Identification and molecular docking of xanthine oxidase and α-glucosidase inhibitors in Opuntia ficus-indica fruit.

Opuntia ficus-indica fruit (OFI) is rich in bioactive compounds, which can promote human health. In this work, the purified OFI extract was prepared from OFI and its bioactivities were investigated. Xanthine oxidase (XOD) and α-glucosidase (α-Glu) inhibitors of the purified OFI extract were screened and identified by bio-affinity ultrafiltration combined with UPLC-QTRAP-MS/MS technology. The inhibitory effect of these inhibitors on enzymes were verified, and the potential mechanism of action and binding sites of inhibitors with enzymes were revealed based on molecular docking. The results showed that the total phenolic content of the purified OFI extract was 355.03 mg GAE/g DW, which had excellent antioxidant activity. Additionally, the extract had a certain inhibitory effect on XOD (IC50 = 199.00 ± 0.14 µg/mL) and α-Glu (IC50 = 159.67 ± 0.01 µg/mL). Seven XOD inhibitors and eight α-Glu inhibitors were identified. Furthermore, XOD and α-Glu inhibition experiments in vitro confirmed that inhibitors such as chlorogenic acid, taxifolin, and naringenin had significant inhibitory effects on XOD and α-Glu. The molecular docking results indicated that inhibitors could bind to the corresponding enzymes and had strong binding force. These findings demonstrate that OFI contains potential substances for the treatment of hyperuricemia and hyperglycemia.

The long-term efficacy of imatinib with hepatic resection or other local treatment for gastrointestinal stromal tumours liver metastases: a retrospective cohort study.

BACKGROUND: The liver is the most common site of metastasis from gastrointestinal stromal tumors (GISTs). The authors aimed to evaluate imatinib (IM) combined with hepatic resection (HR) or other local treatments such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), compared to IM monotherapy in long-term survival benefits in patients suffering from GIST liver metastases. METHODS: Our research encompassed 238 patients diagnosed with liver metastases of GISTs from January 2002 to April 2022 at the First Affiliated Hospital of Sun Yat-Sen University. The oncological outcomes of concern included overall survival (OS), progression-free survival (PFS), and liver-specific PFS. RESULTS: Of all 238 patients, 126 were treated with IM alone (IM group), 81 with IM combined with HR (IM+HR group), and 31 with IM combined with RFA/TACE (IM+RFA/TACE group). The median follow-up time was 44.83 months. The median OS in the IM group was 132.60 months and was not reached in either the IM+HR group or the IM+RFA/TACE group. The 10-year OS rate in the IM+HR group was significantly superior to the IM group and the IM+RFA/TACE group (91.9% vs. 61.1% vs. 55.2%, respectively, P =0.015), and the liver-specific PFS ( P =0.642) and PFS ( P =0.369) in the three groups showed a beneficial trend in the combined treatment group. Multivariate analyses showed that age less than or equal to 60 years (HR 0.280, P< 0.001) and IM+HR (HR 0.361, P =0.047) were independently associated with better OS. Achieving no evidence of disease through surgical intervention was independently correlated with enhanced OS (HR 0.099, P =0.034), liver-specific PFS (HR 0.388, P =0.014), and PFS (HR 0.402, P =0.004). CONCLUSIONS: In patients with GIST liver metastases, IM combined with HR might improve OS in selected patients compared with IM alone and IM combined with RFA/TACE. Achieving no evidence of disease status with surgical treatment of patients results in significant prolonging of OS, liver-specific PFS, and PFS.

Adjuvant Transarterial Chemoembolization With Sorafenib for Portal Vein Tumor Thrombus: A Randomized Clinical Trial.

Importance: Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence. Objective: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus. Design, Setting, and Participants: This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included. Interventions: Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib. Main Outcomes and Measures: The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment. Results: Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group. Conclusion and Relevance: In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04143191.

Th17 Cells Secrete TWEAK to Trigger Epithelial-Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis.

Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM. SIGNIFICANCE: TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK-Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.

