate (2,3-BPG). In the HBV-negative HCC cells, miRNA-30b-5p/MINPP1 could not regulate the glycolytic bypass to promote the tumorigenesis. However, once HBV was introduced into these cells, miRNA-30b-5p/MINPP1 significantly enhanced the proliferation, migration of tumor cells, and promoted the glycolytic bypass. We further revealed that HBV infection promoted the expression of miRNA-30b-5p through the interaction of HBV protein P (HBp) with FOXO3. Bioinformatics analysis on a large cohort dataset showed that high expression of MINPP1 was associated with favorable survival of HBV-positive HCC patients, which could lead to a slower progress of this disease. CONCLUSION: Our study found that the HBp/FOXO3/miRNA-30b-5p/MINPP1 axis contributes to the development of HBV-positive HCC cells through the glycolytic bypass. We also presented miRNA-30b-5p/MINPP1 as a novel biomarker for HBV-positive HCC early diagnosis and a potential pharmaceutical target for antitumor therapy.

The association between IL-1 family gene polymorphisms and colorectal cancer: A meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is a major public health problem given its high incidence and mortality. This study focuses on examining the associations between IL-1α, IL-1ß, and IL-1RN polymorphisms and colorectal cancer susceptibility. METHODS: A systematic literature search of PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure) and Wan Fang databases was conducted to identify relevant studies. Relevant data were extracted from the original included studies. The correlation was demonstrated based on the odds ratio (OR) and corresponding 95% confidence intervals (95% CIs). Publication bias was investigated by Egger's line regression test and Begg's funnel plot. RESULTS: Eighteen independent studies involving 6218 cases and 10160 controls were eligible for this pooled analysis. Overall, the result revealed that the IL-1α rs3783553 polymorphism was significantly associated with an increased risk of CRC (G vs. C, OR = 1.02, 95% CI = 0.90-1.15, I2 = 51%, P = 0.78; GG vs. CC, OR = 1.97, 95% CI = 1.04-3.74, I2 = 70%, P = 0.04; GC vs. CC, OR = 1.75, 95% CI = 1.12-2.75, I2 = 42%, P = 0.01; GG + GC vs. CC, OR = 1.85, 95% CI = 1.08-3.18, I2 = 63%, P = 0.03; and GG vs. GC + CC, OR = 1.28, 95% CI = 1.04-1.58, I2 = 39%, P = 0.02), and significance was also noted for IL-1RN VNTR under the dominant model (22 + 2L vs. LL, OR = 1.49, 95% CI = 1.01-2.19, I2 = 77%, P = 0.045) and allelic contrast model (2 vs. L, OR = 1.28, 95% CI = 1.00-1.64, I2 = 58.6%, P = 0.047). For IL-1ß + 31C/T, significance was observed in the dominant model (CC + CT vs. TT, OR = 0.83, 95% CI = 0.69-0.99, I2 = 52%, P = 0.034) and the heterozygous model (CT vs. TT, OR = 0.80, 95% CI = 0.65-0.98, I2 = 60%, P = 0.04). For IL-1ß + 511 C/T, a significant association was noted in four gene models (CT vs. TT, OR = 0.72, 95% CI = 0.63-0.83, I2 = 0%, P < 0.001; CC + CT vs. TT, OR = 0.74, 95% CI = 0.65-0.84, I2 = 0%, P < 0.001; CC vs. TT, OR = 0.77, 95% CI = 0.65-0.91, I2 = 30.9%, P = 0.003; C vs. T, OR = 0.87, 95% CI = 0.80-0.95, I2 = 38%, P = 0.001), but a significant relationship was not found in the recessive model (CC vs. CT + TT, OR = 1.09, 95% CI = 0.86-1.38, I2 = 57.1%, P = 0.25). In addition, borderline statistical significance was noted between IL-1ß + 3954 Ins/Del and CRC in the homozygous model, but no significance was identified for IL-1ß + 3737 G/A, Il-1ß + 1464 G/C, and IL-1RN + 2018 T/C under all five genetic models. In the subgroup analysis of ethnic groups, significant associations with CRC were found for IL-1ß + 31 (CC vs. TT: OR = 0.82, 95% CI = 0.67-0.99, I2 = 20.2%, P = 0.04; CT vs. TT: OR = 0.62, 95% CI = 0.47-0.82, I2 = 0%, P < 0.001; CC + CT vs. TT: OR = 0.69, 95% CI = 0.55-0.87, I2 = 29.7%, P = 0.001), IL-1ß + 511 (CT vs. TT, OR = 0.65, 95% CI = 0.55-0.77, I2 = 0%, P < 0.001; CC + CT vs. TT, OR = 0.67, 95% CI = 0.58-0.78, I2 = 0%, P < 0.001; C vs. T, OR = 0.83, 95% CI = 0.75-0.92, I2 = 49.6%, P < 0.001) and IL-1RN + 2018 T/C in the allelic contrast model (T vs. C, OR = 0.66, 95% CI = 0.44-0.98, I2 = 0%, P = 0.04) among Asians but not in Caucasians. A significant association between IL-1ß + 1464 G/C polymorphisms in Caucasians was observed under the recessive model (OR = 0.87, 95% CI = 0.77-0.98, I2 = 45%, P = 0.03). CONCLUSION: The current meta-analysis demonstrated that IL-1α rs3783553, IL-1ß + 31C/T, IL-1ß + 511C/T, and IL-1RN VNTR are critical genes for CRC susceptibility.

