Crosstalk between endothelial progenitor cells and HCC through periostin/CCL2/CD36 supports formation of the pro-metastatic microenvironment in HCC.

Metastasis causes most cancer-related deaths, and the role and mechanism of periostin (POSTN) in the metastasis of hepatocellular carcinoma (HCC) remain undiscovered. In this study, DEN and HTVi HCC models were performed in hepatic-specific Postn ablation and Postn knock-in mouse to reveal the role of POSTN in HCC metastasis. Furthermore, POSTN was positively correlated with circulating EPCs level and promoted EPC mobilization and tumour infiltration. POSTN also mediated the crosstalk between HCC and EPCs, which promoted metastasis ability and upregulated CD36 expression in HCC through indirect crosstalk. Chemokine arrays further revealed that hepatic-derived POSTN induced elevated CCL2 expression and secretion in EPCs, and CCL2 promoted prometastatic traits in HCC. Mechanistic studies showed that POSTN upregulated CCL2 expression in EPCs via the αvß3/ILK/NF-κB pathway. CCL2 further induced CD36 expression via the CCR2/STAT3 pathway by directly binding to the promoter region of CD36. Finally, CD36 was verified to have a prometastatic role in vitro and to be correlated with POSTN expression, metastasis and recurrence in HCC in clinical samples. Our findings revealed that crosstalk between HCC and EPCs is mediated by periostin/CCL2/CD36 signalling which promotes HCC metastasis and emphasizes a potential therapeutic strategy for preventing HCC metastasis.

Prognostic value of diffuse reduction of spleen density on postoperative survival of pancreatic ductal adenocarcinoma: A retrospective study.

PURPOSE: It is difficult to predict the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) before radical operation. The purpose of this study was to explore the connection between the diffuse reduction of spleen density on computed tomography (DROSD) and the postoperative prognosis of patients with PDAC. PATIENTS AND METHODS: A total of 160 patients with PDAC who underwent radical surgery in the First Affiliated Hospital of Wenzhou Medical University were enrolled. Cox regression analysis was used to cast the overall survival (OS) and evaluate the prognostic factors. Nomogram was used to forecast the possibility of 1-year, 3-year, and 5-year OS. The prediction accuracy and clinical net benefit are performed by concordance index (C-index), calibration curve, time-dependent receiver operating characteristics (tdROC), and decision curve analysis. RESULTS: In multivariable Cox analysis, DROSD is independently related to OS. Advanced age, TNM stage, neutrophil/lymphocyte ratio, and severe complications were also independent prognostic factors. The calibration curves of nomogram showed optimal agreement between prediction and observation. The C-index of nomogram is 0.662 (95%CI, 0.606-0.754). The area under tdROC curve for a 3-year OS of nomogram is 0.770. CONCLUSION: DROSD is an independent risk factor for an OS of PDAC. We developed a nomogram that combined imaging features, clinicopathological factors, and systemic inflammatory response to provide a personalized risk assessment for patients with PDAC.

Breast cancer organoids and their applications for precision cancer immunotherapy.

Immunotherapy is garnering increasing attention as a therapeutic strategy for breast cancer (BC); however, the application of precise immunotherapy in BC has not been fully studied. Further studies on BC immunotherapy have a growing demand for preclinical models that reliably recapitulate the composition and function of the tumor microenvironment (TME) of BC. However, the classic two-dimensional in vitro and animal in vivo models inadequately recapitulate the intricate TME of the original tumor. Organoid models which allow the regular culture of primitive human tumor tissue are increasingly reported that they can incorporate immune components. Therefore, organoid platforms can be used to replicate the BC-TME to achieve the immunotherapeutic reaction modeling and facilitate relevant preclinical trial. In this study, we have investigated different organoid culture methods for BC-TME modeling and their applications for precision immunotherapy in BC.

AZGP1 activation by lenvatinib suppresses intrahepatic cholangiocarcinoma epithelial-mesenchymal transition through the TGF-ß1/Smad3 pathway.

