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Immune checkpoint inhibitors are generally contraindicated for post-transplant patients. However, we report two patients with metastatic hepatocellular carcinoma (HCC) treated with camrelizumab (SHR-1210), an anti-programmed cell death 1 (PD-1) agent, after liver transplant. Before undergoing immunotherapy, both patients underwent liver allograft biopsy and obtained negative PD-L1 expression in tumor and liver graft specimens by immunohistochemistry. Then, camrelizumab (200 mg) was administered once every 3 weeks. During immunotherapy, the targeted therapy was continued, and the immunosuppression regimen was adjusted to a low-dose level. No graft rejection or other severe adverse reactions were observed. The disease remained stable (SD, mRECIST) for 3 months in one patient and 10 months in the other. Therefore, camrelizumab may have safety and potential benefits in advanced HCC after liver transplant.

Background CTCs play a critical role in the diagnosis and prognosis of liver cancer. However, there are few studies on whether different types of CTCs can predict the prognosis in patients with HCC following LT. Methods Retrospective data including CTCs detected by the CanPatrolTM platform combined with RNA-ISH were collected and analyzed on 56 patients from December 2016 to December 2019 at the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. Results During the study period, fifty-six patients (51 males, 5 females) were included with an mean age of 52 ± 9 years. The 1-, 2- and 3-year recurrence rates of postoperative interstitial CTC-positive and CTC-negative groups were 21.7% vs 10.8%, 37.5% vs 10.8% and 55.5% vs 10.8%, confirming a statistically significant difference between the 2 groups (p = 0.044). The 1-, 2- and 3-year recurrence rates of the increasing interstitial CTCs group were 25.2%, 36.9% and 66.9%, while 12.6%, 24.4% and 24.4% in the decreasing and unchanged group, indicating a significant difference (p = 0.038). Conclusion CanPatrolTM platform presents a superior analytical sensitivity, and may be used as a dynamic monitoring tool for CTCs. And interstitial CTCs which are more aggressive and metastatic caused by EMT can be regarded as a predictor of post-transplant tumor recurrence after LT for HCC.

Tianxing Dai,1,* Jing Li,2,* Xu Lu,3,* Linsen Ye,1 Haoyuan Yu,1 Lele Zhang,1 Mingbin Deng,1 Shuguang Zhu,1 Wei Liu,3 Guoying Wang,4 Yang Yang1 1Department of Hepatic Surgery and Liver Transplant Program, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoying WangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiangxi Road, Guangzhou, 510120, People’s Republic of ChinaTel +86-020-83062703Fax +86-020-83395651Email wanggy3@126.comYang YangDepartment of Hepatic Surgery and Liver Transplant Program, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, People’s Republic of ChinaTel +86-020-85252177Fax +86-020-85252276Email yysysu@163.comPurpose: Ferroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC).Methods: The ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs’ expression was further evaluated by quantitative real-time polymerase chain reaction in HCC.Results: A total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues.Conclusion: These results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.Keywords: hepatocellular carcinoma, ferroptosis, metabolism, gene signature, prognosis

Numerous studies have explored the important role of N6-methyladenosine (m6A) in cancer. Nonetheless, the interaction between m6A and long noncoding RNAs (lncRNAs) is poorly investigated. Herein, we systematically analyzed the role and prognostic value of m6A-related lncRNAs in hepatocellular carcinoma (HCC).

Advances in the field of stem cells have led to the development of a technology called organoids. Organoids are cell cluster structures formed by the cultivation of stem cells in a three-dimensional environment in vitro, and they can simulate the living environment of cells in vivo. Organoids play an important role in the screening of drugs for tumor therapy. Compared with traditional drug screening models, tumor organoid models derived from patient tumors have higher sensitivity, heterogeneity, and stability and can restore the real situation of tumors more effectively. Researchers have conducted a number of researches on the feasibility of using organoid technology in drug screening. By testing and comparing the effects of antitumor drugs in organoids and primary tumors, we can select the most appropriate treatment drugs for patients. In the past ten years, organoids from dozens of tissues and biological sample banks from several main organs have been established, and a large number of anticancer drugs have been screened out. This article summarizes the advantages and disadvantages of traditional drug screening models, discusses the development history of organoid technology, and reviews the research results on organoids from tumor drug screening. In addition, the combination of organoid technology and other modern biotechnologies is put forward to further promote the role of organoid technology in the medical field. Finally, this article reviews the history, progress, and prospect on organoids from the view of antitumor drug screening.

