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Pancreatic cancer is one of the most common causes of death in Taiwan. Previous studies have shown that more than 90% of pancreatic cancer cells presented epidermal growth factor receptor (EGFR) cell marker, and this marker is thought to be important as it is related to activation of cancer cell proliferation, angiogenesis, and cancer progression. Moreover, tumor-associated fibroblasts were involved in tumor proliferation and progression. In this study, we fabricated an anti-EGFR and anti-fibroblast activation protein bispecific antibody-targeted liposomal irinotecan (BS−LipoIRI), which could specifically bind to pancreatic cancer cells and tumor-associated fibroblasts. The drug encapsulation efficiency of BS−LipoIRI was 80.95%, and the drug loading was 8.41%. We proved that both pancreatic cancer cells and fibroblasts could be targeted by BS−LipoIRI, which showed better cellular uptake efficacy compared to LipoIRI. Furthermore, an in vivo mouse tumor test indicated that BS−LipoIRI could inhibit pancreatic cancer growth up to 46.2% compared to phosphate-buffered saline control, suggesting that BS−LipoIRI could be useful in clinical cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma is one of the deadliest cancers worldwide. Early detection has been shown to enable more effective treatments, thus decreasing morbidity and mortality. Non-invasive cancer detection via circulating tumour DNA (ctDNA) has emerged as a promising approach to monitor the molecular changes in liver tumour cells. We aimed to use ctDNA methylation and fragmentation signals to develop a blood-based assay for hepatocellular carcinoma early detection, named HcSeer.Methods: A targeted methylation sequencing panel was designed to integrate 1601 liver cancer-informative methylation markers, on the basis of in-house data and data from the public databases The Cancer Genome Atlas and Gene Expression Omnibus. Various methylation features were constructed from methylation sequencing data, including methylation haplotype load and methylated haplotype fraction. Low-pass whole-genome sequencing data from plasma samples were also analysed at a mean sequencing depth of 10×. Fragmentomic features, such as end motif, breakpoint motif, fragmentation size ratio, and copy number variation, were extracted from whole-genome sequencing data. A two-step deep neural network model was built to classify cancer and healthy samples with selected features of both types. The robustness of entire approach was verified with a 3× cross-validation by randomly splitting samples into training set and test set at a 2:1 ratio.Findings: In the discovery phase, a case-control study was designed to develop the HcSeer assay for the early detection of hepatocellular carcinoma. A total of 401 participants were recruited (200 healthy individuals and 201 patients with hepatocellular carcinoma). Most patients with cancer were at early stages standardised by Chinese liver cancer staging (109 [54%] at stage I and 25 [12%] at stage II). The classification model of HcSeer assay was built and cross-validated to achieve an average area under the curve of 0·99 (sensitivity 94% [189 of 201; 95% CI 90-97%] and specificity 96% [192 of 200; 92-98%]). The detection accuracy was observed to increase with cancer stages, with 91% (99 of 109; 95% CI 83-95%) sensitivity for stage I, 96% (24 of 25; 77-100%) for stage II, 98% (43 of 44; 86-100%) for stage III, and 100% (23 of 23, 84-100%) for stage IV. The validation cohort is ongoing, with the aim of reaching 510 plasma samples from multiple centres, including a full spectrum of liver diseases and age-matched healthy controls. The validation phase is expected to be completed in June, 2022.Interpretation: We have developed the HcSeer assay to combine the signatures of DNA methylation and genome-wide fragmentome. In a case-control study, we showed its feasibility to detect early-stage hepatocellular carcinoma with high accuracy. We propose it as a potential aid for non-invasive diagnostics of hepatocellular carcinoma. The performance of the assay is being validated in an independent sample set collected through a multicentre study, which was approved by the Ethical Committee of Zhongshan Hospital affiliated to Fudan University (number B2020-299R).Funding: This study was supported by the National Key Research and Development Program of China (grant number 2019YFC1315800). [ABSTRACT FROM AUTHOR]

• The construction of a formal definition/classification system for recursion. • An experimental study of child acquisition of tail-, nested- and mixed-recursion relative clause sequences. • Different levels and subtypes of recursive sequences are acquired at significantly different ages. • The results suggest which part of Chomsky's Hierarchy is unique to language. Starting with constructing a formal definition/classification system for recursion and consequently dividing recursive sequences into different levels and subtypes, the current paper presents an experimental study of Mandarin-speaking children's acquisition of three subtypes of 2-level recursive sequences exemplified with the so-called "recursive relative clauses (RCs)", reanalyzed as the 2-level tail-, nested-, and mixed-recursion RC sequences. 249 Mandarin-speaking children aged 4–9 years and 46 adult controls are recruited to finish a most-structured elicited Production task. The main findings are as follows: in general, children have acquired 1-level recursive RC sequences by the age of 4, but they have not acquired 2-level tail-recursion RC sequences until the age of 6, they have not acquired 2-level mixed-recursion RC sequences until the age of 8–9, and they have not acquired 2-level nested-recursion RC sequences until the age of at least 10; before acquiring 2-level recursive RC sequences, children tend to replace them with 1-level recursive RC sequences or coordinate structures. This experimental study provides new data and accounts for the development of the faculty of linguistic recursion, and also evidence in support of the formal definition/classification system for recursion. Further, this study makes more elaborate by subdivision the part of Chomsky Hierarchy (1959) claimed to be unique to natural language. [ABSTRACT FROM AUTHOR]

Purpose: Radiation therapy (RT) is one of the main treatments for patients with unresectable hepatocellular carcinoma (HCC). Emerging evidence indicates that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) stimulator of interferon gene (STING) pathway is crucial in RT-induced antitumor immune responses. Here, we discovered that activation of the cancer cell-intrinsic cGAS-STING pathway mediated immune cloaking after RT-induced DNA damage.Methods and Materials: Key regulatory proteins in the cGAS-STING signaling pathway in human and murine HCC cell lines were knocked out or down using CRISPR and CRISPR-associated protein 9 or small interfering RNA. The underlying mechanism of immune cloaking and clinical significance of cGAS-STING-induced programmed cell death ligand 1 (PD-L1) expression were studied with both ex vivo analyses and in vitro experiments.Results: RT upregulated PD-L1 in patients with HCC, which correlated with poor survival. RT activated cGAS-STING, increasing immune-checkpoint PD-L1 expression in human and mouse liver cancer cells. Ionizing radiation activated the STING-TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) innate immune pathway, leading to PD-L1 upregulation in HCC cells and inhibiting cytotoxic T-lymphocyte activity and protecting tumor cells from immune-mediated eradication. Knockdown of cGAS, STING, TBK1, and IRF3 reversed the antitumor effect of cytotoxic T-lymphocyte-mediated cytotoxicity after ionizing radiation in vitro or in vivo. RT potentiated the antitumor effect of programmed cell death protein 1 and PD-L1 axis blockade and augmented cytotoxic T-cell (CTL) infiltration in HCC tumors in immunocompetent mice. CD8 depletion compromised the synergetic antitumor effect of combined RT and anti-PD-L1 blockade, demonstrating that CD8+ CTLs are required for antitumor immunity induced by combination therapy.Conclusions: Our results identified an immune-cloaking mechanism for RT-activated, innate immune cGAS-STING and suggested that RT enhances HCC immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a prevalent malignancy with poor prognosis. As a cell adhesion molecule, poliovirus receptor (PVR/CD155) is abnormally overexpressed in tumour cells, and related to tumour proliferation and invasion. However, the potential role and mechanism of CD155 have not yet been elucidated in HCC. Methods: Immunohistochemistry, RT‐PCR and Western blot assays were used to determine CD155 expression in HCC cell lines and tissues. Cell Counting Kit‐8 and colony formation assays were used to examine cell proliferation. Transwell and wound healing assays were used to evaluate cell migration and invasion. Cell apoptosis and cycle distribution were assessed by flow cytometry. Cox regression and Kaplan–Meier analyses were performed to explore the clinical significance of CD155. The role of CD155 in vivo was evaluated by establishing liver orthotropic xenograft mice model. RNA sequencing, bioinformatics analysis and co‐immunoprecipitation assay were used to explore the downstream signalling pathway of CD155. Results: CD155 was upregulated in HCC tissues and represented a promising prognostic indicator for HCC patients (n = 189) undergoing curative resection. High CD155 expression enhanced cell proliferation, migration and invasion, and contributed to cell survival in HCC. CD155 overexpression also induced epithelial–mesenchymal transition in HCC cells. CD155 function in HCC involved SRC/p38 MAPK signalling pathway. CD155 interacted with SRC homology‐2 domain of SRC and promoted SRC activation, further inhibiting the downstream p38 MAPK signalling pathway in HCC. Conclusions: CD155 promotes HCC progression via the SRC/p38 MAPK signalling pathway. CD155 may represent a predictor for poor postsurgery prognosis in HCC patients. [ABSTRACT FROM AUTHOR]