A TGF-ß-dominant chemoresistant phenotype of hepatoblastoma associated with aflatoxin exposure in children.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need. APPROACH AND RESULTS: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-ß cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-ß of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-ß. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis. CONCLUSIONS: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

Comparison of clinical efficacy between LAPS and ALPPS in the treatment of hepatitis B virus-related hepatocellular carcinoma.

Background: Insufficient post-operative future liver remnant (FLR) limits the feasibility of hepatectomy for patients. Staged hepatectomy is an effective surgical approach that can improve the resection rate of hepatocellular carcinoma (HCC). This study aimed to compare the safety and efficacy of laparoscopic microwave ablation and portal vein ligation for staged hepatectomy (LAPS) and classical associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in the treatment of hepatitis B virus (HBV)-related HCC. Methods: Clinical data of patients with HBV-related HCC who underwent LAPS or ALPPS in our institute between January 2017 and May 2022 were retrospectively analysed. Results: A total of 18 patients with HBV-related HCC were retrospectively analysed and divided into the LAPS group (n = 9) and ALPPS group (n = 9). Eight patients in the LAPS group and eight patients in the ALPPS group proceeded to a similar resection rate (88.9% vs 88.9%, P = 1.000). The patients undergoing LAPS had a lower total comprehensive complication index than those undergoing ALPPS but there was not a significant different between the two groups (8.66 vs 35.87, P = 0.054). The hypertrophy rate of FLR induced by ALPPS tended to be more rapid than that induced by LAPS (24.29 vs 13.17 mL/d, P = 0.095). The 2-year recurrence-free survival (RFS) was 0% for ALPPS and 35.7% for LAPS (P = 0.009), whereas the 2-year overall survival for ALPPS and LAPS was 33.3% and 100.0% (P = 0.052), respectively. Conclusions: LAPS tended to induce lower morbidity and FLR hypertrophy more slowly than ALPPS, with a comparable resection rate and better long-term RFS in HBV-related HCC patients.

Thiacalix[4]arene-protected alkynyl Agn (n = 9, 18) nanoclusters: syntheses, structural characterizations, photocurrent responses and fluorescence properties.

Two thiacalix[4]arene-protected silver(I) alkynyl nanoclusters, [Na2(H2O)2][Ag9(TC4A)(tBuCC)4(CH3OH)2(SbF6)0.5(OH)2.5]·3.5H2O·CH3OH (1, abbreviated as Ag9) and [Ag9(TC4A)(tBuCC)4(CF3COO)]2·4CH3OH (2, abbreviated as Ag18), were synthesized by the reaction of [tBuCCAg]n, p-tert-butylthiacalix[4]arene (H4TC4A), NaBH4, and AgSbF6 or CF3COOAg in the mixed solvent of methanol-trichloromethane-toluene under solvothermal conditions, respectively. Driven by SbF6- and CF3COO- with different coordination properties, the structural unit [Ag9(TC4A)(tBuCC)4]+ in both the compounds migrated in different modes, accompanied by distinct Ag⋯Ag distances. Ag9 and Ag18 exhibit similar UV-Vis absorption and diffuse reflection spectra along with contrary tendency between photocurrent responses and solid-state fluorescence. The solution stability of Ag9 and Ag18 was demonstrated by 1H NMR and MALDI-TOF mass spectrometry. The fluorescence responses of Ag9 and Ag18 towards different organic molecules were also investigated, which indicated that the polarity of solvent has a certain effect on the emission intensities of Ag9 and Ag18. This study provides a positive guide for the controlled synthesis and further study of the structure-activity relationship of thiacalix[4]arene-protected silver alkynyl nanoclusters.