Anxiety and Depression Prevalence and Risk Factors Among Patients With Cardiovascular Diseases in Post-COVID-19 China.

Objective: Data are limited on the psychological disorders of patients with cardiovascular disease during the post-COVID-19 period, although mental health status is associated with morbidity and mortality. We aimed to investigate the prevalence of anxiety and depression and risk factors among patients with cardiovascular disease in the post-pandemic period. Method: A cross-sectional survey was conducted through opportunistic and snowball sampling in southeast China from 10 October to 24 November. Anxiety and depression were assessed on the hospital anxiety and depression scale (HADS). Results: A total of 435 patients with hypertension (48.05%), atrial fibrillation (17.24%), coronary artery disease (14.48%), heart failure (9.89%) and other heart diseases (10.34%) completed the survey. Interestingly, most patients reported monthly income comparable to (90.11%) or even greater than (8.51%) pre-pandemic income. The occurrence of anxiety and depression was 11.72 and 9.20%, respectively. Marital status and treatment interruption during the pandemic were independent risk factors for both anxiety and depression. Moreover, current monthly income and access to telemedicine during the pandemic were independent risk factors for anxiety. Conclusion: Patients with cardiovascular disease may experience anxiety and depression not only because of disease complications but also because of the effects of the pandemic. In facing the global challenge posed by the coronavirus, efforts should be made to improve patients' psychological well-being in the management of populations with cardiovascular disease.

Identification and Analysis of the Blood lncRNA Signature for Liver Cirrhosis and Hepatocellular Carcinoma.

As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is the fifth major cause of cancer-associated mortality worldwide. In 90% of cases, HCC develops in the context of liver cirrhosis and chronic hepatitis B virus (HBV) infection is an important etiology for cirrhosis and HCC, accounting for 53% of all HCC cases. To understand the underlying mechanisms of the dynamic chain reactions from normal to HBV infection, from HBV infection to liver cirrhosis, from liver cirrhosis to HCC, we analyzed the blood lncRNA expression profiles from 38 healthy control samples, 45 chronic hepatitis B patients, 46 liver cirrhosis patients, and 46 HCC patients. Advanced machine-learning methods including Monte Carlo feature selection, incremental feature selection (IFS), and support vector machine (SVM) were applied to discover the signature associated with HCC progression and construct the prediction model. One hundred seventy-one key HCC progression-associated lncRNAs were identified and their overall accuracy was 0.823 as evaluated with leave-one-out cross validation (LOOCV). The accuracies of the lncRNA signature for healthy control, chronic hepatitis B, liver cirrhosis, and HCC were 0.895, 0.711, 0.870, and 0.826, respectively. The 171-lncRNA signature is not only useful for early detection and intervention of HCC, but also helpful for understanding the multistage tumorigenic processes of HCC.

Torin2 overcomes sorafenib resistance via suppressing mTORC2-AKT-BAD pathway in hepatocellular carcinoma cells.

BACKGROUND: Sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of sorafenib. As the activation of AKT/mTOR played a pivotal role in sorafenib resistance, we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC cells. METHODS: The sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell lines. The synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay method. Apoptosis induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western blotting. RESULTS: Sorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells, which underscores the significance of AKT activation. Torin2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis induction. Torin2 successfully suppressed the sorafenib-activated mTORC2-AKT axis, leading to the dephosphorylation of Ser136 in BAD protein, and increased the expression of total BAD, which contributed to the apoptosis in sorafenib-resistant HCC cells. CONCLUSIONS: In this study, Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenib-resistant HCC cells, via the suppression of mTORC2-AKT-BAD pathway. Our results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.

Identification of prognostic biomarkers of hepatocellular carcinoma via long noncoding RNA expression and copy number alterations.