Background: While the correlation between PD-L1 expression and KRAS mutation has been previously reported in other solid tumors such as non-small cell lung cancer (NSCLC), whether PD-L1 can be modulated by ERK signaling downstream of KRAS in intrahepatic cholangiocarcinoma (iCCA) and the underlying molecular regulatory mechanism remain unclear. Methods: The expression of ERK, p-ERK, PD-L1 and autophagy markers following KRAS knockdown or Ras/Raf/MEK/ERK signaling inhibitors treatment was examined in two human iCCA cell lines (HuCCT1 and RBE) using western blotting and immunofluorescence. Both pharmacological autophagy inhibitors and short-interfering RNA against ATG7 were applied to inhibit autophagy. The apoptosis rates of iCCA cell lines were detected by flow cytometry and CCK-8 after co-culturing with CD3/CD28-activated human CD8+ T lymphocytes. Immunohistochemistry was applied to detect the correlation of ERK, p-ERK and PD-L1 in 92 iCCA tissues. Results: The present study demonstrated that the PD-L1 expression level was distinctly reduced in KRAS-mutated iCCA cell lines when ERK signaling was inhibited and ERK phosphorylation levels were lowered. The positive association between p-ERK and PD-L1 was also verified in 92 iCCA tissue samples. Moreover, ERK inhibition induced autophagy activation. Both inhibiting autophagy via autophagy inhibitors and genetically silencing the ATG7 expression partially reversed the reduced PD-L1 expression caused by ERK inhibition. In addition, ERK-mediated down-regulation of PD-L1 via autophagy pathways induced the apoptosis of iCCA cells when co-cultured with CD3/CD28-activated human CD8+ T lymphocytes in vitro. Conclusions: Our results suggest that ERK signaling inhibition contributes to the reduction of PD-L1 expression through the autophagy pathway in iCCA. As a supplement to anti-PD-1/PD-L1 immunotherapy, ERK-targeted therapy may serve as a potentially novel treatment strategy for human KRAS-mutated iCCA. [ABSTRACT FROM AUTHOR]

We have shown that respiratory syncytial virus (RSV) can spread hematogenously from infected airways of a pregnant woman to the developing fetal lungs in utero. This study sought to measure RSV replication, cytopathic effects, and protein expression in human lung organoids (HLOs) reproducing architecture and transcriptional profiles of human fetal lungs during the 1st trimester of gestation. HLOs derived from human pluripotent stem cells were microinjected after 50 or 100 days in culture with medium or recombinant RSV-A2 expressing the red fluorescent protein gene (rrRSV). Infection was monitored by fluorescent microscopy and PCR. Immunohistochemistry and proteomic analysis were performed. RSV infected HLOs in a dose- and time-dependent manner. RSV-infected HLOs increased expression of CC10 (Club cells), but had sparse FOXJ1 (ciliated cells). Disruption of F-actin cytoskeleton was consistent with proteomic data showing a significant increase in Rho GTPases proteins. RSV upregulated the transient receptor potential vanilloid 1 (TRPV1) channel and, while β2 adrenergic receptor (β2AR) expression was decreased overall, its phosphorylated form increased. Our data suggest that prenatal RSV infection produces profound changes in fetal lungs' architecture and expression profiles and maybe an essential precursor of chronic airway dysfunction. expression profiles, and possibly be an important precursor of chronic airway dysfunction. [ABSTRACT FROM AUTHOR]

The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TLSs in iCCA. We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples. A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p < 0.001), whereas a high P score signified worse survival (p < 0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p < 0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p < 0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p < 0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p < 0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p < 0.001). These results were validated in an internal and 2 external cohorts. The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs. Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses. [Display omitted] • Tertiary lymphoid structures (TLSs) within and outside the tumor have opposite prognostic impacts on patients with iCCA. • The heterogeneous distribution of Tfh and Treg cells within distinct TLSs might be a determinant of their functional state. • The geographic integration of TLSs stratified iCCAs into 4 immune subclasses with distinct clinical outcomes. [ABSTRACT FROM AUTHOR]

Codonopsis pilosula is a famous edible and medicinal plants, in which polysaccharides are recognized as one of the important active ingredients. A neutral polysaccharide (CPP-1) was purified from C. pilosula. The structure was characterized by HPSEC-MALLS-RID, UV, FT-IR, GC–MS, methylation analysis, and NMR. The results showed that CPP-1 was a homogeneous pure polysaccharide, mainly containing fructose and glucose, and a small amount of arabinose. Methylation analysis showed that CPP-1 composed of →1)-Fru f -(2→, Fru f- (1→ and Glc p -(1→ residues. Combined the NMR results the structure of CPP-1 was confirmed as α-D-Glc p -(1 → [2)-β-D-Fru f -(1 → 2)-β-D-Fru f -(1] 26 → 2)-β-D-Fru f with the molecular weight of 4.890 × 103 Da. The model of AML12 hepatocyte fat damage was established in vitro. The results showed that CPP-1 could increase the activity of SOD and CAT antioxidant enzymes and reduce the content of MDA, thus protecting cells from oxidative damage. Subsequently, the liver protective effect of CPP-1 was studied in the mouse model of nonalcoholic fatty liver disease (NAFLD) induced by the high-fat diet. The results showed that CPP-1 significantly reduced the body weight, liver index, and body fat index of NAFLD mice, and significantly improved liver function. Therefore, CPP-1 should be a potential candidate for the treatment of NAFLD. [Display omitted] • A neutral polysaccharide (CPP-1) was purified from Codonopsis pilosula. • The structural information of CPP-1 was systematically characterized. • CPP-1 protects the AML12 cells by alleviating oxidative damage. • CPP-1 could alleviate liver damage in non-alcoholic fatty liver disease mouse model. [ABSTRACT FROM AUTHOR]

[Display omitted] • Our study included 208 eligible patients with unresectable or advanced HCC who received immunotherapy as first line therapy. We found that PLR < 100 was an independent factor associated with better tumor response of immunotherapy. • Patients with PLR < 100 had longer PFS than other patients, while OS showed no significant difference. In subgroup analysis, we found that PLR had better prognostic value in patients received bevacizumab plus anti-PD-1 antibody therapy. • Our data indicate baseline PLR can serve as a predictor of objective response and survival outcome to immunotherapy in patients with unresectable or advanced HCC, especially who treated with bevacizumab plus anti-PD-1 antibody. • We have provided a clinically feasible approach, since patients with advanced or unresectable HCC are unlikely to provide tumor samples, and standard-of-care blood cell counts can be easily obtained in the clinic. Lymphocyte-related factors were associated with survival outcome of different types of cancers. Nevertheless, the association between lymphocytes-related factors and tumor response of immunotherapy remains unclear. This is a retrospective study. Eligible participants included patients with unresectable or advanced hepatocellular carcinoma (HCC) who underwent immunotherapy as their first-line treatment. Radiological assessment of tumor response adhered to RECIST 1.1 and HCC-specific modified RECIST (mRECIST) criteria. Univariate and multivariate logistic analyses were employed to analyze clinical factors associated with tumor response. Kaplan-Meier survivial analysis were employed to compare progression‐free survival (PFS) and overall survival (OS) across different clinical factors. Furthermore, patients who received treatment with either a combination of bevacizumab and anti-PD-1(L1) antibody (Beva group) or tyrosine-kinase inhibitor (TKI) and anti-PD-1 antibody (TKI group) were examined to explore the relation between clinical factors and tumor response. A total of 208 patients were enrolled in this study. The median PFS and OS were 9.84 months and 24.44 months,respectively. An independent factor associated with a more favorable tumor response to immunotherapy was identified when PLR<100. Patients with PLR<100 had longer PFS than other patients, while OS showed no significant difference. Further analysis revealed that PLR exhibited superior prognostic value in patients of the Beva group as compared to those in the TKI group. There exisits an association between PLR and tumor response as well as survival outcomes in patients receiving immunotherapy, particularly those treated with the combination of bevacizumab and anti-PD-1. [ABSTRACT FROM AUTHOR]

