CircPCNXL2 promotes tumor growth and metastasis by interacting with STRAP to regulate ERK signaling in intrahepatic cholangiocarcinoma.

BACKGROUND: circular RNAs (circRNAs) have been reported to exert important effects in the progression of numerous cancers. However, the functions of circRNAs in intrahepatic cholangiocarcinoma (ICC) are still unclear. METHODS: circPCNXL2 (has_circ_0016956) were identified in paired ICC by circRNA microarray. Then, we assessed the biological functions of circPCNXL2 by CCK8, EdU, clone formation, transwell, wound healing assays, and xenograft models. RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between cirrcPCNXL2 and serine-threonine kinase receptor-associated protein (STRAP). RNA pull-down, RIP and luciferase reporter assays were used to investigate the sponge functions of circPCNXL2. In the end, we explore the effects of circPCNXL2 and trametinib (a MEK1/2 inhibitor) in vivo. RESULTS: circPCNXL2 was upregulated in ICC tissues and cell lines, which promoted the proliferation and metastasis of ICC in vitro and in vivo. In terms of the mechanisms, circPCNXL2 could directly bind to STRAP and induce the interaction between STRAP and MEK1/2, resulting in the tumor promotion in ICC by activation of ERK/MAPK pathways. Besides, circPCNXL2 could regulate the expression of SRSF1 by sponging miR-766-3p and subsequently facilitated the growth of ICC. Finally, circPCNXL2 could partially inhibit the anti-tumor activity of trametinib in vivo. CONCLUSION: circPCNXL2 played a crucial role in the progression of ICC by interacting with STRAP to activate the ERK signaling pathway, as well as by modulating the miR-766-3p/SRSF1 axis. These findings suggest that circPCNXL2 may be a promising biomarker and therapeutic target for ICC.

Exosome-derived miR-182-5p promoted cholangiocarcinoma progression and vasculogenesis by regulating ADK/SEMA5a/PI3K pathway.

BACKGROUND AND AIMS: Increasing evidence suggested that miRNAs regulated the expression of pivotal genes involved in oncogenesis and malignant phenotype. In this project, the purpose was to make an inquiry to the effect and mechanism of miR-182-5p in the progression of cholangiocarcinoma. METHODS: By analysing TCGA and GEO databases, combined with tissue expression levels, miR-182-5p was identified as one of the most valuable miRNAs for research. The function and relationships between miR-182-5p and downstream target genes were both verified by in vitro and in vivo experiments. Methylation-specific PCR and bisulphite sequencing were used to detect the methylation level changes of downstream gene promoter. RESULTS: We found that miR-182-5p could be taken up by exosomes secreted from cholangiocarcinoma. Moreover, exosomal derived miR-182-5p promoted vascular endothelial cell proliferation and migration and induced angiogenesis by targeting ADK/SEMA5a. Subsequently, the PI3K/AKT/mTOR signalling pathway was activated and ultimately caused resistance to gemcitabine and cisplatin. CONCLUSIONS: Our findings suggested that the miR-182-5p/ADK/SEMA5a axis might serve as a potential therapeutic target for cholangiocarcinoma.

Dual-band terahertz chiral metasurface absorber with enhanced circular dichroism based on temperature-tunable InSb for sensing applications.

Circular dichroism (CD) in terahertz (THz) regions has been widely used in biomonitoring, analytical chemistry, communication sensing, and other fields. Herein, we present a simple design for a dual-band THz chiral metasurface absorber (CMA) with a stronger CD effect based on temperature-tunable InSb for enhanced sensing applications. The proposed dual-band CMA consisted of a periodic array of the evolved C-shaped InSb adhered to a copper substrate. The designed CMA at 305 K achieved a right-handed circular polarization (RCP)-selective absorbance of 98.86% and 97.43% at 1.65 THz and 1.89 THz, respectively, and left-handed circular polarization (LCP) absorbance of 9.98% and 22.46%, respectively, and exhibited stronger CD values of 0.89 and 0.75. In addition, the CD properties of the designed CMA can be adjusted by changing the geometrical parameters of the unit-cell structure. The simulated electric field and power follow distributions indicate that this dual-band chiral-selective absorption of the designed CMA is due to the different plasma resonance mode excitations for the incident circular polarization (CP) wave. In addition, the CD properties of the designed CMA can be adjusted by changing the geometrical parameters of the unit-cell structure. Furthermore, CD spectra can be dynamically adjusted by varying the outside temperature and refraction index (RI) of the filled analytes. The designed dual-band CMA can function as a high-performance temperature sensor with sensitivities of 4.68 GHz K-1 and 5.52 GHz K-1 and also as an RI sensor with sensitivities of 1080 GHz RIU-1 and 860 GHz RIU-1, respectively. Our proposed tunable dual-band CMA with its exquisite performance has the potential to be widely applied in diverse areas such as detection, sensing, and other related optoelectronic fields.