Acupressure can reduce preoperative anxiety in adults with elective surgery: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Preoperative anxiety is prevalent amongst adults with elective surgery and is associated with multiple detrimental perioperative physiological effects. Increasing studies support the effectiveness of acupressure in managing preoperative anxiety. However, the magnitude of acupressure's positive association with preoperative anxiety is still unclear due to a lack of rigorous evidence synthesis. OBJECTIVE: To estimate the efficacy of acupressure on preoperative anxiety and physiological parameters amongst adults scheduled for elective surgery. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Search terms were combined for acupressure and preoperative anxiety in PubMed, Cochrane Library, EMBASE, CINAHL, China National Knowledge Infrastructure, and WanFang Data Knowledge Service Platform to search for eligible randomised controlled trials from the inception of each database through September 2022. METHODS: Pairs of researchers independently screened and extracted data from included studies. The risk of bias was assessed using the Cochrane risk of bias tool Version 2.0. Meanwhile, random-effects meta-analysis of overall effects and prespecified subgroup (i.e., surgery types, intervention providers, and acupressure stimulation tools) was conducted using Review Manager Software 5.4.1. Meta-regression was performed to explore study-level variables that may contribute to heterogeneity using STATA 16. RESULTS: Of 24 eligible randomised controlled trials, there were a total of 2537 participants from 5 countries contributed to this synthesis. When comparing acupressure with usual care or placebo, acupressure showed a large effect size for preoperative anxiety (SMD = -1.30; 95%CI = -1.54 to -1.06; p < 0.001; I2 = 86%). The significant mean reduction of heart rate, and systolic and diastolic blood pressure was -4.58 BPM (95%CI = -6.70 to -2.46; I2 = 89%), -6.05 mmHg (95%CI = -8.73 to -3.37; p < 0.001; I2 = 88%), and -3.18 mmHg (95%CI = -5.09 to -1.27; p = 0.001; I2 = 78%), respectively. Exploratory subgroup analyses showed significant differences in surgery types and acupressure stimulation tools, whilst the intervention providers (i.e., healthcare professionals and self-administered) showed no statistically significant difference for acupressure therapy. None of the predefined participants and study-level characteristics moderated preoperative anxiety through meta-regression. CONCLUSION: Acupressure appears efficacious as a therapy for improving preoperative anxiety and physiological parameters amongst adults with elective surgery. Self-administered acupressure, which is effective with a large effect, may be considered as an evidence-based approach to managing preoperative anxiety. Hence, this review aids in the development of acupressure in different types of elective surgeries and the improvement of the rigour of acupressure therapy.

A Semi-supervised Sensing Rate Learning based CMAB scheme to combat COVID-19 by trustful data collection in the crowd.

The recruitment of trustworthy and high-quality workers is an important research issue for MCS. Previous studies either assume that the qualities of workers are known in advance, or assume that the platform knows the qualities of workers once it receives their collected data. In reality, to reduce costs and thus maximize revenue, many strategic workers do not perform their sensing tasks honestly and report fake data to the platform, which is called False data attacks. And it is very hard for the platform to evaluate the authenticity of the received data In this paper, an incentive mechanism named Semi-supervision based Combinatorial Multi-Armed Bandit reverse Auction (SCMABA) is proposed to solve the recruitment problem of multiple unknown and strategic workers in MCS. First, we model the worker recruitment as a multi-armed bandit reverse auction problem and design an UCB-based algorithm to separate the exploration and exploitation, regarding the Sensing Rates (SRs) of recruited workers as the gain of the bandit Next, a Semi-supervised Sensing Rate Learning (SSRL) approach is proposed to quickly and accurately obtain the workers' SRs, which consists of two phases, supervision and self-supervision. Last, SCMABA is designed organically combining the SRs acquisition mechanism with multi-armed bandit reverse auction, where supervised SR learning is used in the exploration, and the self-supervised one is used in the exploitation. We theoretically prove that our SCMABA achieves truthfulness and individual rationality and exhibits outstanding performances of the SCMABA mechanism through in-depth simulations of real-world data traces.