Abstract Endothelial dysfunction (ED) is the initial cause of atherosclerosis (AS) and an early marker of many cardiovascular diseases (CVD). Citronellal (CT), a monoterpenoid natural product extracted from grass plant Citronella, has been shown to have anti-thrombotic, anti-hypertensive and anti-diabetic cardiomyopathy activities. The aim of this study is to investigate the effects of citronellal on vascular endothelial dysfunction and the underlying mechanisms. The left common carotid artery was subjected to one-time balloon injury to cause vascular endothelial injury, and the AS model was established by feeding with high-fat diet. Use of HUVECs H 2 O 2 treatment induced HUVECs oxidative stress damage model. The blood lipid level, histopathology, Western blot, immunohistochemistry, RT-PCR, ELISA and in situ fluorescence hybridization of common carotid artery tissues and HUVECs were studied. CT significantly reduced vascular plate area and endothelial lipid and cholesterol deposition in the common carotid artery of mice in a dose-dependent manner. CT increased the expression of activated protein 2α (AP-2α/TFAP2A) and circRNA_102979, and inhibited the ectopic expression level of miR-133a. However, the constructed lentivirus with AP-2α silencing and circRNA_102979 silencing reversed this phenomenon. The current study verifies CT can increase the expression levels of AP-2α and circRNA_102979 in vascular endothelium, increase the adsorption effect of circRNA_102979 on miR-133a and relieve the inhibitory effect of miR-133a on target genes, thereby alleviating AS-induced ED. CT can promote the gene expression of circRNA_102979 by up-regulating the transcriptional activity of AP-2α, and circRNA_102979 can inhibit the expression of miR-133a by adsorption, thereby contacting its inhibitory effect on target genes and improving vascular endothelial injury. (Drawn by biorender , www.biorender.com.) [Display omitted] [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are the main components in the tumor microenvironment. Tumors activate fibroblasts from quiescent state into activated state by secreting cytokines, and activated CAFs may in turn promote tumor progression and metastasis. Therefore, studies targeting CAFs could enrich the therapeutic options for tumor treatment. In this study, we demonstrate that the content of lipid droplets and the expression of autophagosomes were higher in CAFs than in peri-tumor fibroblasts (PTFs), which was inhibited by 5-(tetradecyloxy)-2-furoic acid(TOFA). The expression of CD36 in CAFs was higher than that in PTFs at both mRNA and protein levels. Inhibition of CD36 activity using either the CD36 inhibitor SSO or siRNA had a significant negative impact on the proliferation and migration abilities of CAFs, which was associated with reduced levels of relevant activated genes (α-SMA, FAP, Vimentin) and cytokines (IL-6, TGF-β and VEGF-α). SSO also inhibited HCC growth and tumorigenesis in nude mice orthotopically implanted with CAFs and HCC cells. Our data further show that CD36+CAFs affected the expression of PD-1 in CTLs leading to CTL exhaustion, and that patients with high CD36 expression in CAFs were correlated with shorter overall survival (OS). Together, our data demonstrate that CAFs were active in lipid metabolism with increased lipid content and lipophagy activity. CD36 may play a key role in the regulation of the biological behaviors of CAFs, which may influence the proliferation and migration of tumor cells by reprograming the lipid metabolism in tumor cells. Thus, CD36 could be an effective therapeutic target for the treatment of HCC. [ABSTRACT FROM AUTHOR]

DNA damage repair (DDR) plays a pivotal role in hepatocellular carcinoma (HCC), driving oncogenesis, progression, and therapeutic response. However, the mechanisms of DDR mediated immune cells and immuno-modulatory pathways in HCC are yet ill-defined. Our study introduces an innovative deep machine learning framework for precise DDR assessment, utilizing single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data. Single-cell RNA sequencing data were obtained and in total 85,628 cells of primary or post-immunotherapy cases were analyzed. Large-scale HCC datasets, including 1027 patients in house together with public datasets, were used for 101 machine-learning models and a novel DDR feature was derived at single-cell resolution (DDRscore). Druggable targets were predicted using the reverse phase protein array (RPPA) proteomic profiling of 169 HCC patients and RNA-seq data from 22 liver cancer cell lines. Our investigation reveals a dynamic interplay of DDR with natural killer cells and B cells in the primary HCC microenvironment, shaping a tumor-promoting immune milieu through metabolic programming. Analysis of HCC post-immunotherapy demonstrates elevated DDR levels that induces epithelial-mesenchymal transition and fibroblast-like transformation, reshaping the fibrotic tumor microenvironment. Conversely, attenuated DDR promotes antigen cross-presentation by dendritic cells and CD8+ T cells, modulating the inflammatory tumor microenvironment. Regulatory network analysis identifies the CXCL10-CXCR3 axis as a key determinant of immunotherapeutic response in low DDR HCC, potentially regulated by transcription factors GATA3, REL, and TBX21. Using machine learning techniques by combining bulk RNA-seq data in house together with public datasets, we introduce DDRscore, a robust consensus DDR scoring system to predict overall survival and resistance to PD-1 therapy in HCC patients. Finally, we identify BRAF as a potential therapeutic target for high DDRscore patients. Our comprehensive findings advance our understanding of DDR and the tumor microenvironment in HCC, providing insights into immune regulatory mechanisms mediated via DDR pathways. • The study integrates multiple omics analyses to depict the heterogeneity of the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) under different DDR statuses, both pre- and post- immunotherapy. • DDR scoring framework is developed using advanced machine learning algorithms, enabling accurate assessment of DDR levels in HCC. • Potential therapeutic targets (BRAF) was identified specifically for patients with high DDR status, offering promising avenues for personalized treatment in HCC. [ABSTRACT FROM AUTHOR]

The idea that tumour microenvironment (TME) is organised in a spatial manner will not surprise many cancer biologists; however, systematically capturing spatial architecture of TME is still not possible until recent decade. The past five years have witnessed a boom in the research of high‐throughput spatial techniques and algorithms to delineate TME at an unprecedented level. Here, we review the technological progress of spatial omics and how advanced computation methods boost multi‐modal spatial data analysis. Then, we discussed the potential clinical translations of spatial omics research in precision oncology, and proposed a transfer of spatial ecological principles to cancer biology in spatial data interpretation. So far, spatial omics is placing us in the golden age of spatial cancer research. Further development and application of spatial omics may lead to a comprehensive decoding of the TME ecosystem and bring the current spatiotemporal molecular medical research into an entirely new paradigm. [ABSTRACT FROM AUTHOR]

Purpose: Microvascular invasion (MVI) is a critical determinant of the early recurrence and poor prognosis of patients with hepatocellular carcinoma (HCC). Prediction of MVI status is clinically significant for the decision of treatment strategies and the assessment of patient's prognosis. A deep learning (DL) model was developed to predict the MVI status and grade in HCC patients based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinical parameters. Methods: HCC patients with pathologically confirmed MVI status from January to December 2016 were enrolled and preoperative DCE-MRI of these patients were collected in this study. Then they were randomly divided into the training and testing cohorts. A DL model with eight conventional neural network (CNN) branches for eight MRI sequences was built to predict the presence of MVI, and further combined with clinical parameters for better prediction. Results: Among 601 HCC patients, 376 patients were pathologically MVI absent, and 225 patients were MVI present. To predict the presence of MVI, the DL model based only on images achieved an area under curve (AUC) of 0.915 in the testing cohort as compared to the radiomics model with an AUC of 0.731. The DL combined with clinical parameters (DLC) model yielded the best predictive performance with an AUC of 0.931. For the MVI-grade stratification, the DLC models achieved an overall accuracy of 0.793. Survival analysis demonstrated that the patients with DLC-predicted MVI status were associated with the poor overall survival (OS) and recurrence-free survival (RFS). Further investigation showed that hepatectomy with the wide resection margin contributes to better OS and RFS in the DLC-predicted MVI present patients. Conclusion: The proposed DLC model can provide a non-invasive approach to evaluate MVI before surgery, which can help surgeons make decisions of surgical strategies and assess patient's prognosis. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC. Method: The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP–ADO pathway amplified by HCC–macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts. Results: Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP–adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance. Conclusion: In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP–adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC. [ABSTRACT FROM AUTHOR]