Differentiation and immunosuppressive function of CD19+CD24hiCD27+ regulatory B cells are regulated through the miR-29a-3p/NFAT5 pathway.

BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.

Direct ink writing 3D-printed optical waveguides for multi-layer interconnect.

Low-cost, short-range optical interconnect technology plays an indispensable role in high-speed board-level data communications. In general, 3D printing technology can easily and quickly produce optical components with free-form shapes, while the traditional manufacturing process is complicated and time-consuming. Here, we present a direct ink writing 3D-printing technology to fabricate optical waveguides for optical interconnects. The waveguide core is 3D printed optical polymethylmethacrylate (PMMA) polymer, with propagation loss of 0.21 dB/cm at 980 nm, 0.42 dB/cm at 1310 nm, and 1.08 dB/cm at 1550 nm, respectively. Furthermore, a high-density multilayer waveguide arrays, including a four-layer waveguide arrays with a total of 144 waveguide channels, is demonstrated. Error-free data transmission at 30 Gb/s is achieved for each waveguide channel, indicating that the printing method can produce optical waveguides with excellent optical transmission performance. We believe this simple, low-cost, highly flexible, and environmentally friendly method has great potential for high-speed short-range optical interconnects.

ACSL4 serves as a novel prognostic biomarker correlated with immune infiltration in Cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CHOL) is the second most common primary hepatic malignant tumor, following hepatocellular carcinoma (HCC). CHOL is highly aggressive and heterogeneous resulting in poor prognosis. The diagnosis and prognosis of CHOL has not improved in the past decade. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is reported to be associated with tumors, however, its role in CHOL has not been revealed. This study is mainly for exploring the prognostic values and potential function of ACSL4 in CHOL. METHODS: We investigated the expression level and prognostic value of ACSL4 in CHOL based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. TIMER2.0, TISIDB and CIBERSORT databases were utilized to assess the associations between ACSL4 and immune infiltration cells in CHOL. Single-cell sequencing data from GSE138709 was analyzed to study the expression of ACSL4 in different types of cells. ACSL4 co-expressed genes were analyzed by Linkedomics. Additionally, Western Blot, qPCR, EdU assay, CCK8 assay, transwell assay and wound healing assay were performed to further confirm the roles of ACSL4 in the pathogenesis of CHOL. RESULTS: We found that the level of ACSL4 was higher in CHOL and it was correlated with the diagnosis and prognosis of CHOL patients. Then, we observed that the infiltration level of immune cells was related to the level of ACSL4 in CHOL. Moreover, ACSL4 and its co-expressed genes were mainly enriched in metabolism-related pathway and ACSL4 is also a key pro-ferroptosis gene in CHOL. Finally, knockdown of ACSL4 could reverse the tumor-promoting effect of ACSL4 in CHOL. CONCLUSIONS: The current findings demonstrated ACSL4 may as a novel biomarker for CHOL patients, which might regulate immune microenvironment and metabolism resulting in poor prognosis.

Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.

BACKGROUND AND AIMS: Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. METHODS: In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. RESULTS: The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. CONCLUSIONS: Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.

EBSD patterns simulating multilayer twins based on dynamical theory of electron diffraction.

Electron backscatter diffraction (EBSD) can be employed to determine crystal structures but has not been used alone to identify defects at the atom scale due to the lack of understanding of the EBSD patterns generated by various structure defects. In the present work, the EBSD patterns of FCC-Fe with 9-layer, 6-layer and 3-layer twin structures are simulated, respectively, using the revised real space (RRS) method and compared with the counterpart of perfect crystals. Our results show that when the electron beam is incident along a direction parallel to the twin plane, the pattern appears symmetrical with respect to the corresponding Kikuchi band of the twin plane, and the diffraction details within the Kikuchi band also exhibit symmetry with respect to the middle line of the Kikuchi band. Moreover, the overall clarity of the patterns decreases, and the pattern becomes more blurred with increasing the distance from the Kikuchi band corresponding to the twin plane. By contrast, the incident electron beam along the direction perpendicular to the twin plane results in diffraction superposition of the matrix region and the shear region, which shows twofold rotational symmetry with respect to the Kikuchi pole corresponding to the normal to the twin plane. In addition, some extra Kikuchi bands appear in the EBSD patterns due to the long-period structures of the multilayer twins. As the number of multilayer twins decreases, the number of extra Kikuchi bands decreases and the area of the blurring pattern increases. The correlation between twin structures and EBSD patterns provides theoretical insights for identifying twin structures by the EBSD technique.