Intrahepatic cholangiocarcinoma (ICC) is a primary liver malignancy and is characterized by highly aggressive and malignant biological behavior. Currently, effective treatment strategies are limited. The effect of lenvatinib on ICC is unknown. In this study, we found that AZGP1 was the key target of lenvatinib in ICC, and its low expression in ICC cancer tissues was associated with a poor prognosis in patients. Lenvatinib is a novel AZGP1 agonist candidate for ICC that inhibits ICC-EMT by regulating the TGF-ß1/Smad3 signaling pathway in an AZGP1-dependent manner. Furthermore, we found that lenvatinib could increase AZGP1 expression by increasing the acetylation level of H3K27Ac in the promoter region of the AZGP1 gene, thereby inhibiting EMT in ICC cells. In conclusion, lenvatinib activates AZGP1 by increasing the acetylation level of H3K27Ac on the AZGP1 promoter region and regulates the TGF-ß1/Smad3 signaling pathway in an AZGP1-dependent manner to inhibit ICC-EMT. This study offers new insight into the mechanism of lenvatinib in the treatment of ICC and provides a theoretical basis for new treatment methods.

Exploration and validation of a novel ferroptosis-related gene signature predicting the prognosis of intrahepatic cholangiocarcinoma.

Ferroptosis plays an important role in intrahepatic cholangiocarcinoma (ICC). We aim to develop a new ferroptosis-related gene signature predicting the prognosis of ICC. We download RNA expression profiles and clinical data of ICC from TCGA and GEO databases. Ferroptosis-related differentially expressed genes (DEGs) are screened by the Wilcoxon signed-rank test. GO and KEGG enrichment analyses are performed to understand the function of DEGs and co-expressed genes. Univariate Cox and LASSO regression are used to develop a ferroptosis-related gene signature. Receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analysis were used to evaluate the prognostic value. RNA sequencing is performed in 30 patients with ICC in our medical center to validate the prognostic value of the gene signature. We identify 44 ferroptosis-related DEGs, among which four (ACSL4, IREB2, NFE2L2, and TP53) are associated with overall survival (OS). Functional enrichment analysis shows that ferroptosis-associated DEGs have an important impact on ICC carcinogenesis. A new ferroptosis-related gene signature based on DEGs is built, and the prognostic ability is confirmed by KM and ROC curves (AUC=0.777, 0.75, 0.799 for 12, 24, and 36 months, respectively). Patients with high risk scores have worse OS ( P=0.0081). In the validation cohort, the expression of DEGs is in accordance with that in the exploration cohort. The four-gene signature is also demonstrated to have a favorable prognostic value (AUC=0.69). A new predictive model based on four ferroptosis-related genes (ACSL4, IREB2, NFE2L2, and TP53) is established and shows favorable prognostic value.

Brusatol suppresses the growth of intrahepatic cholangiocarcinoma by PI3K/Akt pathway.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a hidden onset, high metastasis recurrence rate, and poor prognosis. Research on effective drugs for ICC is important for improving the prognosis of patients in the clinic. Brusatol is a quassinoid extracted from the seeds of Brucea sumatrana and has been shown to have the potential to inhibit tumor metastasis and proliferation. There has been no scientific research on the therapeutic effect of brusatol on ICC. Our study offers a novel strategy for the therapy of ICC. PURPOSE: Explore effects of brusatol treatment on ICC and clarify the possible mechanism. STUDY DESIGN: Various cell functional experiments and basic experimental techniques were applied to ICC cell lines to explore the influences of brusatol on ICC cells; this conclusion was further verified in animal models. METHODS: The anti-cancer effects of the drug on the cell, protein, and RNA level were verified by cell functional experiments, WB blotting and transcriptome sequencing experiments, respectively. Finally, the experimental results were verified using subcutaneous tumor experiments in nude mice. RESULTS: The consequences exhibited that the levels of epithelial markers of ICC cells increased after brusatol treatment, and the levels of interstitial indicators decreased, suppressing the epithelial-mesenchymal transition (EMT) process. Brusatol inhibited proliferation, induced apoptosis, and suppressed the migration and invasion abilities of Hucc-T1 and RBE oncocytes via activating PI3K/Akt pathway. It also suppressed the growth of Hucc-T1 xenografts in nude mice. CONCLUSION: Brusatol inhibits the proliferation and EMT process in ICC oncocytes by the PI3K/Akt pathway and promotes apoptosis in oncocytes.