Aim: This study aimed to identify long noncoding RNAs (lncRNAs) with potential to be prognostic biomarkers of hepatocellular carcinoma (HCC) by analyzing copy number alterations (CNAs). Methods: RNA Sequencing data of 369 HCC patients was downloaded from The Cancer Genome Atlas database and analyzed with a series of systematic bioinformatics methods. Results: LncRNA-CNA association analysis revealed that many lncRNAs were located in sites frequently amplified or deleted. Three upregulated lncRNAs (LINC00689, SNHG20 and MAFG-AS1) with copy amplification and one downregulated lncRNA TMEM220-AS1 with copy deletion were associated with poor prognosis of HCC. Conclusion: This study reveals that differentially expressed lncRNAs correlate with CNAs in HCC. Moreover, the differentially expressed lncRNAs and their copy amplification/deletions could be promising prognostic biomarkers of HCC.

Investigation of proper home blood pressure with atrial fibrillation recurrence in patients undergoing radiofrequency catheter ablation.

BACKGROUND: Hypertension is an important target for interventions to improve ablation outcome in atrial fibrillation (AF) patients. No studies to date have determined the blood pressure level at which AF is less likely to recur in patients without hypertension. METHODS: A total of 503 AF patients undergoing radiofrequency catheter ablation (RFCA) (mean age, 59.6±9.6 years; 319 males [63.4%]) were identified for the study cohort and analysis. Patients received a pocket diary to record their home blood pressure (HBP) before RFCA and routine 48-hour Holter-ECGs to evaluate AF recurrence after RFCA. RESULTS: A total of 383 (76.1%) patients were free of AF recurrence one year after RFCA. Blood pressure (BP), including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP), had different effects on AF recurrence one year after RFCA. A χ2 test showed that when SBP was <110 mmHg, it was associated with a lower AF recurrence in patients with hypertension (P=0.029). AF recurrence decreased (P=0.002) when SBP increased from <110 mmHg to >130 mmHg in patients without hypertension. Regression analysis indicated a significant linear correlation between BP and LAD in all patients. CONCLUSIONS: SBP should be strictly maintained at 110 mmHg after RFCA to minimize AF recurrence in patients with hypertension. Low SBP might be a risk factor for AF recurrence among patients without hypertension.

Clinical significance of the immune cell landscape in hepatocellular carcinoma patients with different degrees of fibrosis.

BACKGROUND: The major causes of morbidity and mortality of patients with chronic liver disease are liver fibrosis and cirrhosis. Previous studies have been concerned with immune dysfunction in the pathogenesis of cirrhosis progress. However, the potential molecular mechanism of how the liver's fibrotic state favors tumor progression is still unclear. We attempted to reveal deviations of the immune cell landscape between various liver tissues and identify key biomarkers associated with patients' outcomes. METHOD: CIBERSORT was used for estimating the proportions of immune cells in various liver tissues. Comparative studies were carried out by Kruskal-Wallis test and Wilcoxon test. For survival analyses, the Cox proportional hazard regression model, Kaplan-Meier estimates, and log-rank test were used. RESULTS: Significantly different adaptive and innate immune cell types were selected, including T cells, plasma cells, and resting mast cells. Meanwhile, the immune cell landscapes in The Cancer Genome Atlas' (TCGA) hepatocellular carcinoma (HCC) patients with different degrees of fibrosis were also calculated. Comparative studies and survival analysis were carried out. Resting mast cell and activated NK cells in HCC patients with fibrosis was significantly lower than that in other HCC patients without fibrosis. Then, the potential genes involved in immune cells and significantly associated with patients' outcome were identified. These genes may be potential novel checkpoints for immunotherapy, including PVRIG related to NK resting/activated cells and T cell CD8+ infiltration which was recently targeted in breast cancer. Furthermore, Pearson correlation coefficient analysis suggested that PVRIG is significantly positively related to other checkpoint molecules and Teff gene signatures. CONCLUSIONS: Alternative treatments, including immunotherapies, are necessary and urgent for HCC. Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. Our studies may find possible ways to select novel targets and improve immunotherapy efficacy by disrupting their function and promoting immune infiltration in advanced HCC patients with higher fibrosis and even cirrhosis.

U-Shaped Relationship Between Left Atrium Size on Echocardiography and 1-Year Recurrence of Atrial Fibrillation After Radiofrequency Catheter Ablation　- Prognostic Value Study.