M2 Macrophage-Derived Exosomes Facilitate HCC Metastasis by Transferring αM ß2 Integrin to Tumor Cells.

BACKGROUND AND AIMS: The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined. APPROACH AND RESULTS: The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, αM ß2 (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration. CONCLUSIONS: Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.

Development and validation of a gradient boosting machine to predict prognosis after liver resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Accurate prognosis assessment is essential for surgically resected intrahepatic cholangiocarcinoma (ICC) while published prognostic tools are limited by modest performance. We therefore aimed to establish a novel model to predict survival in resected ICC based on readily-available clinical parameters using machine learning technique. METHODS: A gradient boosting machine (GBM) was trained and validated to predict the likelihood of cancer-specific survival (CSS) on data from a Chinese hospital-based database using nested cross-validation, and then tested on the Surveillance, Epidemiology, and End Results (SEER) database. The performance of GBM model was compared with that of proposed prognostic score and staging system. RESULTS: A total of 1050 ICC patients (401 from China and 649 from SEER) treated with resection were included. Seven covariates were identified and entered into the GBM model: age, tumor size, tumor number, vascular invasion, number of regional lymph node metastasis, histological grade, and type of surgery. The GBM model predicted CSS with C-Statistics ≥ 0.72 and outperformed proposed prognostic score or system across study cohorts, even in sub-cohort with missing data. Calibration plots of predicted probabilities against observed survival rates indicated excellent concordance. Decision curve analysis demonstrated that the model had high clinical utility. The GBM model was able to stratify 5-year CSS ranging from over 54% in low-risk subset to 0% in high-risk subset. CONCLUSIONS: We trained and validated a GBM model that allows a more accurate estimation of patient survival after resection compared with other prognostic indices. Such a model is readily integrated into a decision-support electronic health record system, and may improve therapeutic strategies for patients with resected ICC.

A cross-scale study on the relationship between urban expansion and ecosystem services in China.

Clarifying the relationship between urban expansion and ecosystem services (ESs) is critical for sustainable management of land resources and ecosystems. However, little is known about the relationship between the two at the cross-scale (particularly at the national-provincial scale). Therefore, we conducted a systematic assessment of the spatiotemporal dynamics and the relationship between urban expansion and ESs including food production (FP), soil conservation (SC), carbon sequestration (CS), and water yield (WY) in China from 1992 to 2020 on the national-provincial scale. The results show that China's urban expansion took up a large amount of cropland, accounting for 79.35% of the newly-added built-up land. Shandong had the largest expansion scale and the highest speed, Shanghai had the most pronounced expansion intensity, and more than 50% of the provinces were dominated by outlying expansion pattern. In terms of total change, the three ESs of FP, SC, and WY increased by 286.5 × 106 t, 1893.61 × 106 t, and 8337.20 × 106 mm, respectively, and CS decreased by 683.90 × 106 Mg C. However, in the urban expansion area, FP and CS net decreased by 1757.6 × 104 t and 19,640.19 × 104 Mg C, respectively, while SC and WY net increased by 347.52 × 104 t and 20,264.11 × 104 mm, respectively. Shandong contributed the most to changes in ESs in urban expansion areas. Urban expansion was significantly negatively correlated with FP and CS with the correlation coefficients > -0.8; it was significantly positively correlated with SC and WY, with coefficients of 0.714 and 0.413, respectively, and urban expansion had a lagged effect on ESs. The impact of urban expansion on ESs had a spatial spillover effect and showed prominent spatial clustering in Anhui, Henan, and Shandong. Based on these results, we proposed urban planning countermeasures grounded in the perspective of ES improvement, which would provide policy references for the sustainable management of the ecological environment and land resources.

miRNA-130b-5p promotes hepatic stellate cell activation and the development of liver fibrosis by suppressing SIRT4 expression.