• The specimen with the ECC layer could delay the debonding of the CFRP plate and transfer the interfacial shear stress. • The thickness of the ECC attached to the CFRP plate increased with the increase of freeze–thaw cycles. • The bearing capacity of single-shear specimens decreased by 2.4%-27.3% with the increase of freeze–thaw cycles. • The proposed fracture energy model considering freeze–thaw cycles can predict the bearing capacity of single-shear specimens. A very important subject in the application of civil engineering reinforcement is the durability of interfacial bonding behavior between fiber reinforce plastic (FRP) and concrete under freeze–thaw cycles. Premature debonding of the FRP plates (underutilization of FRP plates) would results in the potential safety hazards in FRP plates reinforced concrete structures. The use of engineered cementitious composites (ECCs) can effectively delay the peeling off of the FRPs and improve the durability and bearing capacity of FRP reinforced concrete structures. To strengthen the concrete structures under freeze–thaw cycles environments more economically and safely, it is necessary to study the bonding performance of the FRP-ECC-concrete composite interface. In this research, single-shear tests were carried out on CFRP plate-ECC-concrete composite interface specimens under freeze–thaw cycles. Taking the concrete/ECC strength as the research variables, the bonding properties of the composite interface under different freeze–thaw cycles were studied. The results show that the CFRP plate-ECC-concrete composite interface can effectively delay the peeling off of the CFRP plate, and effect of delaying the peeling off of the CFRP plate is reduced with the increasing of freeze–thaw cycles. The bearing capacity of single-shear specimens decreased by 2.4%-27.3% with the increase of freeze–thaw cycles, but the bearing capacity increased by 12.6%–32.4% with the increase of concrete/ECC strength. The ultimate strain of the CFRP in single-shear specimens decreases by about 29.2% under freeze–thaw cycles. The proposed fracture energy prediction model considering freeze–thaw cycles can accurately predict the bearing capacity of single-shear specimens with the composite interface. The bond-slip constitutive relationship considering the interface softening descending stage is in good agreement with the experimental results. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a class of regulatory RNAs with complex roles in healthy and diseased tissues. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) remains poorly understood, including the mechanisms by which the circular ubiquitin-binding associated protein 2 (circUBAP2) contributes to tumorigenesis. We analyzed the expression of circUBAP2 in 20 paired samples of HCC and healthy tissue as well as in seven HCC cell lines via quantitative real-time polymerase chain reaction. Functional experiments, such as CCK8 viability assays, colony formation assays, wound healing, transwell assays and flow cytometry, were conducted to assess the effects of circUBAP2 in vitro. To further elucidate the mechanisms by which circUBAP2 acts, we conducted dual-luciferase assays, western blots, RNA pull-down assays and rescue experiments. CircUBAP2 was highly upregulated in most HCC tissues and was associated with poor prognosis. HCC patients with high circUBAP2 expression had greater vascular invasion and worse differentiation. Functionally, circUBAP2 overexpression enhanced HCC cell proliferation, migration and invasion and inhibited apoptosis. Furthermore, we found that circUBAP2 upregulated c-Myc expression by sponging miR-1294, thus contributing to hepatocarcinogenesis. Inhibiting circUBAP2 expression in HCC attenuated the oncogenic effects of c-Myc. These findings suggest that circUBAP2 promotes HCC growth and metastasis. CircUBAP2 may have value as an independent prognostic biomarker or as a new target for the treatment of HCC. [ABSTRACT FROM AUTHOR]

We calculate the destructive interference factors between the Higgs decay H→γγ produced in gluon-fusion and the Standard Model (SM) continuum gg→γγ process, as a function of the scattering angle in the center-of-mass frame of the final two photons. The interference factors are studied with the selections based on the acceptance criteria of the ATLAS and CMS H→γγ searches at the LHC. The result shows that the destructive interference is only at an order of 2.5% for the SM Higgs analysis at the LHC. The factors are almost the same for the same Higgs mass hypothesis but with different proton-proton collisions at , 8 TeV, 13 TeV and 14 TeV. The destructive interference is far below the present uncertainty on the total cross-section prediction of Higgs, which is about 15% used at the LHC. A destructive interference factor of -2.5% is suggested to be used in the H→γγ analysis at the LHC, due to the effect from the interference for this decay channel. [ABSTRACT FROM AUTHOR]

A general and efficient method for amide bond synthesis has been developed. The method allows for synthesis of tertiary amides from readily available tertiary amines and anhydrides in the presence of FeCl2 as catalyst and tert-butyl hydroperoxide in water (T-Hydro) as oxidant. Mechanistic studies indicated that the in situ-generated α-amino peroxide of tertiary amine and iminium ion act as key intermediates in this oxidative transformation. [ABSTRACT FROM AUTHOR]

Abstract: This paper proposes an integrated roughness measurement system that is based on adaptive optics (AO) and binary analysis of speckle pattern images. The aim of this study was to demonstrate the necessity for AO compensation in regions containing both heat and fluid flow turbulences. A speckle image was obtained by projecting a laser beam onto the specimen surface, and the laser pattern image reflected from the surface was binarized to experimentally correlate the intensity with the surface roughness. In the absence of the AO correction scheme, induced turbulences can severely increase the residual rms error from 0.14 to 1.4μm. After a real-time closed-loop AO correction, we can reduce the wavefront root mean square (rms) error to 0.12μm, which not only compensates for the aberration error from induced disturbances but also improves the overall performance of the optical system. In addition, an AO system having different gains was investigated, and a threshold gain value was found to be able to steadily compensate for the wavefront errors in less than 2s. Measurement results of five steel samples having roughness ranging from 0.2 to 3.125μm (0.3λ and 5λ, where λ is the diode laser wavelength) demonstrate an excellent correlation between the intensity distribution of binary images and average roughness with a correlation coefficient of 0.9982. Furthermore, the proposed AO-assisted system is in good agreement with the stylus method and less than 9.73% error values can be consistently obtained. [Copyright &y& Elsevier]

Background: We aimed to develop a clinicopathological model that would predict the risk of bone metastasis (BM) in hepatocellular carcinoma (HCC). Methods: We first evaluated a training cohort of 201 HCC patients who had undergone hepatectomy and found that the following factors independently predicted BM development: vascular invasion, tumor-node-metastasis stage, CXCR4, connective tissue growth factor, and interleukin-11. These variables were used to construct a clinicopathological prediction model that may be scored from 0 to 19. The predictive value of the model was demonstrated in a validation cohort of 179 post-hepatectomy HCC patients. Results: During a median follow-up of 54.3 months for the training cohort and 52.5 months for the validation cohort, 23 patients (11.4%) in the former and 19 patients (10.6%) in the latter developed BM. A cutoff value of 9.4 best discriminated BM risk and was able to exclude future BM development with high accuracy in the validation cohort. The sensitivity and specificity of the method were 73.7 and 78.7%, respectively, the positive predictive value was 29.2%, and the negative predictive value 96.2%. The 1- and 2-year cumulative BM rates were (respectively) 10.8% and 27.4% in the high-risk group and 2.4 and 4.3% in the low-risk group. The hazard ratio for BM of the high- versus low-risk group was 9.240 (95% CI: 3.319-25.722). Conclusion: The simple prediction model constructed from clinicopathological parameters is accurate in predicting BM development in HCC patients. [ABSTRACT FROM AUTHOR]

Adjustable fluidic adaptive lenses have been extensively studied because of the advantage of changing the geometric shape or refractive index without any mechanical moving parts. However, the induced aberrations were rarely discussed before. We address this issue by first clarifying the aberrations experimentally due to injected fluidic volumes. Experimental results show that under the injected fluidic volume of 0.1 ml, the main aberrations come from Z1 (piston), Z2 (tip), and Z5 (defocus) and Zernike coefficients are 0.97, 0.31, and 1.31 μm, respectively. In what follows, a series of tests specifically designed to explore the convex/concave interfaces and refractive-index-mismatch (RIM). Furthermore, we demonstrate the capability of adaptive optics (AO) correction on aberrations induced by combinative effects of multiple layers with convex/concave interfaces and RIM. A microelectro-mechanical system (MEMS) deformable mirror (DM) with 140 actuators was used in conjunction with Shack-Hartmann wavefront sensor to realize the experimentation. In particular, we consider the aberration introduced by interfaces of RIM between water/oil and glass. After AO correction, we can improve wavefront with root mean square (RMS) of 2.17-0.17 μm for an interface between water and glass. As for the interface between oil and glass, we are capable of improving RMS of 0.24-0.10 μm. © 2011 Wiley Periodicals, Inc. Microwave Opt Technol Lett 53:2610-2615, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/mop.26323 [ABSTRACT FROM AUTHOR]

Purpose: An immune function assay has been proposed as a new strategy to monitor immunosuppression after organ transplantation. However, there are limited data regarding its role in liver transplant recipients with hepatocellular carcinoma (HCC). In this study, we sought to determine the utility of this functional assay in assessing the risk of infection, rejection, and tumor recurrence in liver transplant recipients. Methods: Immune function was determined by ImmuKnow assay that measures the amount of adenosine triphosphate (ATP) produced by CD4 (+) T cells to monitor the global immune status in 342 whole blood samples from 105 liver transplant recipients. The association between ATP value and post-transplant tumor recurrence was evaluated in 60 HCC patients. The ATP value in predicting tumor recurrence in other independent cohort of 92 recipients with HCC was analyzed prospectively. Results: The mean ATP values of liver transplant recipients with infection (145.2 ± 87.0 ng/ml) or acute rejection (418.9 ± 169.5 ng/ml) were different from those with stable state (286.6 ± 143.9 ng/ml, P < 0.05). In recipients with HCC who developed recurrent tumors, the values were significantly lower than those without recurrence (137.8 ± 66.4 vs. 289 ± 133.9 ng/ml, P < 0.01); the optimal threshold value to predict post-transplant tumor recurrence was 175 ng/ml. Comparing with the patients in lower immune group (ATP ≤ 175 ng/ml), patients in the higher immune group (ATP > 175 ng/ml) experienced significantly better disease-free survival ( P < 0.01). Multivariate Cox regression analysis showed the ATP value was an independent predictor of HCC recurrence. Conclusions: The immune function assay has the potential to assess the risk of infection and rejection in liver transplantation and to predict post-transplant tumor recurrence in recipients with HCC. [ABSTRACT FROM AUTHOR]

