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Background: Artificial intelligence (AI)-assisted clinical trial screening is a promising prospect, although previous matching systems were developed in English, and relevant studies have only been conducted in Western countries. Therefore, we evaluated an AI-based clinical trial matching system (CTMS) that extracts medical data from the electronic health record system and matches them to clinical trials automatically. Methods: This study included 1,053 consecutive inpatients primarily diagnosed with hepatocellular carcinoma who were referred to the liver tumor center of an academic medical center in China between January and December 2019. The eligibility criteria extracted from two clinical trials, patient attributes, and gold standard were decided manually. We evaluated the performance of the CTMS against the established gold standard by measuring the accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and run time required. Results: The manual reviewers demonstrated acceptable interrater reliability (Cohen’s kappa 0.65–0.88). The performance results for the CTMS were as follows: accuracy, 92.9–98.0%; sensitivity, 51.9–83.5%; specificity, 99.0–99.1%; PPV, 75.7–85.1%; and NPV, 97.4–98.9%. The time required for eligibility determination by the CTMS and manual reviewers was 2 and 150 h, respectively. Conclusions: We found that the CTMS is particularly reliable in excluding ineligible patients in a significantly reduced amount of time. The CTMS excluded ineligible patients for clinical trials with good performance, reducing 98.7% of the work time. Thus, such AI-based systems with natural language processing and machine learning have potential utility in Chinese clinical trials. [ABSTRACT FROM AUTHOR]

Background: Whether serum hepatitis B virus (HBV) RNA associates with hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients has not been fully elucidated.Methods: We enrolled 2974 patients receiving nucleos(t)ide analogues (NAs) from a prospective, observational CHB cohort to investigate the effect of serum HBV RNA, measured at study entry (baseline), on HCC development, using Cox regression analyses.Results: During median follow-up of 4.4 years, 90 patients developed HCC. Patients with detectable baseline HBV RNA (n = 2072) exhibited significantly higher HCC risk than those with undetectable level (5-year HCC incidence estimated by Kaplan-Meier method: 4.1% versus 1.8%, P = .009; adjusted hazard ratio [aHR] = 2.21, P = .005). HBV RNA levels of 609-99 999 and ≥100 000 copies/mL were associated with incrementally increasing HCC risk (aHR = 2.15 and 3.05, respectively; P for trend = .003), compared to undetectable level (<609 copies/mL). Moreover, patients with single-detectable either HBV DNA or RNA and double-detectable DNA and RNA had 1.57- and 4.02-fold higher HCC risk, respectively, than those with double-undetectable DNA and RNA (P for trend = .001).Conclusions: High-level HBV RNA is associated with increased HCC risk in NAs-treated patients. Achieving undetectable HBV RNA may contribute to better clinical outcomes, indicating it could be a valuable endpoint of anti-HBV treatment. [ABSTRACT FROM AUTHOR]

Background: Combining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC). Aims: To explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC. Methods: This multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety. Results: By March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events. Conclusion: First-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

The responses of forests to nitrogen (N) deposition largely depend on the fates of deposited N within the ecosystem. Nitrogen‐fixing legume trees widely occur in terrestrial forests, but the fates of deposited N in legume‐dominated forests remain unclear, which limit a global evaluation of N deposition impacts and feedbacks on carbon sequestration. Here, we performed the first ecosystem‐scale 15N labeling experiment in a typical legume‐dominated forest as well as in a nearby non‐legume forest to determine the fates of N deposition between two different forest types and to explore their underlying mechanisms. The 15N was sprayed bimonthly for 1 year to the forest floor in control and N addition (50 kg N ha−1 year−1 for 10 years) plots in both forests. We unexpectedly found a strong capacity of the legume forest to retain deposited N, with 75 ± 5% labeled N recovered in plants and soils, which was higher than that in the non‐legume forest (56 ± 4%). The higher 15N recovery in legume forest was mainly driven by uptake by the legume trees, in which 15N recovery was approximately 15% more than that in the nearby non‐legume trees. This indicates higher N‐demand by the legume than non‐legume trees. Mineral soil was the major sink for deposited N, with 39 ± 4% and 34 ± 3% labeled N retained in the legume and non‐legume forests, respectively. Moreover, N addition did not significantly change the 15N recovery patterns of both forests. Overall, these findings indicate that legume‐dominated forests act as a strong sink for deposited N regardless of high soil N availability under long‐term atmospheric N deposition, which suggest a necessity to incorporate legume‐dominated forests into N‐cycling models of Earth systems to improve the understanding and prediction of terrestrial N budgets and the global N deposition effects. [ABSTRACT FROM AUTHOR]