Liver fibrosis is a progressive disease accompanied by the deposition of extracellular matrix (ECM). Numerous reports have demonstrated that alterations in the expression of microRNAs (miRNAs) are related to liver disease. However, the effect of individual miRNAs on liver fibrosis has not been studied. Hepatic stellate cells (HSCs), being responsible for producing ECM, exert an important influence on liver fibrosis. Then, microarray analysis of non-activated and activated HSCs induced by transforming growth factor ß1 (TGF-ß1) showed that miR-130b-5p expression was strongly up-regulated during HSC activation. Moreover, the progression of liver fibrosis had a close connection with the expression of miR-130b-5p in different liver fibrosis mouse models. Then, we identified that there were specific binding sites between miR-130b-5p and the 3' UTR of Sirtuin 4 (SIRT4) via a luciferase reporter assay. Knockdown of miR-130b-5p increased SIRT4 expression and ameliorated liver fibrosis in mice transfected with antagomiR-130b-5p oligos. In general, our results suggested that miR-130b-5p promoted HSC activation by targeting SIRT4, which participates in the AMPK/TGF-ß/Smad2/3 signalling pathway. Hence, regulating miR-130b-5p maybe serve as a crucial therapeutic treatment for hepatic fibrosis.

Integrating Machine Learning and Tumor Immune Signature to Predict Oncologic Outcomes in Resected Biliary Tract Cancer.

BACKGROUND: Improved methods are needed to predict outcomes in biliary tract cancers (BTCs). We aimed to build an immune-related signature and establish holistic models using machine learning. METHODS: Samples were from 305 BTC patients treated with curative-intent resection, divided into derivation and validation cohorts in a two-to-one ratio. Spatial resolution of T cell infiltration and PD-1/PD-L1 expression was assessed by immunohistochemistry. An immune signature was constructed using classification and regression tree. Machine learning was applied to develop prediction models for disease-specific survival (DSS) and recurrence-free survival (RFS). RESULTS: The immune signature composed of CD3+, CD8+, and PD-1+ cell densities and PD-L1 expression within tumor epithelium significantly stratified patients into three clusters, with median DSS varying from 11.7 to 80.8 months and median RFS varying from 6.2 to 62.0 months. Gradient boosting machines (GBM) outperformed rival machine-learning algorithms and selected the same 11 covariates for DSS and RFS prediction: immune signature, tumor site, age, bilirubin, albumin, carcinoembryonic antigen, cancer antigen 19-9, tumor size, tumor differentiation, resection margin, and nodal metastasis. The clinical-immune GBM models accurately predicted DSS and RFS, with respective concordance index of 0.776-0.816 and 0.741-0.781. GBM models showed significantly improved performance compared with tumor-node-metastasis staging system. CONCLUSIONS: The immune signature promises to stratify prognosis and allocate treatment in resected BTC. The clinical-immune GBM models accurately predict recurrence and death from BTC following surgery.

Development and external validation of a nomogram for predicting the effect of tumor size on cancer-specific survival of resected gallbladder cancer: a population-based study.

BACKGROUND: The impact of tumor size on account of the long-term survival results in gallbladder cancer (GBC) patients has been controversial. It is urgent necessary to identify the optimal cut-off value of tumor size in resected GBC, and we attempted to integrate tumor size with other prognostic factors into a prognostic nomogram to predict the cancer-specific survival (CSS) of GBC patients. METHODS: 1639 patients with resected GBC were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cut-off value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year CSS based on the independent risk factors chosen by univariate and multivariable cox analyses. The precision of the nomogram for predicting survival was validated with Harrell's concordance index (C-index), calibration curves, and receiver operating characteristic curve (ROC) internally and externally. RESULTS: Patients with GBC were classified into 1-13 mm, 14-63 mm and 64 mm subgroup based on the optimal cut-off for tumor size in terms of CSS. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th tumor-node-metastasis (TNM) stage systems. CONCLUSIONS: The results demonstrated that increased tumor size is closely associated with the worse CSS. Our novel nomogram, which outperforms the conventional TNM staging system, showed satisfactory accuracy and clinically practicality for predicting the outcome of resected GBC patients.

The lncRNA Gm15622 stimulates SREBP-1c expression and hepatic lipid accumulation by sponging the miR-742-3p in mice.