Background & Aims: Neutrophil infiltration has been linked to clinical outcome of various cancer types. However, its role in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated prognostic values for intratumoral and peritumoral neutrophils in HCC patients undergoing curative resection. Methods: The expression of CD66b, CD8, TGF-beta, and CD34 was assessed by immunohistochemistry in tissue microarrays containing paired intratumoral and peritumoral tissues from 197 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated. Results: Intratumoral CD66b+ neutrophils significantly correlated with CD8+ T cells (r =0.240, p =0.004), TGF-beta expression (p =0.012), BCLC stage (p =0.016), and early recurrence (p =0.041). Increased intratumoral neutrophils were significantly associated with decreased RFS/OS (p =0.001 and p <0.001, respectively) in univariate analysis and were identified as an independent prognostic factor (HR=1.845, 95% CI=1.169–2.911, p =0.008 for RFS; HR=2.578, 95% CI=1.618–4.106, p <0.001 for OS) in multivariate analysis. Intratumoral neutrophil-to-CD8+ T cell ratio (iNTR) better predicted the outcome in terms of minimum p values. Intratumoral neutrophils were also demonstrated to be statistically predictive for RFS/OS in the normal AFP subgroup, small HCC subgroup, and validation cohort. However, peritumoral neutrophils were not associated with the outcome of HCC. Conclusions: The presence of intratumoral neutrophils was a poor prognostic factor for HCC after resection. Intratumoral neutrophil-to-CD8+ T cell ratio was a better predictor of outcome. [Copyright &y& Elsevier]

A simple, efficient, one-pot method has been developed for the synthesis of tetrahydro-4H-chromene derivatives by concurrent reaction of aryl aldehydes, active methylene compounds, and 1,3-cyclohexanedins using a catalytic amount of lithium bromide in aqueous media. The present approach offers several advantages such as shorter reaction times, good yields, low cost, recycling of the catalyst, and simple workup. [ABSTRACT FROM AUTHOR]

Salicylic acid, which is biosynthesized inside plant and is often found and accumulated in soil due to plant debris decaying, is considered as a signaling substance during plant–microbe interactions. It is involved in the cycling of biogeochemistry and related to plant resistance to biotic and abiotic stress. The antibiotic effect of salicylic acid on Fusarium oxysporum f.sp.niveum (FON) was studied to investigate the relationships between the salicylic acid and the fungus in the ecological interaction of plant–microbe. Results showed that the biomass, colony diameter, number of conidium germination and conidium production of FON were decreased by 52.0%, 25.7%, 100% and 100% at concentrations of 800mgL−1. However, mycotoxin yield was increased by 233%, pectinase activity raised by 168.0% and cellulase activity increased by 1325% compared to control at higher concentrations. It was concluded that salicylic acid as an allelochemical greatly inhibited FON growth and conidia formation and germination, though stimulated mycotoxin production and activities of hydrolytic enzymes by FON. [Copyright &y& Elsevier]

Abstract: Biomechanical properties and microcirculation of peripheral nerves under circular compression are vital factors for nerve repair and for developing neural prostheses. Quasi-static circular compression experiments on six rabbit sciatic nerves were performed. The mean estimated Young''s modulus of the sciatic nerves in the transverse direction was 66.9±8.0kPa. The blood perfusion of the nerve started to decrease at a mean pressure of 30.5mmHg and reached a stable lower level of 30% of pre-compression value at 102.8mmHg. The findings may make a contribution to safer design of cuff electrodes to be used in neural prostheses. [Copyright &y& Elsevier]

Objectives: To evaluate the role of radiotherapy (RT) for hepatocellular carcinoma (HCC) patients with abdominal lymph node (LN) metastasis at our institution in the past 7 years. Methods and Materials: We identified 125 patients with HCC metastasis to regional LNs treated with or without external beam RT (EBRT) between 1998 and 2004. Clinical characteristics collected included α-fetoprotein status, γ-glutamyltransferase, status of intrahepatic tumors (size and number), previous therapy for intrahepatic tumors, metastatic LN status (location, number, and size), tumor thrombi, and Child-Pugh classification. Of the 125 patients, 62 received local limited EBRT and were classified as the EBRT group. They received locoregional LN irradiation. The tumor dose ranged from 40 to 60 Gy in daily 2.0-Gy fractions, 5 times weekly. Another 63 patients, who did not receive EBRT, were selected from hospitalized patients in the same period and were classified as the non-EBRT group. The parameters studied included survival rates and tumor response to EBRT both as demonstrated by clinical symptoms and as seen on CT. The Kaplan-Meier method was used to evaluate the survival rates, and the Cox regression model was used to identify predictors of outcome. Results: After EBRT, partial responses and complete responses were observed in 37.1% and 59.7% of patients, respectively. The median survival was 9.4 months (95% confidence interval 5.8–13.0) for the EBRT group and 3.3 months (95% confidence interval, 2.7–3.9) for the non-EBRT group (p < 0.001). Multivariate analysis showed that multiple intrahepatic primary tumors, occurrence of tumor thrombi, no therapy for intrahepatic tumors, and greater Child-Pugh classification were related to a poorer prognosis in all patients. In the EBRT group, the survival periods decreased as the distance of LN involvement from the liver increased (following the natural flow of lymph) and was also associated with the intrahepatic primary tumor size. The incidence of death resulting from LN-related complications was lower in the EBRT group. Conclusion: Lymph node metastasis from HCC is sensitive to EBRT. EBRT with 25 fractions of 2 Gy is an effective palliative treatment for patients with LN metastases from HCC presenting with good performance status and may prolong overall survival. [Copyright &y& Elsevier]

Background: Non-sputum methods are urgently needed to improve tuberculosis diagnosis and treatment monitoring in children. This study evaluated the ability of a serum assay quantifying a species-specific peptide of the Mycobacterium tuberculosis CFP-10 virulence factor via nanotechnology and matrix-assisted laser desorption ionization time-of-flight mass spectrometry to diagnose tuberculosis in HIV-infected and HIV-uninfected infants.Methods: Serum CFP-10 peptide signal was blinded evaluated in cryopreserved sera of 519 BCG-immunized, HIV-exposed infants (284 HIV-infected, 235 HIV-uninfected) from a multi-center randomized placebo-controlled isoniazid prophylaxis trial conducted in southern Africa between 2004 and 2008, who were followed up to 192 weeks for Mtb infection and TB. Children were classified as confirmed, unconfirmed, or unlikely tuberculosis cases using 2015 NIH diagnostic criteria for pediatric TB.Results: In HIV-infected infants, CFP-10 signal had 100% sensitivity for confirmed TB (5/5, 95% CI, 47.8-100) and 83.7% sensitivity for unconfirmed TB (36/43, 95% CI 69.3-93.2), with 93.1% specificity (203/218, 95% CI 88.9-96.1). In HIV-uninfected infants, CFP-10 signal detected the single confirmed TB case and 75.0% of unconfirmed TB cases (15/20; 95% CI 50.9-91.3), with 96.2% specificity (177/184, 95% CI, 92.3-98.5). Serum CFP-10 achieved 77% diagnostic sensitivity for confirmed and unconfirmed TB (13/17, 95% CI, 50-93%) at ≤ 24 weeks pre-diagnosis, and both CFP-10-positivity and concentration declined following anti-TB therapy initiation.Conclusions: Serum CFP-10 signal exhibited high diagnostic sensitivity and specificity for tuberculosis in HIV-infected and HIV-uninfected infants and potential utility for early TB detection and monitoring of anti-TB treatment responses. [ABSTRACT FROM AUTHOR]

Background: Cirrhosis is a recognized risk factor for developing hepatocellular carcinoma (HCC). Few studies have reported the expression profile of circRNAs in HCC samples compared to paratumour dysplastic nodule (DN) samples. Methods: The Arraystar Human circRNA Array combined with laser capture microdissection (LCM) was used to analyse the expression profile of circRNAs in HCC samples compared to paratumour DN samples. Then, both in vitro and in vivo HCC models were used to determine the role and mechanism of key circRNA in HCC progression and treatment sensitivity. Results: We found that circMEMO1 was significantly downregulated in HCC samples and that the level of circMEMO1 was closely related to the OS and disease-free survival (DFS) of HCC patients. Mechanistic analysis revealed that circMEMO1 can modulate the promoter methylation and gene expression of TCF21 to regulate HCC progression by acting as a sponge for miR-106b-5p, which targets the TET family of genes and increases the 5hmC level. More importantly, circMEMO1 can increase the sensitivity of HCC cells to sorafenib treatment. Conclusion: Our study determined that circMEMO1 can promote the demethylation and expression of TCF21 and can be considered a crucial epigenetic modifier in HCC progression. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV‐related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value. Methods: We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan‐Meier analysis and log‐rank test to identify lncRNA CNV with prognostic value. We conducted loss‐ and gain‐of‐function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR‐seq), quantitative real‐time PCR (qRT‐PCR), western blot, and dual‐luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull‐down, RNA immunoprecipitation, qRT‐PCR, and western blot analyses. Results: Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR‐199a‐5p, resulting in enhanced expression of SNAI1, which induced epithelial‐to‐mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway. Conclusions: LINC01133 promotes HCC progression by sponging miR‐199a‐5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC. [ABSTRACT FROM AUTHOR]