Effectiveness of auricular acupoint therapy targeting menstrual pain for primary dysmenorrhea: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Primary dysmenorrhea (PD) is a global public health concern affecting women's health and quality of life, leading to productivity loss and increased medical expenses. As a non-pharmacological intervention, auricular acupoint therapy (AAT) has been increasingly applied to treat PD, but the overall effectiveness remains unclear. AIMS: The aim of this review was to synthesize the effects of AAT targeting menstrual pain among females with PD. METHODS: Eight databases (PubMed, EMBASE, AMED, CINAHL Plus, Cochrane Library, Web of Science, China National Knowledge Infrastructure and Wanfang Data) and three registries (ClinicalTrials.gov, ISRCTN Registry and the Chinese Clinical Trial Registry) were searched to identify existing randomized controlled trials (RCTs) from inception to 21 August 2022. Two reviewers independently screened, extracted the data, and appraised the methodological quality and the evidence strength using the Cochrane risk-of-bias tool for randomized trials (RoB 2) and the GRADE approach. RESULTS: A total of 793 participants from 11 RCTs were included. Despite substantial heterogeneity, AAT was more effective in reducing menstrual pain and related symptoms than placebo and nonsteroidal anti-inflammatory medications (NSAIDs). No significant subgroup differences were found between study locations as well as invasiveness, duration, type, acupoints number, ear selection and provider of AAT. Only minor adverse effects of AAT were reported. LINKING EVIDENCE TO ACTION: AAT can help women with PD, particularly those who are refrained from pharmaceuticals. Primary healthcare professionals, including nurses, can be well-equipped to provide evidence-based and effective AAT for people with PD. AAT can be used in a broader global clinical community. To provide an optimal effect and have wider usability, a unified practice standard is required, which would necessitate further adaptation of clinical care of people with PD. AAT effectively decreased menstrual pain and other accompanying symptoms of PD. More research is needed to identify effective AAT features and explore optimal therapy regimes for PD.

Development and external validation of a prognosis model to predict outcomes after curative resection of early-stage intrahepatic cholangiocarcinoma.

Background: Early-stage intrahepatic cholangiocarcinoma (ESICC) with curative resection and lymph node-negative still has the risk of poor prognosis, and there lacks prognosis-assessing tools for these patients. The objective of this study was to develop a prognosis model to predict outcomes and identify risk stratification for ESICC after resection. Methods: Totally 263 patients with ESICC after hepatectomy from January 2012 to January 2022 were analyzed. Clinicopathological factors were selected using multivariable Cox regression analysis and a prognosis model was developed. The performance of the model was evaluated by concordance index (C-index), calibration plots, decision curves analysis (DCA), and net reclassification index (NRI). Kaplan-Meier curves were analyzed for risk stratification of overall survival (OS) and recurrence-free survival (RFS) based on the prognosis model. Results: The clinicopathological features that were independently associated with OS of ESICC included carbohydrate antigen19-9, carcinoembryonic antigen, tumor size, tumor differentiation, and T stage. The prognosis model based on these prognostic factors demonstrated excellent discriminatory performance in both derivation cohort (C-index, 0.71) and external validation cohort (C-index, 0.78), which outperformed the TNM staging system (C-index, 0.59) and individual prognostic factors (all C-index < 0.7). Calibration plots, DCA and NRI also showed superior predictive performance. According to the risk for survival, the model stratified patients into low risk (median OS, 66.6 months; median RFS, 24.3 months) and high risk (median OS, 24.0 months; median RFS, 6.4 months) (P < 0.001). Conclusions: Our prognosis model can robustly predict the outcomes of ESICC after curative resection and provide precise evaluation on prognosis risk, facilitating clinicians to develop individualized postoperative treatment options.

High-efficiency ultrathin metasurfaces with simultaneous control of complete phase, amplitude, and polarization.

Metasurfaces that can simultaneously manipulate both amplitude and phase have garnered interest and have promising applications owing to their strong beam-steering ability; however, achieving a high maximum transmission while covering the full phase shift remains challenging. This paper proposes a chiral-structured meta-atom composed of two external cross-polarized patches and an internal coupling structure. It enables the independent modulation of the phase, amplitude, and polarization at large incidence angles and ensures a high maximum transmission with a complete phase shift enabled by the two internal rotation structures. The transmission phase and amplitude can be independently controlled by adjusting the geometry and rotation angle of the meta-atoms. The performance and feasibility of the method were verified using an ultra-thin high-order Bessel beam generator sample with a thickness of 2 mm (about λ0/11 at 14 GHz). This design can meet arbitrary requirements for extreme beam steering and has broad application prospects in the fields of electromagnetism and photonics.