Background This study aimed to investigate the relationship between the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation and mammalian target of rapamycin (mTOR) pathway-related genes-TSC1/2. Methods We retrospectively analyzed the clinical data of 46 patients who underwent liver transplantation for HCC and performed next generation sequencing to analyze the relationship between the efficacy of sirolimus after liver transplantation for HCC and mutations in mTOR pathway-related genes, especially tuberous sclerosis complex (TSC) mutations. Results The average age of 46 patients with liver transplantation for HCC was 51±21 years. After surgery, 35 patients received an anti-rejection/anti-tumor regimen that included sirolimus, and 11 patients did not receive sirolimus. There was no significant difference in survival rate between the two groups (P=0.761). The gene sequencing results showed mTOR-related pathway mutations in 10 patients, of whom five (10.9%) had TSC1/2 mutations. Of the 35 patients using sirolimus, those with mTOR-related mutations had significantly better survival rates than patients without mTOR-related mutations (P=0.016). Conclusions According to genetic sequencing results, a personalized treatment plan for specific genetic mutations should be selected in patients undergoing liver transplantation for HCC. Patients with mTOR-related gene mutations, especially TSC mutations, can gain significant benefits from the use of mTOR inhibitors such as sirolimus.

BackgroundEmerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity. Previous studies demonstrate that the conventional chemotherapy agent, teniposide, effectively promotes the therapeutic efficacy of programmed cell death protein-1 antibody (PD-1 Ab) through robust cGAS-STING activation. Unfortunately, the cGAS expression of tumor cells is reported to be severely suppressed by the hypoxic status in solid tumor. Clinically, enhancing chemotherapy-induced, DNA-activated tumor STING signaling by alleviating tumor hypoxia might be one possible direction for improving the currently poor response rates of patients with hepatocellular carcinoma (HCC) to PD-1 Ab.MethodsTeniposide was first screened out from several chemotherapy drugs according to their potency in inducing cGAS-STING signaling in human HCC cells. Teniposide-treated HCC cells were then cultured under hypoxia, normoxia or reoxygenation condition to detect change in cGAS-STING signaling. Next, oxaliplatin/teniposide chemotherapy alone or combined with hyperbaric oxygen (HBO) therapy was administered on liver orthotopic mouse tumor models, after which the tumor microenvironment (TME) was surveyed. Lastly, teniposide alone or combined with HBO was performed on multiple mouse tumor models and the subsequent anti-PD-1 therapeutic responses were observed.ResultsCompared with the first-line oxaliplatin chemotherapy, teniposide chemotherapy induced stronger cGAS-STING signaling in human HCC cells. Teniposide-induced cGAS-STING activation was significantly inhibited by hypoxia inducible factor 1α in an oxygen-deficient environment in vitro and the inhibition was rapidly removed via effective reoxygenation. HBO remarkably enhanced the cGAS-STING-dependent tumor type Ⅰ interferon and nuclear factor kappa-B signaling induced by teniposide in vivo, both of which contributed to the activation of dendritic cells and subsequent cytotoxic T cells. Combined HBO with teniposide chemotherapy improved the therapeutic effect of PD-1 Ab in multiple tumor models.ConclusionsBy combination of two therapies approved by the Food and Drug Administration, we safely stimulated an immunogenic, T cell-inflamed HCC TME, leading to further sensitization of tumors to anti-PD-1 immunotherapy. These findings might enrich therapeutic strategies for advanced HCC andwe can attempt to improve the response rates of patients with HCC to PD-1 Ab by enhancing DNA-activated STING signaling through effective tumor reoxygenation.

Common lung diseases are first diagnosed using chest X-rays. Here, we show that a fully automated deep-learning pipeline for the standardization of chest X-ray images, for the visualization of lesions and for disease diagnosis can identify viral pneumonia caused by coronavirus disease 2019 (COVID-19) and assess its severity, and can also discriminate between viral pneumonia caused by COVID-19 and other types of pneumonia. The deep-learning system was developed using a heterogeneous multicentre dataset of 145,202 images, and tested retrospectively and prospectively with thousands of additional images across four patient cohorts and multiple countries. The system generalized across settings, discriminating between viral pneumonia, other types of pneumonia and the absence of disease with areas under the receiver operating characteristic curve (AUCs) of 0.94-0.98; between severe and non-severe COVID-19 with an AUC of 0.87; and between COVID-19 pneumonia and other viral or non-viral pneumonia with AUCs of 0.87-0.97. In an independent set of 440 chest X-rays, the system performed comparably to senior radiologists and improved the performance of junior radiologists. Automated deep-learning systems for the assessment of pneumonia could facilitate early intervention and provide support for clinical decision-making.