More than 95% of all human genes are alternatively spliced after transcription, which enriches the diversity of proteins and regulates transcript and/or protein levels. The splicing isoforms produced from the same gene can manifest distinctly, even exerting opposite effects. Mounting evidence indicates that the alternative splicing (AS) mechanism is ubiquitous in various cancers and drives the generation and maintenance of various hallmarks of cancer, such as enhanced proliferation, inhibited apoptosis, invasion and metastasis, and angiogenesis. Splicing factors (SFs) play pivotal roles in the recognition of splice sites and the assembly of spliceosomes during AS. In this review, we mainly discuss the similarities and differences of SF domains, the details of SF function in AS, the effect of SF-driven pathological AS on different hallmarks of cancer, and the main drivers of SF expression level and subcellular localization. In addition, we briefly introduce the application prospects of targeted therapeutic strategies, including small-molecule inhibitors, siRNAs and splice-switching oligonucleotides (SSOs), from three perspectives (drivers, SFs and pathological AS). Finally, we share our insights into the potential direction of research on SF-centric AS-related regulatory networks. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver transplantation (LTx) is one of the most effective treatments for hepatocellular carcinoma (HCC); however, tumour recurrence after LTx often leads to poor outcomes. This study investigated the value of circulating tumour cells (CTCs) as a predictor of recurrence following LTx in patients with HCC. Methods: This analysis included 193 patients with HCC who underwent LTx at our institute and accepted pre‐ and post‐operative CTC detection; 38 were selected for serial CTC monitoring. The predictive value of CTCs for tumour recurrence in patients with HCC following LTx was evaluated. Single‐cell whole genome sequencing was used to characterize CTCs. Results: Overall, the CTC burden decreased after LTx (P <.05). Post‐operative CTC count ≥ 1 per 5 mL peripheral blood was identified as a potential biomarker for predicting tumour recurrence after LTx, especially in patients with no detectable CTCs prior to LTx and negative tumour serological biomarkers. The predictive value of post‐operative CTC count ≥ 1 per 5 mL blood was retained in patients who did not meet the Milan criteria, University of California San Francisco (UCSF) criteria, or Fudan criteria (all P <.05). Furthermore, post‐operative serial CTC detection may be useful in post‐surgical surveillance for HCC recurrence. Conclusions: CTCs may be a useful biomarker to evaluate recurrence risk following LTx in patients with HCC. Evaluation based on CTC detection may enhance the post‐transplant management of HCC, and improve the therapeutic efficacy of LTx. [ABSTRACT FROM AUTHOR]

Background: The concurrent presence of liver cirrhosis and hepatocellular carcinoma (HCC) poses a challenge for laparoscopic surgeons to establish a routine practice. The aim of this study was to gather evidence and produce recommendations on the safe and effective practice of laparoscopic hepatectomy for patients with solitary HCC (≤ 5 cm) and liver cirrhosis. Methods: Between October 2013 and October 2014, 356 curative hepatectomies were performed for patients pathologically diagnosed with solitary HCC (≤ 5 cm) accompanied by cirrhosis (stage 4 fibrosis). To overcome selection bias, a 1:2 match using propensity score matching analysis was conducted between laparoscopic and open hepatectomy. Perioperative outcomes were compared between the groups, including hospitalization, operation time, blood loss, and surgical complications. Perioperative inflammation-based markers, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were collected from medical records and analyzed. Results: There were 43 and 77 patients in the laparoscopic and open groups, respectively. The laparoscopic group had less hepatic inflow occlusion (16.3% vs. 61%; P < 0.001), shorter operation time (155 vs. 170 min; P = 0.004), and shorter postoperative hospital stay (4 vs. 7 days; P < 0.001). Although the difference was not significant (P = 0.154), the rate of postoperative complications tended to be lower in the laparoscopic group (2.3%) compared with the open group (9.1%). The increase in postoperative SII, NLR, and LMR for laparoscopic hepatectomy were significantly lower than for open hepatectomy. NLR < 5.8 on postoperative day 3 was significantly correlated with shorter hospital stay (P < 0.001). Conclusions: Compared with open hepatectomy, laparoscopic hepatectomy for selected HCC patients, even in the presence of cirrhosis, might result in better perioperative outcomes and postoperative inflammatory response attenuation, and ultimately promote faster recovery. This provides evidence for considering routine laparoscopic hepatectomy through careful selection of patients with HCC. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) is considered a valuable asset in China's medical tradition. YPF is a classic prescription that has been derived from the "Jiu Yuan Fang" formula and consists of three herbs: Huangqi (Astragalus membranaceus Bunge), Baizhu (Atractylodes rubra Dekker), and Fangfeng (Saposhnikovia divaricata (Turcz.) Schischk). This prescription is widely acclaimed for its exceptional pharmacological properties, including potent antioxidant effects, hormone regulation, and immune modulation effects. Previous research provides evidence suggesting that YPF may have therapeutic effects on pulmonary fibrosis. Further exploration is essential to confirm its effectiveness and elucidate the fundamental processes. First, the active components and target genes of YPF were extracted from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Next, the GSE53845 dataset, which contains information on pulmonary fibrosis, was downloaded from the GEO database. Network informatics methods was then be utilized to identify target genes associated with pulmonary fibrosis. A YPF-based network of protein-protein interactions was constructed to pinpoint possible target genes for pulmonary fibrosis treatment. Additionally, an in vitro model of pulmonary fibrosis induced by bleomycin (BLM) was established to further investigate and validate the possible mechanisms underlying the effectiveness of YPF. In this study, a total of 24 active ingredients of YPF, along with 178 target genes associated with the treatment, were identified. Additionally, 615 target genes related to pulmonary fibrosis were identified. Functional enrichment analysis revealed that 18 candidate genes (CGs) exhibited significant responses to tumor necrosis factor, NF-kB survival signaling, and positive regulation of apoptosis processes. Among these CGs, CAV1, VCAM1, and TP63 were identified as key target genes. Furthermore, cell experiments confirmed that the expression of CAV1 protein and RNA expression was increased in pulmonary fibrosis, but significantly decreased after treatment with YPF. Additionally, the expression of pSmad2, α-SMA, TGF-β1, and TNF-α was also decreased following YPF treatment. Network pharmacology analysis revealed that YPF exhibits significant potential as a therapeutic intervention for pulmonary fibrosis by targeting various compounds and pathways. This study emphasizes that the efficacy of YPF in treating pulmonary fibrosis may be attributed to its ability to up-regulate CAV1 expression and inhibiting pulmonary fibrosis via modulation of the TGF-β1/Smad2 signaling pathway. These findings underscore the promising role of YPF and its ability to potentially alleviate pulmonary fibrosis. [Display omitted] • YPF has significant potential as a therapeutic intervention for pulmonary fibrosis. • CAV1 may contribute to the therapeutic effects of YPF in treating pulmonary fibrosis. • YPF can inhibit pulmonary fibrosis by modulating the TGF-β1/Smad2 signaling pathway. [ABSTRACT FROM AUTHOR]

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies. [ABSTRACT FROM AUTHOR]