MicroRNAs are a group of endogenous small non-coding RNAs commonly dysregulated in tumorigenesis, including glioblastoma (GBM), the most malignant brain tumor with rapid proliferation, diffuse invasion, and therapeutic resistance. Accumulating evidence has manifested that miR-1258 exerts an inhibitory role in many human cancers. However, the expression pattern of miR-1258 and its potential function in GBM tumorigenesis remain unclear. In this study, we reported that miR-1258 expression decreased with the ascending pathological grade of glioma, which indicated an unfavorable prognosis of patients. Functional assays revealed an inhibitory effect of miR-1258 on malignant proliferation, therapeutic resistance, migration, and invasion of GBM in vitro. Moreover, xenograft models also suggested a repression effect of miR-1258 on gliomagenesis. Mechanistically, miR-1258 directly targeted E2F1 in 3'-untranslated regions and attenuated E2F1-mediated downstream gene PCNA and MMP2 transcriptions. Furthermore, restoration of E2F1 expression in GBM cells effectively rescued the tumor-suppressive effect of miR-1258. Our studies illustrated that miR-1258 functioned as a tumor suppressor in GBM by directly targeting E2F1, subsequently inhibiting PCNA and MMP2 transcriptions, which contributed to new potential targets for GBM therapy and other E2F1-driven cancers. [ABSTRACT FROM AUTHOR]

Background: There is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC. Aim: The aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients. Methods: A total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly: training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility. Results: Eight radiomics features from the whole tumor and peritumoral regions were selected and comprised of the Fusion Radiomics score. Together with two clinical factors (tumor embolus and ALBI grade), a radiomics nomogram was developed with an area under the curve (AUC) of 0.894 (95% CI, 0.797–0.991) and 0.883 (95% CI, 0.716–0.998) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) confirmed that nomogram had good consistency and clinical usefulness. Conclusions: This study has developed and validated a radiomics nomogram by incorporating the pretreatment CECT images and clinical factors to predict the anti-PD-1 treatment efficacy in patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Introduction: Previous trials demonstrated that anti-angiogenesis or anti-programmed death protein 1 (PD-1) monotherapy showed unsatisfied effect in advanced hepatocellular carcinoma (HCC). No study existed that focus on the effects of camrelizumab and apatinib ("C+A") combination therapy for HCC patients with the location and extent of portal vein tumor thrombus (PVTT) as the main variable being assessed. This study was to compare the efficacy and tolerability of "C+A" for HCC patients with PVTT. Methods: We retrospectively analyzed patients with advanced HCC and PVTT who underwent "C+A" therapy in a multicenter retrospective cohort from Jan 2019 to July 2020. Outcomes of patients who underwent "C+A" were analyzed by using the Kaplan–Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). Results: Sixty-three patients were finally included and the mean duration of follow-up was 12.6 ± 4.5 months. The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 44.0% and 75.0%, respectively. The median overall survival (OS), progression-free survival (PFS) and time to progression (TTP) were 14.8 months, 11.8 months and not yet reached (NR), respectively. Patients with type B (OS, 15.9 months; PFS, 14.0 months; TTP, NR) or type C (OS, 16.0 months; PFS, 14.9 months; NR) PVTT appear to have better survival benefits compared with type A (OS, 5.8 months; PFS, 5.0 months; TTP, 7.0 months). Along with AFP, the absence of main PVTT was an independent predictive factor for survival at uni- and multivariate analysis. Conclusion: Camrelizumab and apatinib yielded a promising outcome in patients with advanced HCC who developed a tumor thrombus in the first lower-order portal vein branches and was generally safe and had manageable side effects. [ABSTRACT FROM AUTHOR]