The paper aims to assess the association between Hepatitis B Virus infection and colorectal liver metastasis by conducting a meta-analysis. The relevant studies were searched until 24 July 2020, Studies that assessed the correlation between HBV infection and CRLM were recruited. A random effects model was applied to calculate the odds ratio (OR) with 95% confidence interval (CI). All data analyses were performed by STATA 12.0 software. Ten studies involving 17529 participants were included in the study. The results shown that there was obvious association between HBV infection and CRLM (OR: 0.51, 95% CI: 0.28–0.91). The study type and case–control rate may be the main causes of heterogeneity. In addition, HBV infection had no association with extrahepatic metastasis or prognosis of patients with CRLM. Sensitivity analyses confirmed that the results were stable, and Egg’s test indicated that there was no publication bias. Patients with HBV infection have the reduced risk of CRLM., GRAPHICAL ABSTRACT

The evolution of defects such as pores at elevated temperatures is crucial for revealing the thermal stability of lithium hydride ceramic. The in situ evolution of pores in sintered lithium hydride ceramic from 25 °C to 500 °C, such as the statistics of pores and the 3D structure of pores, was investigated by X-ray computed tomography. Based on the statistics of pores, the porosity significantly increased from 25 °C to 200 °C and decreased after 200 °C, due to the significant change in the number and total volume of the round-shaped pores and the branched crack-like pores with an increasing temperature. According to the 3D structure of pores, the positions of pores did not change, and the sizes of pores went up in the range of 25–200 °C and went down after 200 °C. Some small round-shaped pores with an Equivalent Diameter of less than 9 μm appeared at 200 °C and disappeared at elevated temperatures. Some adjacent pores of all types connected at 200 °C, and some branched crack-like pores gradually disconnected with an increasing temperature. The expansion of pores at 200 °C caused by the release of residual hydrogen and the contraction of pores after 200 °C because of the migration and diffusion of some hydrogen in pores might be the reason for the evolution of pores with an increasing temperature.

Purpose The aldo-keto reductase (AKR) superfamily members have been proposed with multiple roles in various tumors. Here, a comprehensive analysis on the integral role of AKR genes was conducted to evaluate the expression profile, regulation network, and prognostic significance in hepatocellular carcinoma (HCC). Materials and Methods Transcriptome datasets of HCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Univariate and multivariate Cox regression analyses were used to build a novel risk score model, and then were further used to identify independent prognostic factors for overall survival (OS) of HCC. A prognostic nomogram was developed and validated. The expression of these critical AKR members was also evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry in HCC specimens. Results Eight differentially expressed AKR genes were identified in HCC. The dysregulation of most AKR genes was negatively correlated with DNA methylation, and a regulation network with transcription factors (TFs) was also established. Then, three critical AKR genes (AKR1B10, AKR1D1, and AKR7A3) were screened out to build a novel risk score model. Worse OS was observed in high-risk patients. Besides, a prognostic nomogram based on the model was further established and validated in both the TCGA and GSE14520 cohorts, which showed superior performance in predicting the OS of HCC patients. Notably, close correlations were identified between the risk score and tumor immune microenvironment, somatic mutation profiles, and drug susceptibilities of HCC. Finally, the upregulated AKR1B10 and downregulated AKR1D1 and AKR7A3 were further verified in HCC tumor and adjacent tissues from our institution. Conclusion The dysregulated AKR genes could be mediated by DNA methylation and TFs in HCC. The risk model established with superior prognostic performance further suggested the significant role of AKR genes involved in the progression of HCC., Graphical Abstract

TMCO3, a member of the monovalent cation:proton antiporter-2 family, has been annotated as a NaBioinformatic analyses were conducted using transcriptome data from public databases to determine the expression, prognosis, and functional enrichment of TMCO3 in HCC. TMCO3 expression was further validated in an independent HCC cohort from our institution. The oncogenic role of TMCO3 in HCC was evaluated usingThe upregulated expression of TMCO3 was identified and verified in multiple HCC cohorts, and worse overall survival and recurrence-free survival were observed in patients with high TMCO3 expression. The overexpression and knockdown of TMCO3 could affect the proliferation and metastasis of HCC cells, which might be associated with the p53-induced cell cycle regulation and epithelial-mesenchymal transition, respectively. Notably, significant correlations were found between dysregulated TMCO3 and various antitumor agents. Its role in sorafenib sensitivity was further identified byUpregulated TMCO3 could act as an oncogenic mediator and promote sorafenib resistance in HCC, providing a potential therapeutic target for HCC treatment.