Effectiveness of virtual reality distraction interventions to reduce dental anxiety in paediatric patients: A systematic review and meta-analysis.

OBJECTIVES: To analyse the effectiveness of virtual reality (VR) distraction intervention for the management of dental anxiety in paediatric patients. DATA: Randomised controlled trials (RCTs) of VR distraction interventions for reducing anxiety in paediatric patients, published in English were included. SOURCES: Seven databases, including PubMed, Web of Science, Scopus, MEDLINE via ProQuest, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials, covering the period between January 2000 and September 2022 were searched. STUDY SELECTION: A total of 12 RCTs involving 818 participants were included. Quality appraisal was undertaken using the Cochrane risk-of-bias tool for randomised trials by two authors independently. Random-effects model was used to summarise the effects of the interventions and pool data. CONCLUSIONS: Results showed that VR distraction interventions were effective in reducing the dental anxiety of paediatric patients. In meta-analysis, the VR distraction interventions had a significant effect on reducing paediatric patients' anxiety (SMD = -1.74, 95%CI = -2.46, -1.02, p < 0.001, I² = 95%), pain (SMD = -1.57, 95%CI = -2.22, -0.91, p < 0.001, I² = 91%) and heart rate (MD = -10.54, 95%CI = -20.26, -0.81, p = 0.03, I² = 99%) during dental treatment. However, the evidence of VR in managing dental anxiety would become weak because of the publication bias. CLINICAL SIGNIFICANCE: VR distraction interventions could be an effective approach to alleviate the dental anxiety of paediatric patients. Additional well-designed and high-quality RCTs with larger sample sizes are needed to determine the optimal way to deliver VR interventions in paediatric dental clinics.

Distinct single-cell immune ecosystems distinguish true and de novo HBV-related hepatocellular carcinoma recurrences.

OBJECTIVE: Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies. DESIGN: We performed 5'and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts. RESULTS: Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells' cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients. CONCLUSION: True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.

Strategy for Accurate Diagnosis by Contrast-Enhanced Ultrasound of Focal Liver Lesions in Patients Not at High Risk for Hepatocellular Carcinoma: A Preliminary Study.

OBJECTIVE: To develop an effective strategy for accurate diagnosis of focal liver lesions (FLLs) in patients with non-high risk for hepatocellular carcinoma (HCC). METHODS: From January 2012 to December 2015, consecutive patients with non-high risk for HCC who underwent contrast-enhanced ultrasound (CEUS) were included in this retrospective double-reader study. All patients were stratified into 2 different risks (intermediate, low-risk) groups according to criteria based on clinical characteristics, known as clinical risk stratification criteria. For the intermediate-risk group, the CEUS criteria for identifying benign lesions and HCCs were constructed based on selected CEUS features. The diagnostic performance of the clinical risk stratification criteria, and CEUS criteria for identifying benign lesions and HCCs was evaluated. RESULTS: This study included 348 FLLs in 348 patients. The sensitivity and specificity of the clinical risk stratification criteria for malignancy was 97.8 and 69.8%. Patients were classified as intermediate risk if they were male, or older than 40 years of age, or HBcAb positive, or having positive tumor markers. Otherwise, patients were classified as low risk. Among the 348 patients, 327 were in the intermediate-risk group and 21 were in the low-risk group. In the intermediate-risk group, the CEUS criteria for identifying benign lesions were any of the following features: 1) hyper/isoenhancement in the arterial phase without washout, 2) nonenhancement in all phases, 3) peripheral discontinuous globular enhancement in the arterial phase, 4) centrifugal enhancement or peripheral enhancement followed by no central enhancement, or 5) enhanced septa. The accuracy, sensitivity, and specificity of the CEUS criteria for identifying benign lesions were 94.5, 83.0, and 99.6%, respectively. Arterial phase hyperenhancement followed by mild and late washout (>60 seconds) was more common in HCC patients than in non-HCC patients (P < .001). Using arterial phase hyperenhancement followed by mild and late washout as the CEUS criteria for identifying HCCs, the sensitivity and specificity were 52.6 and 95.3%, but unfortunately, the positive predictive value was only 82.0%. For the low-risk group, no further analysis was performed due to the small sample size. CONCLUSIONS: Initial clinical risk stratification followed by assessment of certain CEUS features appears to be a promising strategy for the accurate diagnosis of FLLs in patients not at high risk for HCC.