Gut microbiome alteration as a diagnostic tool and associated with inflammatory response marker in primary liver cancer.

BACKGROUND: Primary liver cancer has high mortality and morbidity worldwide. However, the characteristic of gut microbiota profile and its correlation with inflammation status in liver cancer patients remains largely unknown, and a gut microbiome-based diagnostic model for liver cancer is still absent. METHODS: Here, we provided a comprehensive analysis based on fecal 16S rRNA sequencing and clinical data in a cohort consisting of 40 healthy volunteers, 143 hepatocellular carcinoma (HCC) patients, and 46 cholangiocarcinoma (CCA) patients. RESULTS: Our results indicated a distinct shift of gut microbiota composition between two primary liver cancer types and compared with healthy volunteers. Based on the diversity constitute of gut microbiome taxonomy and random forest algorithm, eight genera with mean abundance above 0.1% were selected to construct the classification model with half of the randomly selected cohort. Based on this signature, high diagnostic accuracy in the validation cohort to classify liver cancer types (AUC = 0.989, 0.967, 0.920 for Control, HCC, CCA separately) was achieved. Further analysis showed increased Gram-negative bacteria and elevated inflammatory response markers in CCA group versus HCC group. The correlation analysis between inflammatory response markers and composition of gut microbiome revealed decreased potentially beneficial genus and increased opportunistic pathogens positively correlated with adverse prognostic inflammatory response markers. CONCLUSION: Generally, our study established the gut microbiome-based signature for liver cancer prediction and screening and revealed that gut microbiome characteristic in primary liver cancer was correlated with adverse inflammatory response markers in liver cancer.

Identification and Validation of Hub Genes Predicting Prognosis of Hepatocellular Carcinoma.

INTRODUCTION: The aim of this study is selecting the hub genes associated with hepatocellular carcinoma (HCC) to construct a Cox regression model for predicting prognosis in HCC patients. METHODS: Using HCC patient data from the ICGC and TCGA databases, screened for 40 core genes highly correlated with histological grade of HCC. Univariate and multivariate Cox regression analyses were performed on the genes highly associated with HCC prognosis, and the model was established. The expression of those genes was measured by immunohistochemistry in 110 HCC patients who underwent the surgery in the First Affiliated Hospital of Wenzhou Medical University. The survival of HCC patients was analyzed by the Kaplan-Meier method. RESULTS: Eight genes (CDC45, CENPA, MCM10, MELK, CDC20, ASF1B, FANCD2, and NCAPH) were correlated with prognosis, and the same result was observed in 110 HCC patients. Using the regression model, the HCC patients in the training set were classified as high- and low-risk groups. The overall survival of patients in the high-risk group was shorter than that in the low-risk group, and the same results were obtained in the verification set. CONCLUSION: This study found that the risk model according to these 8 genes can be used as a predictor of prognosis in HCC. These genes may become alternative biomarkers and therapeutic targets and provide new therapeutic strategies for HCC.

Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma.