CD8+ T cells are thought to be the primary cytotoxic lymphocytes exerting antitumor effects. However, few studies have focused on the antitumor effects of CD8+ T cell-mediated humoral immunity or on interactions between CD8+ T cells and B cells in hepatocellular carcinoma (HCC). We found that the frequency of IL-21-producing CD8+CXCR5+ T cells was higher in HCC tumor tissue than in peritumoral tissue or peripheral blood from the same patients or in blood from healthy donors. Moreover, CD8+CXCR5+ T cells migrated in response to supernatants from primary HCC (HCC-SN) cells, and HCC-SN cells also powerfully induced CXCR5 expression in CD8+ T cells and IL-21 expression in CD8+CXCR5+ T cells. CD8+CXCR5+ T cells from HCC patients, but not those from healthy individuals, stimulated CD19+ B cells to differentiate into IgG-producing plasmablasts. These findings reveal that CD8+CXCR5+ T cells strongly infiltrate HCC tumors, and their infiltration is predictive of a better prognosis. Surprisingly, moreover, CD8+CXCR5+ T cells produced IL-21, which induced B cells to differentiate into IgG-producing plasmablasts and to play a key role in humoral immunity in HCC.

Background Few studies have focused on the prognostic values of inflammation-related factors for different phases of recurrence in hepatocellular carcinoma (HCC). We aimed to identify the different risk factors for overall, early, and late recurrence, and to establish nomograms based on inflammation-related parameters for predicting the risks of recurrence in a group of HCC patients undergoing hepatectomy. Methods We retrospectively enrolled 383 HCC patients with chronic hepatitis B (CHB) who underwent hepatectomy. Univariate and multivariate Cox analyses were conducted to identify independent risk factors for recurrence. Nomograms for overall, early, and late recurrence-free survival (RFS) were established. The discrimination and calibration abilities of the nomograms were evaluated by concordance indexes (C-index), calibration plots, and Kaplan-Meier curves. Finally, receiver operating characteristic (ROC) curves were used to compare the derived nomograms with other existing models. Results Fibrinogen, lymphocyte-to-monocyte ratio, and S-index inflammation-related factors were independently related to overall and early RFS, but only the S-index correlated with late recurrence. Nomograms with tumor number, diameter, and pathological differentiation for overall and early RFS were established, while nomogram for late recurrence was constructed with tumor number and Child-Pugh grade. The C-indexes for overall, early, and late RFS were 0.679, 0.677, and 0.728, respectively. The calibration plots fit well. The nomograms showed superior discrimination capacities and better performance prediction with larger areas under the curve for recurrence. Conclusions The developed nomograms that integrated inflammation-related factors showed high predictive accuracy for overall, early, and late recurrence in HCC patients with CHB after hepatectomy.

Background: Emerging evidence indicates that bile acids (BAs) play pivotal roles in hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), the receptor of BAs, is considered to be a regulator of the immune response and inflammation in various diseases. However, the relevance of the immune microenvironment to FXR in HCC is unknown. Methods: Flow cytometry analyses were performed to measure the apoptosis rates of HCC cells and the immune checkpoint changes of immune cells. Kaplan-Meier analysis with log-rank test for assessing overall survival and time to recurrence was performed. Exosomes were isolated and cocultured with CD4+ T and CD8+ T cells for functional assays. HCC models were established in a gene-deficient mouse strain to evaluate FXR capability. Findings: We identified a previously unrecognized protumorigenic bile acid subset, Norcholic acid (NorCA). Mechanistic studies suggested that NorCA promotes tumorigenesis and the development of HCC cells by regulating the FXR-SHP-PD-L1 axis. Moreover, tumor-derived Exos formed by NorCA induction affected the immune microenvironment by regulating CD4+ T cells. In addition, we identified a subgroup of FXRlowPD-L1high patients, who have a poor prognosis. Furthermore, a drug combination study demonstrated that the FXR agonist (GW4064) exerted synergistic effects with an anti‐PD‐1 antibody (Ab) in a mouse model. Interpretation: Our results identify a novel protumorigenic bile acid subset demonstrates the immune function of FXR in HCC cells, offering valuable evidence for using FXR agonists combined with an anti‐PD‐1 Ab in combating HCC. Funding: Research supported by grants from fifteen funds. All sources of funding were declared at the end of the text. Declaration of Interest: None potential conflicts of interest were disclosed. Ethical Approval: This study was approved by the Ethics Review Board of the Third Affiliated Hospital, Sun Yat-sen University. Huh-7, LM3, and Hepa1-6 cells were obtained from ATCC

Hepatic ischemia-reperfusion injury (IRI) is the most common cause of liver damage leading to surgical failures in hepatectomy and liver transplantation. Extensive inflammatory reactions and oxidative responses are reported to be the major processes exacerbating IRI. The involvement of Yes-associated protein (YAP) in either process has been suggested, but the role and mechanism of YAP in IRI remain unclear. In this study, we constructed hepatocyte-specific YAP knockout (YAP-HKO) mice and induced a hepatic IRI model. Surprisingly, the amount of serum EVs decreased in YAP-HKO compared to WT mice during hepatic IRI. Then, we found that the activation of YAP increased EV secretion through F-actin by increasing membrane formation, while inhibiting the fusion of multivesicular body (MVB) and lysosomes in hepatocytes. Further, to explore the essential elements of YAP-induced EVs, we applied mass spectrometry and noticed CD47 was among the top targets highly expressed on hepatocyte-derived EVs. Thus, we enriched CD47+ EVs by microbeads and applied the isolated CD47+ EVs on IRI mice. We found ameliorated IRI symptoms after CD47+ EV treatment in these mice, and CD47+ EVs bound to CD172α on the surface of dendritic cells (DCs), which inhibited DC activation and the cascade of inflammatory responses. Our data showed that CD47-enriched EVs were released in a YAP-dependent manner by hepatocytes, which could inhibit DC activation and contribute to the amelioration of hepatic IRI. CD47+ EVs could be a potential strategy for treating hepatic IRI.

Background. The role of ABL1 in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the potential role of ABL1 in the progression of HCC using bioinformatics methods. Methods. We analyzed the expression, prognostic potential, and immune cell effect of ABL1 in HCC by using a variety of datasets. Results. ABL1 is highly expressed in HCC and associated with unfavorable overall survival (OS) and disease-free survival (DFS). Functional network analysis revealed that ABL1 plays an important role in mitochondrial activity, ATP metabolism, protein translation and metabolism, various neurological diseases, nonalcoholic fatty liver disease, and notch signaling pathway. In addition, we found that ABL1 expression was closely correlated with B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells. Furthermore, ABL1 expression was positively associated with the expression levels of immune checkpoint genes, such as PD-1L, TIM3, TIGIT, and CTLA4. Conclusion. ABL1 is associated with immune infiltration and prognosis of HCC.

Background: Chronic kidney disease (CKD) is a common late complication in liver-transplanted patients who have received long-term therapy with calcineurin inhibitors (CNIs). Aims: To analyze kidney disease progression after liver transplantation Methods: We analysed the clinical data of adult single-organ liver transplant recipients performed at our centre between October 2003 and September 2009. The patients with the estimated glomerular filtration rate (eGFR) greater than 60 ml/min/1.73 m2 before surgery were included in the study. Results: 69 patients with complete follow-up data were analysed. We found that eGFR at 1 or 2 years after liver transplantation correlated well with eGFR at 5 years. In addition, our results showed that patients whose eGFR declined below 60 at 2 years after liver transplantation would develop an irreversible renal injury in the following years. At 2 years, 12 patients had an eGFR less than 60, which were maintained in 11 patients at 5 years (Sensitivity = 11/12, 91.67%; Specificity = 57/58, 98.28%, Youden's index = 89.95%). The annual rate of eGFR reduction of the tacrolimus group was greater than that of the tacrolimus sparing group based on the value-time variation curve in our study. Moreover, the tacrolimus concentration influenced the CKD progression at 1 and 2 years with an under the ROC curve of 0.73 and 0.78 when Youden's index was at its maximum and the tacrolimus concentrations were 8.55 and 5.96 ng/ml, respectively. Conclusion: We confirmed that eGFR at 2 years after liver transplantation is useful for observing a meaningful change in eGFR and renal damage. Obtaining the appropriate serum concentration of an early decrease of the dose of CNIs and transforming non-nephrotoxic immunosuppressants would help improve renal function to prevent CKD progression and end-stage renal disease (ESRD).

Hepatic ischemia-reperfusion injury (IRI) is a major cause of liver damage during liver transplantation and hepatectomy, and its amelioration is an urgent unmet clinical need. Excess inflammatory response and oxidative stress contributes to the injury and Yes-associated protein (YAP) in the Hippo signaling pathway has been proved participating in it. In this study, using hepatocyte-specific YAP knockout (YAP-HKO) by crossing Yapflox/flox mice with Alb-Cre mice, we surprisingly noticed in the serum of these mice, the amount of serum extracellular vesicles (EVs) decreased after IRI. Then we found that YAP from hepatocytes regulate EVs secretion through F-actin by increasing membrane formation, as well as inhibiting the fusion of multivesicular body (MVB) and lysosomes. We further explored the essential element of YAP-induced EVs by mass spectrometry, and noticed CD47 was one of the target that highly expressed on hepatocyte-derived EVs in YAP-dependent manner. In addition, we found that CD47+ EVs can inhibit dendritic cells (DCs) activation and inflammatory responses via binding to CD172α on the surface of DCs. Finally, we isolated CD47+ EVs in IRI model and found IRI being ameliorated after treatment, suggesting that CD47+ EVs could be a potential therapeutic strategy for the treating hepatic IRI. Our data showed that CD47-enriched EVs were released in a YAP dependent manner by hepatocytes, which could inhibit DCs activation and contribute to the amelioration of hepatic IRI. Funding Statement: National Key RD the China Postdoctoral Science Foundation, Grant/Award Number: 2020M672980; the National 13th Five-Year Science and Technology Plan Major Projects of China, Grant/Award Number: 2017ZX10203205-006-001; National Natural Science Foundation of China, Grant/Award Number: 81702393, 81770648, 81670601, 81570593, 81802897, 81802897, 81900886; Key Scientific and Technological Projects of Guangdong Province, China, Grant/Award Number: 2015B020226004, 2015A030312013, 2017A030311034; Guangdong Natural Science Foundation, China, Grant/Award Number: 2017A030310373; Science and Technology Planning Project of Guangdong Province, China, Grant/Award Number:2017B030314027, 2017B020209004, 20169013, 2017A020215178; Science and Technology Planning Project of Guangzhou, China, Grant/Award Number: 2014Y2-00200, 2014Y2-00544, 201607010024, 201604020001, 201508020262, 201400000001-3 2017. Declaration of Interests: The authors have declared no conflict of interest. Ethics Approval Statement: The study protocol was approved by the Clinical Ethics Review Board of the Third Affiliated Hospital of Sun Yat- sen University. Informed consent was obtained according to the Declaration of Helsinki. All animal studies were approved and monitored by the animal experimental ethics committee of the Third Affiliated hospital of Sun-Yat Sen University.

OBJECTIVES To investigate hemodynamic changes in the hepatic artery after hepatic ischemia-reperfusion injury (IRI) in rats via ultrasound (US) imaging and to discuss the protective effect of phentolamine (PHT) pretreatment on hepatic IRI. METHODS Fifty rats were randomly divided into 3 groups: a sham operation group (n = 10), a control ischemia-reperfusion group (n = 20), and a PHT pretreatment group (n = 20). Color Doppler flow imaging and contrast-enhanced US examinations were performed in each group at 30 minutes (n = 10) and 90 minutes (n = 10) after reperfusion. Blood samples were obtained to analyze serum alanine aminotransferase and aspartate aminotransferase levels, and liver tissue specimens were collected for pathologic analysis. RESULTS Using US, we found that hepatic artery resistance at 30 minutes after reperfusion in the control group was higher than that in the sham group (mean resistive index [RI] ± SD, 0.65 ± 0.09 versus 0.50 ± 0.09; P

Purpose: We proposed to investigate the effects of miR-452-3p on the proliferation and mobility of hepatocellular carcinoma (HCC) cells by targeting cytoplasmic polyadenylation element binding protein 3/estimated glomerular filtration rate (CPEB3/EGFR) axis. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect miR-452-3p expression in 84 pairs of HCC tissues and adjacent tissues. Luciferase reporter assay was employed to examine the relationship between miR-452-3p and CPEB3. Microculture tetrazolium (MTT) assay, colony formation assay, flow cytometry detection, wound healing assay, and transwell assay were used to detect cell proliferation, cycle arrest, apoptosis, and mobility, respectively, in HCC, HepG2, and Huh-7. Western blot was used to detect protein expression levels in EGFR signaling pathway. Kaplan-Meier survival analysis was conducted to analyze the correlation between the miR-452-3p and CPEB3 expression levels and the survival of patients with HCC. Results: MiRNA-452-3p was found significantly upregulated in 84 human HCC sample tissues and cells in comparison with adjacent tissues and normal liver epithelial cells (P < .01). Luciferase reporter assay demonstrated that CPEB3 was a direct target of miR-452-3p. Overexpression of miR-452-3p promoted cell proliferation and mobility and suppressed apoptosis. MiR-452-3p enhanced EGFR and phosphorylated AKT (pAKT) expression but inhibited p21 expression level. Conclusion: MiR-452-3p promoted HCC cell proliferation and mobility by directly targeting the CPEB3/EGFR axis.

Common lung diseases are first diagnosed using chest X-rays. Here, we show that a fully automated deep-learning pipeline for the standardization of chest X-ray images, for the visualization of lesions and for disease diagnosis can identify viral pneumonia caused by coronavirus disease 2019 (COVID-19) and assess its severity, and can also discriminate between viral pneumonia caused by COVID-19 and other types of pneumonia. The deep-learning system was developed using a heterogeneous multicentre dataset of 145,202 images, and tested retrospectively and prospectively with thousands of additional images across four patient cohorts and multiple countries. The system generalized across settings, discriminating between viral pneumonia, other types of pneumonia and the absence of disease with areas under the receiver operating characteristic curve (AUCs) of 0.94-0.98; between severe and non-severe COVID-19 with an AUC of 0.87; and between COVID-19 pneumonia and other viral or non-viral pneumonia with AUCs of 0.87-0.97. In an independent set of 440 chest X-rays, the system performed comparably to senior radiologists and improved the performance of junior radiologists. Automated deep-learning systems for the assessment of pneumonia could facilitate early intervention and provide support for clinical decision-making.

Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (T(FH)) cells in the gut. The expression of ATF3 in CD4(+) T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4(+) T cells (CD4(cre)Atf3(fl/fl)) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of T(FH) cells, not other T cell subsets, were dramatically decreased in Peyer’s patches from CD4(cre)Atf3(fl/fl) mice compared with Atf3(fl/fl) littermate controls. The defective T(FH) cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of T(FH) or IgA(+) B cells caused significant remission of colitis in CD4(cre)Atf3(fl/fl) mice, indicating the T(FH)–IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4(+) T cells. In summary, we demonstrated ATF3 as a regulator of T(FH) cells in the gut, which may represent a potential immunotherapeutic target in colitis.

Hydrogen isotope catalytic exchange between hydrogen and liquid water is a very effective process for deuterium-depleted potable water production and heavy water detritiation. To improve the characteristics of hydrophobic catalysts for this type of reaction, foamed and cellular structures of hydrophobic carbon-supported platinum catalysts were successfully prepared. Separation of deuterium or tritium from liquid water was carried out by liquid-phase catalytic exchange. At a gas–liquid ratio of 1.53 and exchange temperature of 70 °C, the theoretical plate height of the hydrophobic catalyst (HETP = 34.2 cm) was slightly lower than previously reported values. Changing the concentration of the exchange column outlet water yielded nonlinear changes in the height of the packing layer. Configurations of deuterium-depleted potable water and detritiation of heavy water provide references for practical applications.

Summary Many COVID-19 patients infected by SARS-CoV-2 virus develop pneumonia (called novel coronavirus pneumonia, NCP) and rapidly progress to respiratory failure. However, rapid diagnosis and identification of high-risk patients for early intervention are challenging. Using a large computed Tomography (CT) database from 4,154 patients, we developed an AI system that can diagnose NCP and differentiate it from other common pneumonia and normal controls. The AI system can assist radiologists and physicians in performing a quick diagnosis especially when the health system is overloaded. Significantly, our AI system identified important clinical markers that correlated with the NCP lesion properties. Together with the clinical data, our AI system was able to provide accurate clinical prognosis that can aid clinicians to consider appropriate early clinical management and allocate resources appropriately. We have made this AI system available globally to assist the clinicians to combat COVID-19., Highlights • AI system that can diagnose COVID-19 pneumonia using CT scans • Prediction of progression to critical illness • Potential to improve performance of junior radiologists to the senior level • Can assist evaluation of drug treatment effects with CT quantification, Zhang et al. present an AI-based system, based on hundreds of thousands of human lung CT scan images, that can aid in distinguishing patients with pneumonia caused by SARS-CoV-2 versus other viral infections and can help to predict the prognosis of COVID-19 patients.

Background/Aims: Numerous studies have shown that NIMA-related kinase 2 (NEK2) expression in hepatocellular carcinoma (HCC) tissue is associated with survival and clinicopathological features; however, the evidence remains inconclusive. Thus, we aimed to further explore the prognostic and clinicopathological significance of NEK2 expression in HCC using a two-part study consisting of a retrospective cohort study and a meta-analysis. Methods: In the cohort study, NEK2 expression in 206 HCC samples and adjacent normal liver tissues was detected by immunohistochemistry (IHC). Patients were divided into a high NEK2 expression group and a low NEK2 expression group by the median value of the immunohistochemical scores. The Kaplan–Meier method with the log-rank test was used to analyze survival outcomes in the two groups, and multivariate analysis based on Cox proportional hazard regression models was applied to identify independent prognostic factors. In the meta-analysis, eligible studies were searched in PubMed, EMBASE, Web of Science, and CNKI databases. STATA version 12.0 (Stata Corporation, College Station, TX) was used for statistical analyses. Results: The IHC results of our cohort study showed higher NEK2 expression in HCC tissues compared with adjacent normal liver tissues. Multivariate analysis revealed that high NEK2 expression was an independent risk factor for poor overall survival (OS) [hazard ratio (HR) = 1.763; 95% CI, 1.060–2.935; P = 0.029] and disease-free survival (DFS) [hazard ratio (HR) = 1.687; 95% CI, 1.102–2.584; P = 0.016] in HCC patients. A total of 11 studies with 1,698 patients were enrolled in the meta-analysis, consisting of 10 studies from the database search and our cohort study. The pooled results revealed that high NEK2 expression correlated closely with poor OS among HCC patients (HR = 1.47; 95% CI, 1.21–1.80; P < 0.01), and DFS/recurrence-free survival (RFS) (HR = 1.92; 95% CI, 1.41–2.63; P < 0.01). Additionally, our meta-analysis also showed that the proportion of HCC patients with high NEK2 expression was greater in the group with larger tumors (> 5 cm) than in the group with smaller tumors (≤ 5 cm) [odds ratio (OR) = 2.02; 95% CI, 1.13–3.64; P < 0.01). Conclusion: Our study demonstrated that high NEK2 expression is a risk factor for poor survival in HCC patients. More prospective, homogeneous, and multiethnic studies are required to validate our findings.

Table S5. Univariate and Multivariate Analysis of Prognostic Factors for recurrence-free survival and Overall Survival (NÂ =â 29). (DOCX 18 kb)

Table S3. Flow cytometry panels for analysis of immune cells. (DOCX 17 kb)

Table S6. Univariate and Multivariate Analysis of Prognostic Factors for recurrence-free survival and Overall Survival (Nâ =â 101). (DOCX 19 kb)

Table S2. Characteristics of the study population (NÂ =â 101). (DOCX 15 kb)

Table S4. The antibodies used in our experiments. (DOCX 17 kb)

Table S1. Characteristics of the study population (NÂ =â 51. (DOCX 15 kb)

To improve characteristics of hydrophobic catalysts for hydrogen isotope separation between hydrogen and water which is a key reaction for water detritiation and heavy water production, monodispersed Pt3M bimetal hydrophobic catalysts were fabricated. The average diameters of Pt3M nanoparticles ranged from 2.2 nm to 2.6 nm. The lattice parameters of Pt3M were 3.87 A, 3.83 A, 3.78 A and 3.90 A, respectively. All compositions were well-controlled to the similar value. The addition of the metallic Fe, Ni, Cr, and Co hindered the oxidation of the metallic Pt during the preparation of Pt3M/C catalysts. The catalytic activities for H/D isotope separation increased in the following order: Pt/C < Pt3Ni/C ≈ Pt3CoC < Pt3Fe/C < Pt3Cr/C. Catalytic performance tests demonstrated that selection of Pt3M bimetal is a very effective approach to improve hydrophobic catalytic. Finally, the enhanced activities of Pt3M bimetals over Pt were discussed by different mechanisms.