Background Little is known about cause and intervention for alanine aminotransferase (ALT) elevation after complete viral suppression in patients with chronic hepatitis B (CHB). Methods In this prospective cohort study, patients with CHB who were treated with nucleos(t)ide analogs and maintained undetectable levels of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) for at least 6 months were enrolled. Patients were followed up at 6-month intervals, and anthropometric, biochemical, and virological assessments were performed. Results Of 1965 patients with median follow-up of 18.36 months, one third of patients experienced ALT elevation. Baseline high body mass index ([BMI] defined as ≥25 kg/m2), younger age, and liver cirrhosis independently increased the risk of longitudinal ALT elevation. At the end of follow-up, 89 (4.8%) patients reverted to low BMI, and 92 (5.0%) developed to high BMI. Compared with persistent high BMI, reversion to low BMI reduced the risk of ALT elevation (adjusted odds ratio [aOR], 0.38; 95% confidence interval [CI], 0.19–0.77); compared with persistent low BMI, onset of high BMI increased the risk of ALT elevation (aOR, 1.78; 95% CI, 1.02–3.11). Conclusions High BMI is an independent predictor for ALT elevation after complete HBV DNA suppression. Improvement of BMI may have a beneficial effect on ALT normalization and even long-term outcomes. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a wound-healing response that arises from various aetiologies. Flavonoid compounds have been proved of their anti-liver fibrosis effects. This study aimed to elucidate the protective effect and mechanism of flavonoid compound GL-V9 on CCl 4 -induced and DDC-induced liver fibrosis. Treatment with GL-V9 alleviated hepatic injury and exhibited a dramatic protection effect of liver fibrosis. Further experiments found that GL-V9 treatment inhibited extracellular matrix (ECM) expression. Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. GL-V9 could inhibit the activation of HSCs through directly binding to TGFβRI, subsequently inhibit TGF-β/Smad pathway. In conclusion, this study proved that GL-V9 executed a protective effect on liver fibrosis by inhibiting TGF-β/Smad pathway. Llustration of GL-V9 in the regulation of liver fibrosis. [Display omitted] • GL-V9 attenuates liver fibrosis induced by CCl 4 and DDC. • GL-V9 attenuates liver fibrosis by inhibiting TGF-β/Smad pathway. • L-V9 inhibits TGF-β/Smad pathway by binding to TGFβRI. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in China and frequently occurs with chronic hepatitis B virus infection. To investigate whether cell-based cancer immunotherapy induces tumor specific immune responses in patients with HCC and provides clinical benefits, as well as to elucidate the most immunogenic tumor associated antigens (TAAs), multiple antigen stimulating cellular therapy (MASCT) was applied in addition to standard of care.Methods: Mature dendritic cells (DCs) and activated T cells prepared for MASCT were generated from autologous peripheral blood mononuclear cells (PBMCs). DCs were loaded with a peptide pool of multiple HCC-related tumor antigens, and T cells were stimulated by these DCs.Results: Thirteen patients with HCC received repeated MASCT after tumor resection during which their immune responses were examined. After three courses of MASCT, the frequency of regulatory T cells in the patients' PBMCs significantly decreased (p < 0.001), while the antigen peptide pool-triggered T cell proliferation (p < 0.001) and IFNγ production (p = 0.001) were significantly enhanced. The specific T cell responses against each antigen in the pool were detected in 11 patients, but with individualized distinct patterns. The most immunogenic TAAs for HCC are survivin, CCND1, and RGS5. Moreover, the antigen-specific immune responses observed in tumor-free patients' PBMCs were significantly stronger than that in the patients with recurrence (p = 0.037).Conclusions: Our study demonstrates that MASCT is well-tolerated by patients with HCC and elicits strong and dynamic immune responses specifically against multiple tumor associated antigens, which may correlate with clinical outcomes. [ABSTRACT FROM AUTHOR]