PURPOSE: Pancreatic adenocarcinoma (PAAD) is characterized by low antitumour immune cell infiltration in an immunosuppressive microenvironment. This study aimed to systematically explore the impact on prognostic alternative splicing events (ASs) of tumour immune microenvironment (TIME) in PAAD. METHODS: The ESTIMATE algorithm was implemented to compute the stromal/immune-related scores of each PAAD patient, followed by Kaplan-Meier (KM) survival analysis of patients with different scores grouped by X-tile software. TIME-related differentially expressed ASs (DEASs) were determined and evaluated through functional annotation analysis. In addition, Cox analyses were implemented to construct a TIME-related signature and an AS clinical nomogram. Moreover, comprehensive analyses, including gene set enrichment analysis (GSEA), immune infiltration, immune checkpoint gene expression, and tumour mutation were performed between the two risk groups to understand the potential mechanisms. Finally, Cytoscape was implemented to illuminate the AS-splicing factor (SF) regulatory network. RESULTS: A total of 437 TIME-related DEASs significantly related to PAAD tumorigenesis and the formation of the TIME were identified. Additionally, a robust TIME-related prognostic signature based on seven DEASs was generated, and an AS clinical nomogram combining the signature and four clinical predictors also exhibited prominent discrimination by ROC (0.762 ~ 0.804) and calibration curves. More importantly, the fractions of CD8 T cells, regulatory T cells and activated memory CD4 T cells were lower, and the expression of four immune checkpoints-PD-L1, CD47, CD276, and PVR-was obviously higher in high-risk patients. Finally, functional analysis and tumour mutations revealed that aberrant immune signatures and activated carcinogenic pathways in high-risk patients may be the cause of the poor prognosis. CONCLUSION: We extracted a list of DEASs associated with the TIME through the ESTIMATE algorithm and constructed a prognostic signature on the basis of seven DEASs to predict the prognosis of PAAD patients, which may guide advanced decision-making for personalized precision intervention.

The prognostic value of sarcopenia combined with preoperative fibrinogen-albumin ratio in patients with intrahepatic cholangiocarcinoma after surgery: A multicenter, prospective study.

BACKGROUND: To explore the prognostic value of the fibrinogen-albumin ratio (FAR) combined with sarcopenia in intrahepatic cholangiocarcinoma (ICC) patients after surgery and to develop a nomogram for predicting the survival of ICC patients. MATERIALS AND METHODS: In this prospective cohort study, 116 ICC patients who underwent radical surgery were enrolled as the discovery cohort and another independent cohort of 68 ICC patients was used as the validation cohort. Kaplan-Meier method was used to analyze prognosis. The independent predictor of overall survival (OS) and recurrence-free survival (RFS) was evaluated by univariable and multivariable Cox regression analyses, then developing nomograms. The performance of nomograms was evaluated by concordance index (C-index), calibration curve, receiver operating characteristic curve analysis (ROC), and decision curve analysis (DCA). RESULTS: Patients with high FAR had lower OS and RFS. FAR and sarcopenia were effective predictors of OS and RFS. Patients with high FAR and sarcopenia had a poorer prognosis than other patients. OS nomogram was constructed based on age, FAR, and sarcopenia. RFS nomogram was constructed based on FAR and sarcopenia. C-index for the nomograms of OS and RFS was 0.713 and 0.686. Calibration curves revealed great consistency between actual survival and nomogram prediction. The area under ROC curve (AUC) for the nomograms of OS and RFS was 0.796 and 0.791 in the discovery cohort, 0.823 and 0.726 in the validation cohort. The clinical value of nomograms was confirmed by the DCA. CONCLUSIONS: ICC patients with high FAR and sarcopenia had a poor prognosis, the nomograms developed based on these two factors were accurate and clinically useful in ICC patients who underwent radical resection.

Graphene's Latest Cousin: Plumbene Epitaxial Growth on a "Nano WaterCube".

While theoretical studies predicted the stability and exotic properties of plumbene, the last group-14 cousin of graphene, its realization has remained a challenging quest. Here, it is shown with compelling evidence that plumbene is epitaxially grown by segregation on a Pd1- x Pbx (111) alloy surface. In scanning tunneling microscopy (STM), it exhibits a unique surface morphology resembling the famous Weaire-Phelan bubble structure of the Olympic "WaterCube" in Beijing. The "soap bubbles" of this "Nano WaterCube" are adjustable with their average sizes (in-between 15 and 80 nm) related to the Pb concentration (x < 0.2) dependence of the lattice parameter of the Pd1- x Pbx (111) alloy surface. Angle-resolved core-level measurements demonstrate that a lead sheet overlays the Pd1- x Pbx (111) alloy. Atomic-scale STM images of this Pb sheet show a planar honeycomb structure with a unit cell ranging from 0.48 to 0.49 nm corresponding to that of the standalone 2D topological insulator plumbene.