Targeting tumour-intrinsic N7-methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy.

OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy. DESIGN: Tumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs. Functional analysis and mechanism studies were performed using cell culture, conditional knockout mouse model and hydrodynamic transfection ICC model. The efficacy of single or combined therapy with anti-PD-1 antibody, gene knockout and chemical inhibitor were evaluated in vivo. RESULTS: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in advanced ICCs and significantly correlated with N7-methylguanosine tRNA methyltransferase METTL1. Using diverse in vivo cancer models, we demonstrate the crucial immunomodulator function of METTL1 in regulation of PMN-MDSC accumulation in TIME and ICC progression. Mechanistically, CXCL8 in human and Cxcl5 in mouse are key translational targets of METTL1 that facilitate its function in promoting PMN-MDSC accumulation in TIME and ICC progression in vivo. Co-blockade of METTL1 and its downstream chemokine pathway enhances the anti-PD-1 efficacy in ICC preclinical mouse models. CONCLUSIONS: Our data uncover novel mechanisms underlying chemokine regulation and TIME shaping at the layer of messenger RNA translation level and provide new insights for development of efficient cancer immunotherapeutic strategies.

Beyond controlling cell size: functional analyses of S6K in tumorigenesis.

As a substrate and major effector of the mammalian target of rapamycin complex 1 (mTORC1), the biological functions of ribosomal protein S6 kinase (S6K) have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, and protein synthesis. However, accumulating evidence implies that diverse stimuli and upstream regulators modulate S6K kinase activity, leading to the activation of a plethora of downstream substrates for distinct pathobiological functions. Beyond controlling cell size, S6K simultaneously plays crucial roles in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals. Thus, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for S6K and shed light on S6K as a potential therapeutic target for cancers.

Comparison of Hepatic Resection with Percutaneous Ablation for Hepatocellular Carcinoma in the Caudate Lobe Within Milan Criteria.

PURPOSE: We aimed to compare the efficacy of hepatic resection and percutaneous ablation for resectable caudate HCC within Milan criteria and to investigate the prognostic factors. METHODS: Between August 2006 and August 2020, a total of 67 eligible patients with resectable caudate HCC within Milan criteria in three centers were retrospectively analyzed and divided into hepatic resection group (n = 46) and percutaneous ablation group (n = 21). Recurrence-free survival (RFS) and overall survival (OS) rates were compared between groups of hepatic resection and percutaneous ablation for these resectable caudate HCC patients with Kaplan-Meier curves and log-rank test. Univariable and multivariable Cox regression analyses were performed to identify the prognostic factors of RFS and OS. RESULTS: The 1-, 3-, and 5-year OS rates were 97.6%, 83.6%, and 71.5% for the hepatic resection group, and 89.4%, 58.5%, and 48.8% for the percutaneous ablation group (P = 0.032). The corresponding RFS rates were 77.6%, 47.9%, and 42.6% for the hepatic resection group, and 40.5%, 23.2%, and 15.4% for the percutaneous ablation group (P = 0.010). According to the univariable and multivariable analyses, tumor type (first recurrence) (HR = 3.54; 95%CI, 1.49-8.37; P = 0.004) was a significant independent prognostic factor of RFS for caudate HCC patients after resection or ablation, while total bilirubin (HR = 1.02; 95%CI, 1.01-1.04; P = 0.006) and treatment strategy (HR = 5.97; 95%CI, 1.48-24.12; P = 0.012) were significant independent prognostic factors of OS. CONCLUSIONS: Hepatic resection appears to outperform percutaneous ablation for caudate HCC patients within Milan criteria.