Excessive lipid deposition is a hallmark of NAFLD. Although much has been learned about the enzymes and metabolites involved in NAFLD, few studies have focused on the role of long noncoding RNAs (lncRNAs) in hepatic lipid accumulation. Here, using in vitro and in vivo models of NAFLD, we found that the lncRNA Gm15622 is highly expressed in the liver of obese mice fed a HFD and in murine liver (AML-12) cells treated with free fatty acids. Investigating the molecular mechanism in the liver-enriched expression of Gm15622 and its effects on lipid accumulation in hepatocytes and on NAFLD pathogenesis, we found that Gm15622 acts as a sponge for the microRNA miR-742-3p. This sponging activity increased the expression of the transcriptional regulator SREBP-1c and promoted lipid accumulation in the liver of the HFD mice and AML-12 cells. Moreover, further results indicated that metformin suppresses Gm15622 and alleviates NAFLD-associated lipid deposition in mice. In conclusion, we have identified an lncRNA Gm15622/miR-742-3p/SREBP-1c regulatory circuit associated with NAFLD in mice, a finding that significantly advances our insight into how lipid metabolism and accumulation are altered in this metabolic disorder. Our results also suggest that Gm15622 may be a potential therapeutic target for managing NAFLD.

Radiomic Features at Contrast-enhanced CT Predict Recurrence in Early Stage Hepatocellular Carcinoma: A Multi-Institutional Study.

Background Early stage hepatocellular carcinoma (HCC) is the ideal candidate for resection in patients with preserved liver function; however, cancer will recur in half of these patients and no reliable prognostic tool has been established. Purpose To investigate the effectiveness of radiomic features in predicting tumor recurrence after resection of early stage HCC. Materials and Methods In total, 295 patients (median age, 58 years; interquartile range, 50-65 years; 221 men) who underwent contrast material-enhanced CT and curative resection for early stage HCC that met the Milan criteria between February 2009 and December 2016 were retrospectively recruited from three independent institutions. Follow-up consisted of serum α-fetoprotein level, liver function tests, and dynamic imaging examinations every 3 months during the first 2 years and then every 6 months thereafter. In the development cohort of 177 patients from institution 1, recurrence-related radiomic features were computationally extracted from the tumor and its periphery and a radiomics signature was built with least absolute shrinkage and selection operator regression. Two models, one integrating preoperative and one integrating pre- and postoperative variables, were created by using multivariable Cox regression analysis. An independent external cohort of 118 patients from institutions 2 and 3 was used to validate the proposed models. Results The preoperative model integrated radiomics signature with serum α-fetoprotein level and tumor number; the postoperative model incorporated microvascular invasion and satellite nodules into the above-mentioned predictors. In both study cohorts, two radiomics-based models provided better predictive performance (concordance index ≥0.77, P < .05 for all), lower prediction error (integrated Brier score ≤0.14), and larger net benefits, as determined by means of decision curve analysis, than rival models without radiomics and widely adopted staging systems. The radiomics-based models gave three risk strata with high, intermediate, or low risk of recurrence and distinct profiles of recurrent tumor number. Conclusion The proposed radiomics models with pre- and postresection features helped predict tumor recurrence for early stage hepatocellular carcinoma. © RSNA, 2020 Online supplemental material is available for this article.

Development and external validation of a nomogram for predicting the effect of tumor size on survival of patients with perihilar cholangiocarcinoma.

BACKGROUND: The effect of tumor size on account of long-term survival results in perihilar cholangiocarcinoma (PCCA) patients has remained a controversial debate. It is urgent necessary to identify the optimal cutoff value of tumor size in PCCA and integrate tumor size with other prognostic factors into a nomogram to improve the predictive accuracy of prognosis of patients with PCCA. METHODS: Three hundred sixty-three PCCA patients underwent surgical resection were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cutoff value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year cancer-specific survival (CSS) based on the independent risk factors chosen by Kaplan-Meier methods and multivariable cox regression models. The precision of the nomogram for predicting survival was validated internally and externally. RESULTS: PCCA patients underwent surgical resection were classified into 1-19 mm, 20-33 mm and ≥ 34 mm subgroups based on the optimal cutoff for tumor size in terms of CSS. And we noticed that more larger tumor size group had worse tumor grade, advanced T stage, more positive regional lymph nodes and more frequent vascular invasion. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th Tumor-Node-Metastasis (TNM) stage systems. CONCLUSIONS: The results demonstrated that the larger tumor size of PCCA was, the worse survival would be. The proposed nomogram, which outperforms the conventional TNM staging system, showed relatively good performance and could be considered as convenient individualized predictive tool for prognosis of PCCA patients.

Hypoxia-induced hsa_circ_0000826 is linked to liver metastasis of colorectal cancer.