Dengue virus infection mainly causes dengue hemorrhagic fever (DHF) and/or dengue shock syndrome (DSS). However, ADE (antibody-dependent enhancement) is one of the main patho- genic factors, and its pathogenic mechanism has not been fully elucidated. Recently, with the development of high-throughput sequencing, an increased number of RNAs have been confirmed to play a vital regulatory role in the process of virus infection. However, there is a lack of research on dengue virus infection and ADE. In this study, we used RNA-Seq to detect differentially expressed RNAs (DE RNAs) profiles in mock-infected, DENV-3-infected, and ADE-infected THP-1 cells. Firstly, we found 69 circRNAs, 259 miRNAs, and 18 mRNAs were differentially expressed in THP-1 vs DENV-3. In THP-1 vs ADE, 94 circRNAs, 263 miRNAs, and 111 mRNAs were differentially expressed. In DENV-3 vs ADE, 68 circRNAs, 105 miRNAs, and 94 mRNAs were differentially expressed. Functional enrichment analysis of these DE RNAs mainly focused on immune system, viral infectious diseases, cytokine-cytokine receptor interactions, and NOD/RIG-I-like receptor signaling pathways. In DENV-3 vs ADE, notably, the expression of HBB was up-regulated, which was a FCY Receptor-mediated phagocytosis protein. Additionally, we predicted the encoding ability of DE circRNAs, and it was found that a small peptide was encoded by novel_circ_001562 and that its amino acid sequence was consistent with that of DDX60L, which is a class of interferon-stimulated genes. Finally, we constructed the ceRNA regulatory network pathway. Therefore, our study provides a new strategy for further investigation on DENV-host interactions. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical outcomes of horizontal mattress suture vs free‐edge suture in the all‐inside arthroscopic Broström–Gould procedure. Methods: This retrospective cohort study included 68 chronic lateral ankle instability (CLAI) patients who underwent either a horizontal mattress suture or a free‐edge suture all‐inside arthroscopic Broström–Gould procedure from January 2014 to January 2017. Patients were divided into two groups based on the suture fashion during the all‐inside arthroscopic Broström–Gould procedure. In the horizontal mattress suture group (n = 31), anchor sutures were used to suture the ATFL, capsule, and inferior extensor retinaculum in horizontal mattress suture fashion. In the free‐edge suture group (n = 37), anchor sutures were used to suture the ATFL, capsule, and inferior extensor retinaculum in free‐edge suture fashion. The Visual Analogue Scale (VAS) score, the American Orthopaedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), Anterior Talar Translation (ATT), the rate of return to sports, and ankle proprioceptive recovery were compared in both groups. Results: The operative times and duration of hospitalization between the two groups were comparable (all P > 0.05). The VAS, AOFAS, ATT, the rate of return to sports, and ankle proprioceptive recovery were comparable between the horizontal mattress suture and free‐edge suture groups at 1 and 2 years after surgery. Patients of the free‐edge suture group achieved better KAFS 1 and 2 years after the surgery compared with those of the horizontal mattress suture group. In both groups, incisions were healed by first intention, and complications such as infection, implant reactions, tendon injury, and nervous or vascular injuries were not observed. The ankle proprioceptive recovery in horizontal mattress suture and free‐edge suture groups showed no significant differences at 1 and 2 years after surgery. The mean time of the return to full activity for patients in the horizontal mattress suture group was 10.38 ± 2.02 (range 8 to 12) weeks vs 8.63 ± 2.31 (range 8 to 12) weeks for those in the free‐edge suture group (P = 0.001, power = 0.907). The exercise participation rates were comparable between groups (P > 0.05). At the 2‐year follow‐up, all patients regained normal activities and ankle stability, and no recurrence of CLAI or revision surgery was recorded. Conclusion: All‐inside arthroscopic Broström–Gould surgery for the treatment of CLAI ensures a better functional effect (KAFS) and better recovery time when free‐edge suture is used instead of horizontal mattress suture. [ABSTRACT FROM AUTHOR]

• A new index: Tfr-Tfh index (TTI) was designed based on Tfr and Tfh cells. • Patients with high recurrence had higher levels of TTI. • TTI could work as a new predictor for HCC patients with HBV infection after surgery. T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells were newly identified as the subsets of cluster of CD4+ T cells. As major components of human immune system, they were found in tumor microenvironment and reported to play vital roles in the progression of cancer. But their clinical significance in Hepatocellular carcinoma (HCC) was not elucidated. Thus, this research aimed to investigate their prognostic value in HCC. A total of 210 subjects (including 110 HCC patients, 50 chronic hepatitis patients and 50 healthy individuals) were enrolled in the research. Tfh, Tfr cells and Treg cells from peripheral blood were measured by flow cytometry. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of Tfr-Tfh Index (TTI) in early HCC and relapse status. Its further prognostic valve was assessed by Kaplan-Meier survival estimate and log rank tests. Tfh cells, Tfr cells, Treg cells and TTI were all higher in HCC patients than in chronic hepatitis patients and healthy control. TTI was found to have positive correlation with the load of HBV. The AUC of TTI for early HCC and relapse status was better than other clinical indices in HBV positive patients. An optimal cutoff point for the TTI stratified the HCC patients into high (>21.96) and low index (≤21.96) groups. High TTI was significantly correlated with recurrence. Univariate and multivariate analyses revealed TTI could be a predictor for recurrence. Moreover, it retained prognostic performance for patients with lower recurrence risk. Our research showed that TTI could be a promising indicator for early recurrence in HCC patients with HBV infection. [ABSTRACT FROM AUTHOR]

• sPD-L1 level was significantly elevated in patients with poor HCC outcomes after TACE. • High sPD-L1 was an independent predictive indicator for HCC prognosis after TACE. • High sPD-L1 correlated with high sIL-2R, IL-10 and HBV-loads, which indicated immunosuppressive status. • High sPD-L1 levels correlated with increased numbers of Treg cells, Macrophage cells, and M2-Macrophage cells. The present study aimed to determine the prognostic significance of soluble Programmed Death-ligand 1 (sPD-L1) in hepatocellular carcinoma (HCC) patients undergoing transcatheter arterial chemoembolization (TACE). We treated 114 HCC patients with TACE from 2012 to 2013 and determined their sPD-L1 levels by enzyme-linked immunosorbent assay. We evaluated prognosis according to mRESIST criteria and analyzed prognostic values by Cox regression and Kaplan-Meier analysis. We further evaluated correlations between sPD-L1 level and inflammatory status, as well as immunosuppressive environment. sPD-L1 levels were significantly increased in patients who developed HCC progression (P = 0.002) and death (P < 0.001). Patients with higher pre-treatment sPD-L1 levels had a significantly shorter time to progression (10.50 vs. 18.25 months, P = 0.001) and decreased overall survival (16.50 vs. 28.50 months, P = 0.003). Importantly, sPD-L1 levels positively correlated with SII (r = 0.284, P = 0.002), sIL-2R (r = 0.239, P = 0.010), IL-10 (r = 0.283, P = 0.002), HBV-DNA loads (r = 0.229, P = 0.014), and CRP (r = 0.237, P = 0.011). Moreover, high sPD-L1 levels had increased numbers of Treg cells (FOXP3+; P = 0.026), Macrophage cells (CD68+; P = 0.014), and M2-Macrophage cells (CD163+; P = 0.026) sPD-L1 level is a prognostic indicator of poor outcomes after TACE. High sPD-L1 might reflect increased immune activation in an immunosuppressive environment that hindered anti-tumor response activity. [ABSTRACT FROM AUTHOR]

Dear Editor, Though cancer immune therapy has achieved benefits in partial patients' population, the overall responses remain low, and low immune infiltration status has been deemed as a key factor leading to low response.1 In hepatocellular carcinoma (HCC), we found that tumor intrinsic oncogenic pathways were related to tumor infiltrating immune cells: mutation of I catenin beta 1 i I (CTNNB1) i or activation of the canonical I b-catenin i pathway was related to poor immune infiltration, while high expression of I Kirsten rat sarcoma viral oncogene homolog (KRAS) i was related to a better immune infiltration status, which provides new thoughts on combining immune therapy by targeting tumor intrinsic pathways and gives new markers for preference of treating methods. The protein expression of I KRAS i in HCC tissues was seen in only 37% of patients, while I CTNNB1 i was highly expressed, which may explain the immune suppressive microenvironment in liver tumor. [Extracted from the article]

• Microglia release pro-inflammatory cytokines and chemokine CCL-2 following CH. • Microglia-derived CCL-2 recruits monocyte/macrophage infiltration in cerebellum. • Inhibition of microglia/CCL-2 alleviates CH-induced neuroinflammatory responses. • Inhibition of microglia/CCL-2 prevents apoptosis and dysfunction of Purkinje cells. • Suppression of microglia/CCL-2 ameliorates cerebellar injury and ataxia after CH. Ataxia, characterized by uncoordinated movement, is often found in patients with cerebellar hemorrhage (CH), leading to long-term disability without effective management. Microglia are among the first responders to CNS insult. Yet the role and mechanism of microglia in cerebellar injury and ataxia after CH are still unknown. Using Ki20227, an inhibitor for colony-stimulating factor 1 receptor which mediates the signaling responsible for the survival of microglia, we determined the impact of microglial depletion on cerebellar injury and ataxia in a murine model of CH. Microglial depletion reduced cerebellar lesion volume and alleviated gait abnormality, motor incoordination, and locomotor dysfunction after CH. Suppression of CH-initiated microglial activation with minocycline ameliorated cerebellum infiltration of monocytes/macrophages, as well as production of proinflammatory cytokines and chemokine C–C motif ligand-2 (CCL-2) that recruits monocytes/macrophages. Furthermore, both minocycline and bindarit, a CCL-2 inhibitor, prevented apoptosis and electrophysiological dysfunction of Purkinje cells, the principal neurons and sole outputs of the cerebellar cortex, and consequently improved ataxia-like motor abnormalities. Our findings suggest a detrimental role of microglia in neuroinflammation and ataxic motor symptoms after CH, and pave a new path to understand the neuroimmune mechanism underlying CH-induced cerebellar ataxia. [ABSTRACT FROM AUTHOR]

The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase α1 (P4HA1) expression, which can convert bradykinin (BK) to hydroxyprolyl-BK (Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1α (HIF-1α) and carbonic anhydrase 9 (CA9). Hypoxia-induced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1α dependent, pre-treatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1α and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pre-treatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy. [ABSTRACT FROM AUTHOR]

In this paper, a robust design method for optimizing the static accuracy of a vertical machining center is proposed. First, the accuracy prediction model was established using screw theory to determine the output accuracy of the machine tool, which was verified by using a DBB and laser interferometer. Then, combining the machine tool's output accuracy and accuracy design requirements to identify the performance equation of the machining accuracy, a model to calculate machining accuracy reliability is derived. Because the reliability calculation model is highly nonlinear, this paper uses response surface methodology to obtain a highly approximate solution for reliability, and the worst reliable working position can also be found from this. On this basis, according to the sensitivity analysis of machining accuracy reliability, the key distribution parameters of geometric error elements that have an important impact are identified. According to the principle of accuracy balance, the error distribution parameters are reasonably adjusted to reduce the effect of errors on the reliability to create a robust design for optimizing the machine tool static accuracy. The research results show that the method proposed only needs to optimize the error distribution parameters five times to make the machining accuracy reliability meet design requirements. [ABSTRACT FROM AUTHOR]

Background: Deoxycytidine kinase (DCK), an enzyme in the nucleoside biosynthetic pathway, can affect the development of immune cells. However, the relationships between the expression of DCK, patient prognosis, and tumor-infiltrating immune cells (TIICs) in hepatocellular carcinoma (HCC) are still unclear. Methods: The expression of DCK in HCC was analyzed through the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The impact of DCK on clinical prognosis was investigated via the Kaplan-Meier plotter and verified in the Gene Expression Profiling Interactive Analysis (GEPIA) databases. The interrelationships between DCK expression and TIICs in HCC were analyzed by the TIMER database. Additionally, the relationship between DCK expression and immune cell gene markers was calculated through TIMER and GEPIA databases. Results: Compared with the adjacent normal tissues, high expression of DCK was observed in HCC tissues. Also, the higher expression of DCK was correlated to poorer prognosis in HCC patients, and it was associated with decreased survival in those with early stage and grade. Moreover, DCK expression was positively correlated with TIICs, including CD4+ and CD8+ T cells, B cells, monocytes, tumor-associated macrophages (TAMs), M1 and M2 macrophages, neutrophils, natural killer cells, and dendritic cells. Specifically, DCK expression levels were significantly associated with diverse immune gene marker sets, including those of Tregs and exhausted T cells. Conclusion: These findings suggest that DCK expression is correlated with patient outcomes and tumor infiltration cell levels in HCC patients. Additionally, the increased level of DCK was associated with marker genes of Tregs and exhaustion-related inhibitory receptors, suggesting the potential role of DCK in immunosuppression and immune escape. These findings suggest that DCK can function as a potential novel prognostic biomarker and reflect the immune infiltration status in HCC patients. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC) is usually poor, and effective adjuvant therapy is missing making it important to investigate whether these patients may benefit from adjuvant transarterial chemoembolization (TACE). We aimed to evaluate the efficiency of adjuvant TACE for long-term recurrence and survival after curative resection before and after propensity score matching (PSM) analysis.Methods: In this retrospective study, of 230 patients who underwent resection for CHC between January 1994 and December 2014, 46 (18.0%) patients received adjuvant TACE. Univariate and multivariate regression analyses were used to identify the independent predictive factors of survival. Cox regression analyses and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS) between patients who did or did not receive adjuvant TACE.Results: A total of 230 patients (mean age 52.2 ± 11.9 years; 172 men) were enrolled, and 46 (mean age 52.7 ± 11.1 years; 38 men) patients received TACE. Before PSM, in multivariate regression analysis, γ-glutamyl transpeptidase (γ-GT), tumour nodularity, macrovascular invasion (MVI), lymphoid metastasis, and extrahepatic metastasis were associated with OS. Alanine aminotransferase (ALT), MVI, lymphoid metastasis, and preventive TACE (HR: 2.763, 95% CI: 1.769-4.314, p < 0.001) were independent prognostic factors for DFS. PSM created 46 pairs of patients. Before PSM, adjuvant preventive TACE was not associated with an increased risk of OS (HR: 0.911, 95% CI: 0.545-1.520, p = 0.720) or DFS (HR: 3.345, 95% CI: 1.686-6.638, p = 0.001). After PSM, the 5-year OS and DFS rates were comparable in the TACE group and the non-TACE group (OS: 22.7% vs 14.9%, respectively, p = 0.75; DFS: 11.2% vs 14.4%, respectively, p = 0.06).Conclusions: The present study identified that adjuvant preventive TACE did not influence DFS or OS after curative resection of CHC. [ABSTRACT FROM AUTHOR]

Background: Immunoscore have shown a promising prognostic value in many cancers. We aimed to establish and validate an immune classifier to predict survival after curative resection of hepatocellular carcinoma (HCC) patients who have undergone curative resection.Methods: The immunohistochemistry (IHC) classifier assay was performed on 664 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC. A nine-feature-based HCC-IHC classifier was then constructed by the least absolute shrinkage and selection operator method. The associations between the HCC-IHC classifier and patient outcomes were assessed. Herein, a nomogram was generated from the Cox regression coefficients and evaluated by decision curve analysis.Results: We constructed an HCC-IHC classifier based on nine features; significant differences were found between the low-HCC-IHC classifier patients and high-HCC-IHC classifier patients in the training cohort in the 5-year relapse-free survival rates (46.7% vs. 26.7%, respectively; P < 0.001). The HCC-IHC classifier-based nomogram presented better accuracy than traditional staging systems.Conclusions: In conclusion, the HCC-IHC classifier could effectively predict recurrence in early-stage HCC patients and supplemented the prognostic value of the BCLC staging system. The HCC-IHC classifier may facilitate patient decision-making and individualise the management of postoperative patients with early-stage HCC. [ABSTRACT FROM AUTHOR]

Background: High rates of postoperative tumor recurrence contribute to poor outcome in hepatocellular carcinoma (HCC). Here, we investigated whether circulating tumor cells (CTCs) status can predict the benefit of adjuvant transcatheter arterial chemoembolization (TACE) in patients with HCC. Methods: The retrospective study enrolled 344 HCC patients with preoperative CTCs analysis. Clinical outcomes including recurrence and survival were compared between those who received and who did not receive adjuvant TACE. Similar comparisons were made for patients stratified according to CTC status (CTC‐negative [CTC = 0], n = 123; CTC‐positive [CTC ≥ 1], n = 221). Propensity score matching (PSM) strategy was adopted to offset differences between two groups. Results: In the study cohort as a whole or in CTC‐negative cohort, there were no observable differences in overall survival (OS) or time to recurrence (TTR) between TACE and control group (P >.05). In CTC‐positive patients, PSM generated 64 patient pairs, and patients with adjuvant TACE had significantly better clinical outcomes (OS: not reached vs 36.4 months, P <.001; TTR: 45.8 vs 9.8 months, P <.001). Adjuvant TACE significantly reduced early recurrence (≤2 years) (64.1% vs 31.7%, P <.001) in CTC‐positive patients. Notably, adjuvant TACE influenced TTR and OS even in subgroups of CTC‐positive patients with low risk of recurrence according to traditional evaluation. Conclusions: Preoperative CTC status could serve as an indicator for the administration of adjuvant TACE in HCC patients. Adjuvant TACE benefits CTC‐positive HCC patients mainly by reducing early recurrence. [ABSTRACT FROM AUTHOR]

Background: Alpha-fetoprotein (AFP) is a widely used biomarker for hepatocellular carcinoma (HCC) early detection. However, low sensitivity and false negativity of AFP raise the requirement of more effective early diagnostic approaches for HCC. Methods: We employed a three-phase strategy to identify serum autoantibody (AAb) signature for HCC early diagnosis using protein array-based approach. A total of 1253 serum samples from HCC, liver cirrhosis, and healthy controls were prospectively collected from three liver cancer centers in China. The Human Proteome Microarray, comprising 21,154 unique proteins, was first applied to identify AAb candidates in discovery phase (n = 100) and to further fabricate HCC-focused arrays. Then, an artificial neural network (ANN) model was used to discover AAbs for HCC detection in a test phase (n = 576) and a validation phase (n = 577), respectively. Results: Using HCC-focused array, we identified and validated a novel 7-AAb panel containing CIAPIN1, EGFR, MAS1, SLC44A3, ASAH1, UBL7, and ZNF428 for effective HCC detection. The ANN model of this panel showed improvement of sensitivity (61.6–77.7%) compared to AFP (cutoff 400 ng/mL, 28.4–30.7%). Notably, it was able to detect AFP-negative HCC with AUC values of 0.841–0.948. For early-stage HCC (BCLC 0/A) detection, it outperformed AFP (cutoff 400 ng/mL) with approximately 10% increase in AUC. Conclusions: The 7-AAb panel provides potentially clinical value for non-invasive early detection of HCC, and brings new clues on understanding the immune response against hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]