LR-M Observations on Contrast-Enhanced Ultrasound: Detection of Hepatocellular Carcinoma Using Additional Features in Comparison With Current LI-RADS Criteria.

BACKGROUND. Contrast-enhanced ultrasound (CEUS) LI-RADS assigns category LR-M to observations that are definitely or probably malignant but that on imaging are not specific for hepatocellular carcinoma (HCC). A high percentage of LR-M observations represent HCC. OBJECTIVE. The purpose of this study was to retrospectively evaluate the utility of additional features, beyond conventional LI-RADS major features, for detecting HCC among LR-M observations on CEUS. METHODS. This retrospective study included 174 patients (145 men, 29 women; mean age, 53 years) at high risk of HCC who underwent CEUS from August 2014 to June 2016 that showed an LR-M observation according to CEUS LI-RADS version 2017. Two radiologists independently assessed CEUS images for major features and four additional features (chaotic vessels, peripheral circular artery, clear boundary of tumor enhancement, clear boundary of intratumoral unenhanced area). The diagnostic performance of four proposed criteria for the detection of HCC among LR-M observations was assessed. The impact of criteria based on the additional findings on detection of HCC was further explored. Histology or composite imaging and clinical follow-up were the reference standards. RESULTS. The 174 LR-M observations included 142 HCCs and 32 non-HCC lesions (20 intrahepatic cholangiocarcinomas, five combined hepatocellular-cholangiocarcinomas, seven benign lesions). Interreader agreement on the additional features ranged from κ = 0.65 to κ = 0.88. Two of the additional features had excellent PPV for HCC: chaotic vessels (94.8%) and peripheral circular arteries (98.1%). The presence of either of these two additional features had sensitivity of 50.7%, specificity of 90.6%, PPV of 96.0%, and NPV of 29.3% for HCC. Three other criteria incorporating variations of major LI-RADS features but not the additional features had sensitivities of 55.6-96.5%, specificities of 49.6-68.8%, PPVs of 87.8-90.6%, and NPVs of 25.0-75.0%. On the basis of criteria that included additional features, 75 of 174 LR-M observations were recategorized LR-5; 72 of the 75 were HCC. CONCLUSION. The presence of chaotic vessels and/or peripheral circular artery had high specificity and PPV for HCC among LR-M observations. Other explored criteria based on major features did not have higher specificity or PPV. CLINICAL IMPACT. Clinical adoption of the additional CEUS features could help establish the diagnosis of HCC noninvasively and avoid the need for biopsy of LR-M observations.

High SPINK1 Expression Predicts Poor Prognosis and Promotes Cell Proliferation and Metastasis of Hepatocellular Carcinoma.

BACKGROUND: Serine protease inhibitor Kazal type I (SPINK1) is highly expressed and promotes tumor progress in different cancers. This study aimed to evaluate SPINK1's prognostic value and its role in hepatocellular carcinoma (HCC) progress. METHODS: We use tissue micro-arrays containing 273 tumor and paired para-tumor tissues to evaluate SPINK1's prognostic value in HCC. CCK8 cell proliferation assay, wound healing assays, transwell migration and invasion assays were performed to explore the effect of SPINIK1 on HCC cells. The Cancer Genome Atlas (TCGA) database and Gene set enrichment analysis (GSEA) were used to verify the prognosis value of SPINK1 in HCC and explore the underlying mechanisms. RESULTS: SPINK1 expression was significantly higher in tumor tissues than paired para-tumor tissues (P < 0.001). Higher SPINK1 expression in tumor was significantly associated with portal vein tumor thrombus formation (P = 0.019) and shorter overall survival (P = 0.029). SPINK1 expression in tumor tissue was an independent predictor for overall survival. SPINK1 increased proliferation (P < 0.001), enhanced migration and invasion ability of HCC cell lines (P < 0.001). GSEA revealed that glycine, serine, threonine and bile acid metabolism may be the underlying mechanism of SPINK1 in HCC. CONCLUSIONS: In conclusion, high SPINK1 expression is associated with poor prognosis of HCC. SPINK1 promotes proliferation, migration and invasion ability of HCC cells.