BACKGROUND: hsa_circ_0000826 has been previously linked to CRC through the competing endogenous RNA network; however, the upstream driver of hsa_circ_0000826 elevation remains unknown. In this study, we aim to elucidate the effect of hypoxia-induced hsa_circ_0000826 on CRC tumorigenesis and metastasis. METHODS: RNA scope assay was used to evaluate the expression of hsa_circ_0000826 in CRC cells under hypoxia condition. The effects of hsa_circ_0000826 on phenotypes of CRC cells were evaluated through cell migration and invasion assay. The nude, AOM-DSS model mice and APCMin /+ mice were used to investigate the relationship between circ_0000826, hypoxia, and CRC in mice. A total of 100 CRC tissue samples, as well as the paired adjacent tissues, were collected, and qRT-PCR assay was used to detect the expression of hsa_circ_0000826 in these samples. RESULTS: Hypoxia-induced hsa_circ_0000826 overexpression can increase the malignant phenotypes, tumor formation, and metastasis capability of CRC cells in vitro. mmu_circ_0000826 levels were significantly increased in the CRC tissues from AOM-DSS and APC mice model under hypoxia conditions. Further, the hypoxia-induced upregulation of mmu_circ_0000826 can also promote CRC tumorigenesis and liver metastasis in vivo. The expression of hsa_circ_0000826 in serum was significantly increased in CRC tissues in 100-pair of CRC and according to the adjacent normal tissues by qRT-PCR assays. Moreover, the expression levels of hsa_circ_0000826 in serum of patient with liver metastasis were significantly increased than those without metastasis. CONCLUSION: Our results suggested that hsa_circ_0000826 was induced by the hypoxia in CRC, which can be a potential biomarker of CRC liver metastasis.

Long noncoding RNA DDX11-AS1 epigenetically represses LATS2 by interacting with EZH2 and DNMT1 in hepatocellular carcinoma.

Long noncoding RNAs (lncRNAs), a group of transcripts without protein coding potential, have been reported to play critical roles in progression of hepatocellular carcinoma (HCC). However, the biological role of DDX11-AS1 in HCC is not clear. In this study, we found that DDX11-AS1 expression was dramatically higher in HCC tissues and cell lines. Higher DDX11-AS1 expression predicted poor overall survival of patients. Functionally, the proliferation, cell cycle progression, migration, and invasion of HCC cells were inhibited by DDX11-AS1 silencing, while promoted by ectopic expression of DDX11-AS1. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays validated that DDX11-AS1 suppressed LATS2 expression by interacting with EZH2 and DNMT1 in HCC cells. Knockdown of DDX11-AS1 increased the mRNA and protein levels of LATS2. Overexpression of LATS2 abolished the promotive effect of DDX11-AS1 on cell growth and invasion. Besides, DDX11-AS1 promoted tumor formation in vivo. The mRNA levels of LATS2 were markedly decreased in tumor tissues and negatively correlated with DDX11-AS1 expression. Taken together, our data indicated that DDX11-AS1 may be a novel oncogene in hepatocarcinogenesis by repressing LATS2, providing a potential therapeutic target for HCC treatment.

Biliary Tract Cancer at CT: A Radiomics-based Model to Predict Lymph Node Metastasis and Survival Outcomes.

Purpose To evaluate a radiomics model for predicting lymph node (LN) metastasis in biliary tract cancers (BTCs) and to determine its prognostic value for disease-specific and recurrence-free survival. Materials and Methods For this retrospective study, a radiomics model was developed on the basis of a primary cohort of 177 patients with BTC who underwent resection and LN dissection between June 2010 and December 2016. Radiomic features were extracted from portal venous CT scans. A radiomics signature was built on the basis of reproducible features by using the least absolute shrinkage and selection operator method. Multivariable logistic regression model was adopted to establish a radiomics nomogram. Nomogram performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 70 consecutive patients with BTC between January 2017 and February 2018. Results The radiomics signature, composed of three LN-status-related features, was associated with LN metastasis in primary and validation cohorts (P < .001). The radiomics nomogram that incorporated radiomics signature and CT-reported LN status showed good calibration and discrimination in primary cohort (area under the curve, 0.81) and validation cohort (area under the curve, 0.80). Patients at high risk of LN metastasis portended lower disease-specific and recurrence-free survival than did those at low risk after surgery (both P < .001). High-risk LN metastasis was an independent preoperative predictor of disease-specific survival (hazard ratio, 3.37; P < .001) and recurrence-free survival (hazard ratio, 1.98; P = .003). Conclusion A radiomics model derived from portal phase CT of the liver has good performance for predicting lymph node metastasis in biliary tract cancer and may help to improve clinical decision making. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Laghi and Voena in this issue.