The above article from British Journal of Clinical Pharmacology, published online on July 5, 2020 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn by agreement among the authors and John Wiley & Sons Ltd on behalf of the British Pharmacology Society. The withdrawal has been agreed in accordance with the authors' decision to revise their study providing the latest data. [ABSTRACT FROM AUTHOR]

Background: The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response. Methods: This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC. Results: A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules (n = 8), and in the expansion, patients received 600 mg BID capsules (n = 28) or 400 mg BID tablets (n = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)]. Conclusions: Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC. Trial registration: ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827 [ABSTRACT FROM AUTHOR]

There are no data validating the performance of spleen stiffness measurement in ruling out high-risk varices in patients with HBV-related cirrhosis under maintained viral suppression. Thus, we aimed to prospectively validate the performance of spleen stiffness measurement (cut-off 46 kPa) combined with Baveno VI criteria in ruling out high-risk varices in these patients. Patients with cirrhosis were enrolled from April to December 2019 at the hepatology unit of the Nanfang Hospital, China. Liver and spleen transient elastography and esophagogastroduodenoscopy were performed at enrollment. Antiviral regimen(s) and virological responses, evaluated every 3-6 months, were recorded. Overall 341 patients with HBV-related cirrhosis under maintained viral suppression were enrolled, and the prevalence of high-risk varices was 20.5% (70/341). Baveno VI criteria spared 37.0% (126/341) esophagogastroduodenoscopies and no high-risk varices were missed (0/70). Eight cases of high-risk varices (8/70, 11.4%) were misclassified in patients (208/341, 61.0%) within the expanded Baveno VI criteria. The spleen stiffness measurement cut-off (≤46.0 kPa) was shown to safely rule out high-risk varices in these patients (the percentage of missed high-risk varices was 4.3%). Over half (61.6%, 210/341) of patients met the combined model (Baveno VI criteria and spleen stiffness measurement cut-off ≤46 kPa) and 4.3% (3/70) of high-risk varices cases were misclassified. This combined model exhibited a sensitivity of 95.71%, specificity of 76.38%, negative predictive value of 98.57%, and negative likelihood ratio of 0.06 for ruling out high-risk varices. We validated the excellent performance of Baveno VI criteria combined with spleen stiffness measurement (cut-off 46 kPa) for safely ruling out high-risk varices in patients with HBV-related cirrhosis under viral suppression; more than half of esophagogastroduodenoscopy procedures were spared using this combination. NCT04123509 Esophageal varices have important prognostic implications in patients with cirrhosis. Thus, their timely identification is important so that treatment can be initiated early. Herein, we validated the excellent performance of the combination of Baveno VI criteria with spleen stiffness measurement (cut-off 46 kPa) for ruling out high-risk esophageal varices in patients with HBV-related cirrhosis under maintained viral suppression (with antiviral treatment). This combined model was able to safely rule out high-risk varices (missed/total <5%) and over half (61.6%) of esophagogastroduodenoscopy procedures were spared. • Largest prospective study validating the performance of Baveno VI criteria in patients with cirrhosis under HBV suppression. • SSM (≤46 kPa) for ruling out high-risk varices was well validated in patients with cirrhosis under viral suppression. • More unnecessary endoscopies (>50%) can be safely avoided by combining Baveno VI criteria and SSM model. [ABSTRACT FROM AUTHOR]