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Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from bile duct epithelium. Its characteristics include an insidious onset and frequent recurrence or metastasis after surgery. Current chemotherapies and molecular target therapies provide only modest survival benefits to patients with ICC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that has good antitumor effects in a variety of solid tumors. However, there are few studies of anlotinib-associated mechanisms and use as a treatment in ICC. In this study using in vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration and invasion restraint, and cell-cycle arrestment. Anlotinib treatment affected induction of apoptosis and the mesenchymal–epithelial transition. Patient-derived xenograft models generated directly from patients with ICC revealed that anlotinib treatment dramatically hindered in vivo tumor growth. We also examined anlotinib’s mechanism of action using transcriptional profiling. We found that anlotinib treatment might mainly inhibit tumor cell proliferation and invasion and promote apoptosis via cell-cycle arrestment by inactivating the VEGF/PI3K/AKT signaling pathway, as evidenced by significantly decreased phosphorylation levels of these kinases. The activation of vascular endothelial growth factor receptor 2 (VEGFR2) can subsequently activate PI3K/AKT signaling. We identified VEGRF2 as the main target of anlotinib. High VEGFR2 expression might serve as a promising indicator when used to predict a favorable therapeutic response. Taken together, these results indicated that anlotinib had excellent antitumor activity in ICC, mainly via inhibiting the phosphorylation level of VEGFR2 and subsequent inactivation of PIK3/AKT signaling. This work provides evidence and a rationale for using anlotinib to treat patients with ICC in the future.

Crystalline borates have received great attention due to their various structures and wide applications. For a long time, the corner-sharing B–O unit is considered a basic rule in borate structural chemistry. The Dy4B6O15 synthesized under high-pressure is the first oxoborate with edge-sharing [BO4] tetrahedra, while the KZnB3O6 is the first ambient pressure borate with the edge-sharing [BO4] tetrahedra. The edge-sharing connection modes greatly enrich the structural chemistry of borates and are expected to expand new applications in the future. In this review, we summarize the recent progress in crystalline borates with edge-sharing [BO4] tetrahedra. We discuss the synthesis, fundamental building blocks, structural features, and possible applications of these edge-sharing borates. Finally, we also discuss the future perspectives in this field.

Accumulating evidence suggests that circular RNAs (circRNAs) play essential roles in regulating cancer progression, but many circRNAs in hepatocellular carcinoma (HCC) remain unknown. Dysregulated circRNAs in HCC were identified through bioinformatics analysis of Gene Expression Omnibus data sets. Quantitative real‐time PCR (qRT‐PCR), Sanger sequencing, RNase R digestion and actinomycin D treatment were conducted to confirm the characterization of circRNAs. CCK‐8, wound‐healing and Transwell assays were performed to assess the functional roles of Hsa_circ_0003945 (Circ_0003945) in HCC cell lines. Subcellular fractionation and fluorescence in situ hybridization (FISH) were performed to locate Circ_0003945 in HCC cells. Dual‐luciferase reporter assay was executed to verify the binding of Circ_0003945 to microRNAs (miRNAs) or the miRNAs to their target genes. In this study, we found that Circ_0003945 was upregulated in HCC tissue, and higher Circ_0003945 expression was positively correlated with tumour size and tumour stage. Furthermore, high plasma levels of circulating Circ_0003945 were confirmed in HCC patients compared with those in non‐HCC groups. The functional experiments revealed that overexpression or knockdown of Circ_0003945 promoted or attenuated tumour growth and migration, respectively. Mechanistically, Circ_0003945 might exert as a miR‐34c‐5p sponge to upregulate the expression of leucine‐rich repeat‐containing G protein‐coupled receptor 4 (LGR4), activating the β‐catenin pathway, and finally facilitating HCC progression. Additionally, a β‐catenin activator could reverse the effect of Circ_0003945 knockdown. In conclusion, Circ_0003945 exerts a tumour‐promoting role in HCC cells by regulating the miR‐34c‐5p/LGR4/β‐catenin axis, which may be a potential target for HCC therapy.

Objective Differentiation‐inducing therapy for tumors is a strategy that aims to induce the differentiation and maturation of cancer stem cells (CSCs). The differentiation‐inducing capacity of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC) and the underlying mechanism were previously unknown. Methods In the present study, we explored the ATO‐induced differentiation of CSCs in HCC by detecting the expression of CSC‐related markers and tumorigenicity variation in vivo and in vitro. We developed a combined chemotherapeutic approach to HCC by characterizing the effects of combinatorial treatment with 5‐fluorouracil (5‐FU)/cisplatin and ATO in vitro and in patient‐derived xenograft models. Changes in gene expression patterns were investigated by gene microarray analysis. Results ATO effectively induced differentiation of CSCs by downregulation of CSC‐related genes and suppression of tumorigenicity capability. Combinatorial treatment with ATO and 5‐FU/cisplatin significantly enhanced therapeutic effects in HCC cells compared with the treatment with 5‐FU/cisplatin alone. Synergistic inhibition of the LIF/JAK1/STAT3 and NF‐kB signaling pathways by ATO and 5‐FU/cisplatin is a potential molecular mechanism underlying the differentiation effect. Conclusions ATO induced the differentiation of HCC CSCs and potentiated the cytotoxic effects of 5‐FU/cisplatin through synergistic inhibition of the LIF/JAK1/STAT3 and NF‐kB signaling pathways. These results offer new insights for the clinical treatment of HCC. Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF‐kB signaling pathways synergistically

Background Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood‐based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. Methods A three‐phase multicentre study was conducted to screen, optimise and validate HCC‐specific differentially methylated regions (DMRs) using next‐generation sequencing and quantitative methylation‐specific PCR (qMSP). Results Genome‐wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre‐ and postoperative plasma samples from 103 HCC patients and correlated with 2‐year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). Conclusions HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC‐specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at‐risk populations. The HepaAiQ assay integrates the most effective HCC‐specific methylation biomarkers using multilocus quantitative PCR. In multicentre studies, the HepaAiQ model accurately distinguishes HCC from other liver diseases, surpassing existing serum tests. The HepaAiQ excels in early‐stage HCC detection in high‐risk patients and post‐resection assessment, potentially fulfilling clinical needs with high accuracy, accessibility and affordability.

Background The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. Objective This research explored the effectiveness of integrating anlotinib (a broad‐spectrum tyrosine kinase inhibitor) with programmed death‐1 (PD‐1) blockade and offers mechanistic insights into more effective strategies for treating HCC. Methods Using patient‐derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD‐1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time‐of‐flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. Results The combination of anlotinib with an anti‐PD‐1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF‐1α signaling axis. CD8+ T‐cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti‐PD‐1 therapy in patients with HCC. Conclusions Our findings highlight anlotinib's potential to augment the efficacy of anti‐PD‐1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14‐mediated CD8+ T‐cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. Highlights Synergistic effects of anlotinib and anti‐PD‐1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF‐1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T‐cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti‐PD‐1‐based therapies in advanced HCC patients. Schematic depiction of the mechanism underlying how anlotinib enhances the tumour response to anti‐PD‐1 immunotherapy.

Current therapeutic options for intrahepatic cholangiocarcinoma (ICC) are very limited, which is largely attributed to poor understanding of molecular pathogenesis of ICC. Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) has been reported to be a broad-spectrum tumor suppressor in many tumor types, yet its role in ICC remains unknown. The aim of this study was to investigate the clinical implications and biological function of BAP1 in ICC. Our results showed that the messenger RNA and protein levels of BAP1 were significantly downregulated in ICC versus paired non-tumor tissues. Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo. Conversely, knockdown of BAP1 yielded opposing effects. Mechanistically, BAP1 functioned as a tumor suppressor in ICC by inhibiting the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase/c-Jun pathways, and this function was abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated with aggressive tumor characteristics, such as larger tumor size, presence of lymphatic metastasis, and advanced tumor node metastasis stage. Survival analysis revealed that low BAP1 expression was significantly and independently associated with poor overall survival and relapse-free survival after curative surgery. In conclusion, BAP1 is a putative tumor suppressor of ICC, and may serve as a valuable prognostic biomarker as well as potential therapeutic target for ICC.

We developed an integrated workflow for circulating tumor cell (CTC) detection and downstream single‐cell analysis based on a novel ChimeraX®‐i120 platform. The platform facilitates negative enrichment, immunofluorescent labeling, and machine learning‐based identification of CTCs. The CTC captured by the platform is also compatible for single‐cell molecular analysis. In this study, potential utility of our workflow was validated in clinical setting. Circulating tumor cell (CTC) analysis holds great potential to be a noninvasive solution for clinical cancer management. A complete workflow that combined CTC detection and single‐cell molecular analysis is required. We developed the ChimeraX®‐i120 platform to facilitate negative enrichment, immunofluorescent labeling, and machine learning‐based identification of CTCs. Analytical performances were evaluated, and a total of 477 participants were enrolled to validate the clinical feasibility of ChimeraX®‐i120 CTC detection. We analyzed copy number alteration profiles of isolated single cells. The ChimeraX®‐i120 platform had high sensitivity, accuracy, and reproducibility for CTC detection. In clinical samples, an average value of > 60% CTC‐positive rate was found for five cancer types (i.e., liver, biliary duct, breast, colorectal, and lung), while CTCs were rarely identified in blood from healthy donors. In hepatocellular carcinoma patients treated with curative resection, CTC status was significantly associated with tumor characteristics, prognosis, and treatment response (all P < 0.05). Single‐cell sequencing analysis revealed that heterogeneous genomic alteration patterns resided in different cells, patients, and cancers. Our results suggest that the use of this ChimeraX®‐i120 platform and the integrated workflow has validity as a tool for CTC detection and downstream genomic profiling in the clinical setting.

Background Gastrointestinal (GI) cancers are among the most prevalent and lethal malignancies worldwide. Early, non-invasive detection is essential for timely intervention and improved survival. To address this clinical need, we developed GutSeer, a blood-based assay combining DNA methylation and fragmentomics for multi-GI cancer detection. Methods Genome-wide methylome profiling identified 1,656 markers specific to five major GI cancers and their tissue origins. Based on these findings, we designed GutSeer, a targeted bisulfite sequencing panel, which was trained and validated using plasma samples from 1,057 cancer patients and 1,415 non-cancer controls. The locked model was blindly tested in an independent cohort of 846 participants, encompassing both inpatient and outpatient settings across five hospitals. Results In the validation cohort, GutSeer achieved an area under the curve (AUC) of 0.950 [95% Confidence Interval (CI): 0.937–0.962] for cancer detection, with 82.8% sensitivity (95% CI: 79.5–86.0) and 95.8% specificity (95% CI: 94.3–97.2). It detected 92.2% of colorectal, 75.5% of esophageal, 65.3% of gastric, 92.9% of liver, and 88.6% of pancreatic cancers. The independent test cohort included 198 early-stage cancers (stage I/II, 66.4%) and 63 advanced precancerous lesions. GutSeer maintained robust performance, with 81.5% sensitivity (95% CI: 77.1–85.9) for GI cancers and 94.4% specificity (95% CI: 92.4–96.5). It also demonstrated the ability to detect advanced precancerous lesions in the colorectum, esophagus, and stomach as a single, non-invasive blood test. Conclusions By integrating DNA methylation and fragmentomics into a compact panel, GutSeer outperformed genome-wide sequencing in both accuracy and clinical applicability. Its high sensitivity for early-stage GI cancers and practicality as a non-invasive assay highlights its potential to revolutionize early cancer detection and improve patient outcomes. Trial registration ClinicalTrials.gov identifier: NCT05431621.

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. CD155 is highly expressed in hepatocellular carcinoma (HCC) tissues, and its overexpression predicts poor postsurgery prognosis in HCC patients. CD155 promotes HCC progression via its cell‐intrinsic role in regulating cell proliferation, migration, invasion and epithelial–mesenchymal transition (EMT). CD155 enhances SRC activation through interacting with SH2 domain of SRC, further inhibiting the downstream p38 MAPK signalling pathway in HCC.