BACKGROUND: The larger the left atrium anteroposterior dimension (LAD) and left atrium volume (LAV), the stronger the association with recurrent atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). Patients with a smaller left atrium (LA) size, however, also have increased AF recurrence.Methods and Results:In 521 patients, routine 48-h Holter electrocardiogram and echocardiography were obtained at each outpatient visit every 3 months for 12 months. On multivariate analysis, AF type, LAD, and LAV calculated using the ellipsoid model/body surface area (LAVe/BSA) were independent predictors of AF recurrence. Patients were divided into 7 groups at 0.4-cm increments of LAD: ≤3 cm, LAD≤3 cm, 3.05.0 cm. Compared with the 3.4-3.8-cm group, the adjusted HR were 3.88 (95% CI: 2.02-7.46, P<0.001), 1.03 (95% CI: 0.50-2.12, P=0.939), 0.96 (95% CI: 0.52-1.77, P=0.901), 1.36 (95% CI: 0.72-2.57, P=0.347), 3.04 (95% CI: 1.67-5.53, P<0.001), and 4.07 (95% CI: 1.93-8.60, P<0.001), respectively. Similarly, we divided LAVe/BSA into 8 groups and also observed a U-shaped curve for AF recurrence. CONCLUSIONS: Both larger and smaller LAD and LAVe/BSA were associated with a higher risk of AF recurrence 1 year after RFCA. The association of LA size and AF recurrence after RFCA is represented by a U-shaped curve.

MicroRNA­223 promotes hepatocellular carcinoma cell resistance to sorafenib by targeting FBW7.

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy associated with a poor patient prognosis. We investigated the relationship between microRNA­223 (miR­223) expression and the sensitivity of HCC cells to sorafenib treatment. miR­223 expression was determined in HCC cell lines with differential sorafenib sensitivity using reverse transcription­quantitative PCR. miR­223 inhibitor, miR­223 mimic, and F­box and WD repeat domain­containing 7 (FBW7) short interfering RNAs (siRNAs) were transfected into the HCC cells to regulate the expression levels of miR­223 and FBW7. Cell proliferation was evaluated using an ethynyl deoxyuridine (EdU) incorporation assay and Cell Counting Kit­8. FBW7 protein expression levels were observed using western blotting. miR­223 expression was increased in the HCC cells with sorafenib resistance. HCC cells with miR­223 knockdown had significantly increased sorafenib sensitivity, but the miR­223 mimic had the opposite effect. The TargetScan web server predicted that FBW7 is a target of miR­223, which was confirmed by western blotting. Furthermore, FBW7 siRNA transfection increased HCC cell resistance to sorafenib in an obvious manner, and entirely eliminated the effect of the miR­223 inhibitor on enhancing sorafenib sensitivity. To conclude, miR­223 expression is upregulated in sorafenib­resistant HCC cells, and miR­223 knockdown significantly enhances HCC cell sensitivity to sorafenib by increasing expression of the target gene, FBW7, suggesting that miR­223 may be a new therapeutic target for overcoming sorafenib resistance.

Risk stratification of decompensated cirrhosis patients by Chronic Liver Failure Consortium scores: Classification and regression tree analysis.

AIM: Decompensated cirrhosis patients have greatly variable prognosis. The aim of the study was to carry out a risk stratification for those patients by Chronic Liver Failure (CLIF) Consortium scores. METHODS: The performance of CLIF Consortium acute-on-chronic liver failure scores (CLIF-C ACLFs) and CLIF Consortium Acute Decompensation scores (CLIF-C ADs) were validated in 209 patients with ACLF and 1245 patients without ACLF at admission from the Ningbo Cohort. A classification and regression tree (CRT) analysis by CLIF-C ACLFs/CLIF-C ADs was carried out to stratify death risk among patients. RESULTS: The CLIF-C ACLFs and CLIF-C ADs showed higher predictive accuracy than Model for End-stage Liver Disease (MELD) scores, MELD plus serum sodium (MELD-Na) scores, and Child-Turcotte-Pugh classification (CP) at main time points (28, 90, 180, and 365 days), determined by area under the receiver-operating characteristic curve and concordance index in ACLF and no-ACLF patients at admission. The CRT analysis categorized ACLF patients into two groups (advanced and early ACLF), and no-ACLF patients into three groups (high-, medium-, and low-risk AD) according to risk of death. However, early ACLF and high-risk AD patients had comparable mortality at the main time points. The CRT model had a higher area under the receiver-operating characteristic curve than MELDs, MELD-Nas, and CPs in predicting prognosis in all patients. CONCLUSIONS: The CLIF-C ACLF and CLIF-C AD are better prognostic scores than MELD, MELD-Na, and CP in predicting mortality of ACLF and no-ACLF patients. A combined use of CLIF- Sequential Organ Failure Assessment, CLIF-C ACLFs, and CLIF-C ADs could identify cirrhosis patients at high death risk and assist clinical decisions for management.

Interferon and lamivudine combination therapy versus lamivudine monotherapy for hepatitis B e antigen-negative hepatitis B treatment: a meta-analysis of randomized controlled trials.

BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos(t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively], though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation.