Publications by authors named "Weilin Wang"

275 Publications

Polysiloxane Bonded Silica Aerogel with Enhanced Thermal Insulation and Strength.

Materials (Basel) 2021 Apr 19;14(8). Epub 2021 Apr 19.

Key Laboratory for Advanced Ceramics and Machining Technology of Ministry of Education, School of Materials Science and Engineering, Tianjin University, Tianjin 300072, China.

In order to improve the mechanical properties of SiO aerogels, PHMS/VTES-SiO composite aerogels (P/V-SiO) were prepared. Using vinyltriethoxysilane (VTES) as a coupling agent, the PHMS/VTES complex was prepared by conducting an addition reaction with polyhydromethylsiloxane (PHMS) and VTES and then reacting it with inorganic silica sol to prepare the organic-inorganic composite aerogels. The PHMS/VTES complex forms a coating structure on the aerogel particles, enhancing the network structure of the composite aerogels. The composite aerogels can maintain the high specific surface area and excellent thermal insulation properties, and they have better mechanical properties. We studied the reaction mechanism during preparation and discussed the effects of the organic components on the structure and properties of the composite aerogels. The composite aerogels we prepared have a thermal conductivity of 0.03773 W·m·K at room temperature and a compressive strength of 1.87 MPa. The compressive strength is several times greater than that of inorganic SiO aerogels. The organic-inorganic composite aerogels have excellent comprehensive properties, which helps to expand the application fields of silicon-based aerogels.
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http://dx.doi.org/10.3390/ma14082046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074007PMC
April 2021

The DNA cytosine-5-methyltransferase 3 (DNMT3) involved in regulation of CgIL-17 expression in the immune response of oyster Crassostrea gigas.

Dev Comp Immunol 2021 Apr 2:104092. Epub 2021 Apr 2.

Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China. Electronic address:

DNA methyltransferase, a key enzyme mediating DNA methylation, is involved in numerous processes including genomic imprinting, X chromosome inactivation, transposable element suppression, and immune defense in vertebrates. In the present study, a DNA cytosine-5-methyltransferase 3 was identified from oyster Crassostrea gigas (designed as CgDNMT3). There were a PWWP domain, a PHD domain and a DNA-methylase domain in the deduced amino acid sequences of CgDNMT3, and the conserved motifs I, IV, VI, Ⅷ, IX and X were identified in its C-terminal catalytic DNA-methylase domain. The mRNA transcripts of CgDNMT3 were detected in haemocytes, mantle, gill, adductor muscle, digestive gland and labial palp, with higher expression level in haemocytes (6.54 folds of those in gill, p < 0.01). The expression level of CgDNMT3 mRNA in haemocytes increased significantly after LPS primed (2.87 folds of that in control group, p < 0.05) in vitro or Vibrio splendidus challenging (1.94 folds of that in control group, p < 0.05) in vivo. Immunocytochemical analysis revealed that CgDNMT3 protein was distributed mainly in cytoplasm and partial in nucleus of oyster haemocytes. After CgDNMT3 was transfected and expressed in HEK293T cells, the DNA 5-methylcytosine (5-mc) level in the transfected group was significantly increased, which was 1.22 folds (p < 0.05) of the pcDNA-3.1 group (p < 0.05). The expressions of oyster CgIL17-1, CgIL17-2 and CgIL17-5 in haemocytes increased (13.05 folds, 4.78 folds and 9.41 folds of that in control group, respectively) at 12 h after V. splendidus challenging, but the increase were significantly inhibited when the oysters were pre-treated with DNA methyltransferase inhibitor 5-Azacytidine, which were 9 folds, 1.93 folds and 3.22 folds of that in control group, respectively. These results collectively suggested that CgDNMT3 was a conserved member of DNA methyltransferase 3 family in oysters, and participated in regulating the expression of cytokines during immune response.
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http://dx.doi.org/10.1016/j.dci.2021.104092DOI Listing
April 2021

IL-35: A Novel Immunomodulator in Hepatitis B Virus-Related Liver Diseases.

Front Cell Dev Biol 2021 11;9:614847. Epub 2021 Mar 11.

Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Chronic hepatitis B virus (HBV) infection is a risk factor for liver cirrhosis (LC) and hepatocellular carcinoma (HCC), however, little is known about the mechanisms involved in the progression of HBV-related diseases. It has been well acknowledged that host immune response was closely related to the clinical outcomes of patients with HBV infection. As the factors closely related to the immunomodulatory process, cytokines are crucial in the cell-cell communication and the host responses to HBV infection. Recently, a newly discovered cytokine, designated as interleukin-35 (IL-35), has been proved to be essential for the progression of chronic HBV infection, the development of cirrhosis, the transformation of cirrhosis to HCC, and the metastasis of HCC. Specifically, it showed various biological activities such as inhibiting the HBV-specific cytotoxic T lymphocyte (CTL) proliferation and cytotoxicity, deactivating the immature effector T-cells (Teffs), as well as delaying the proliferation of dendritic cells. It regulated the immune responses by acting as a "brake" on the activation of Teffs, which subsequently played important roles in the pathogenesis of various inflammatory diseases and malignancies. In this review, we focused on the most recent data on the relationship between IL-35 and chronic HBV infection, LC and HCC.
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http://dx.doi.org/10.3389/fcell.2021.614847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990793PMC
March 2021

linc‑ROR facilitates hepatocellular carcinoma resistance to doxorubicin by regulating TWIST1‑mediated epithelial‑mesenchymal transition.

Mol Med Rep 2021 May 24;23(5). Epub 2021 Mar 24.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.

Long non‑coding RNAs are associated with cancer progression. Long intergenic non‑protein coding RNA (linc)‑regulator of reprogramming (ROR) enhances tumor development in hepatocellular carcinoma (HCC). However, the effect of chemoresistance and its underlying mechanisms in HCC are not completely understood. The present study aimed to identify the effect of ROR on sensitivity to doxorubicin (DOX) in HCC cells. In the present study, Cell Counting Kit‑8 and EdU assays were performed to assess cell viability and proliferation, respectively. In addition, E‑cadherin and vimentin protein expression levels were assessed via western blotting and immunofluorescence.The results of the present study demonstrated that HCC cells with high linc‑ROR expression levels were more resistant to DOX, and linc‑ROR knockdown increased HCC cell DOX sensitivity compared with the control group. The results indicated that compared with the NC siRNA group, linc‑ROR knockdown notably suppressed epithelial‑mesenchymal transition by downregulating twist family bHLH transcription factor 1 (TWIST1) expression. TWIST1 knockdown displayed a similar effect on HCC cell DOX sensitivity to linc‑ROR knockdown. Moreover, linc‑ROR knockdown‑induced HCC cell DOX sensitivity was inhibited by TWIST1 overexpression. The present study provided evidence that linc‑ROR promoted HCC resistance to DOX by inducing EMT via interacting with TWIST1. Therefore, linc‑ROR might serve as a therapeutic target for reducing DOX resistance in HCC.
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http://dx.doi.org/10.3892/mmr.2021.11979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974311PMC
May 2021

Number of Positive Lymph Nodes Is Superior to LNR and LODDS for Predicting the Prognosis of Pancreatic Neuroendocrine Neoplasms.

Front Endocrinol (Lausanne) 2021 5;12:613755. Epub 2021 Mar 5.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: The American Joint Committee on Cancer (AJCC) staging for pancreatic neuroendocrine neoplasms (PanNENs) based on the number of positive lymph nodes (PLNs) is the most widely accepted nodal staging system. New nodal staging schemes that take both the number of PLNs and the number of examined lymph nodes into consideration have emerged as useful prognostic tools. The aim of the current study was to determine the most effective nodal staging system, among the 8th edition AJCC N staging (or PLN staging), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS), for predicting the cause-specific survival of patients with PanNENs.

Methods: The clinicopathological and prognostic data of 2,295 patients from the Surveillance, Epidemiology, and End Results (SEER) database, diagnosed with PanNENs between 1988 and 2015, were reviewed retrospectively.

Results: A multivariate analysis identified PLN and LNR staging as independent prognostic factors, but not LODDS. The PLN staging exhibited higher C-index and area under the curve values than those of the LNR and LODDS, indicating better predictive discriminatory capacity. No significant difference in the survival of patients was observed within the same PLN staging subgroup according to the number (high or low) of examined lymph nodes. In contrast, intra-group heterogeneity was seen with use of LNR and LODDS staging, due to overestimation of the risk of insufficient examined lymph nodes, and LODDS failed to stratify patients without lymph nodes metastasis into different risk groups.

Conclusions: The PLN staging is more reliable than LNR and LODDS staging for predicting the cause-specific survival of PanNENs.
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http://dx.doi.org/10.3389/fendo.2021.613755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977716PMC
March 2021

Effect of short-chain chlorinated paraffins (SCCPs) on lipid membranes: Combination of molecular dynamics and membrane damage experiments.

Sci Total Environ 2021 Jun 3;775:144906. Epub 2021 Feb 3.

School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address:

In recent years, more attention has been paid to the biological effects of short-chain chlorinated paraffin (SCCP). Studies have shown that SCCPs exposure could cause metabolic damage and lipid metabolic damage. In the present work, based on E. coli membrane damage experiments and molecular dynamics (MD) simulation, the effects of SCCPs on the membrane structure and membrane properties were studied to explore the possible toxic damage effects of SCCPs on cell membrane. Experiments results showed that SCCPs had a significant inhibitory effect on E. coli. The E. coli cell membrane of the bacteria was broken and the macromolecules of the cell flowed out when exposed to SCCPs. SCCPs would lead to the decrease and depolarization of cell membrane potential, and then affect the integrity and permeability of cell membrane. The further molecular dynamic simulation revealed that SCCP molecules can easily enter the lipid DPPC membranes from the aqueous phase and tended to aggregate inside bilayer stably. The bound of SCCPs could lead to significant variations in DPPC bilayer with a less dense, more disorder and rougher layer, which thus made the damage of cell membrane. In a word, although the overall toxicity of SCCPs to cell was relatively weak, the damage to the cell membrane may be one of the mechanisms of its toxicity. MAIN FINDING OF THE WORK: The exposure of SCCPs could cause structural change of cell membrane in E. coli, which verified the damage to the cell membrane may be one of the mechanisms of its toxicity.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144906DOI Listing
June 2021

Preoperative Portal Vein Embolization for Liver Resection: An updated meta-analysis.

J Cancer 2021 21;12(6):1770-1778. Epub 2021 Jan 21.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009.

Portal vein embolization (PVE) is performed before major liver resection to increase liver volume remnant, controversy remains on the adverse effect of PVE on liver tumor patients. The current study highlighted the effect of PVE on the degree of hypertrophy of future liver remnant (FLR) and summarized PVE-related complications, aiming to provide a guideline for surgeons. A search of current published studies on PVE was performed. Meta-analysis was conducted to assess the effect of PVE on hypertrophy of FLR and summarized PVE-related complications. 26 studies including 2335 patients were enrolled in the meta-analysis. All enrolled studies reported data regarding FLR hypertrophy rate, pooled effect size (ES) for FLR hypertrophy rate using a fixed-effect model was 0.105 (95%CI: 0.094-0.117, p=0.000), indicating PVE is favored in inducing FLR hypertrophy. Metatrim method indicated no obvious evidence of publication bias in the present meta-analysis. 247 (10.6%) patients exhibited PVE-related complications, receiving expectant treatment without affecting planned liver resection. Total 1782 patients (76%) underwent a subsequent liver resection after PVE, which is an encouraging result comparing with traditional resection rate in liver tumor patients. PVE is a safe and effective procedure with a low occurrence of related complications for inducing sufficient hypertrophy of FLR in liver tumor patients, which could elevate the resection rate of liver tumor patients. Careful patient cohort selection is crucial to avoid overuse of PVE in technically resectable patients. Further multiple central clinical trials are conducive to select optimal patient cohorts and provide a guideline for surgeons.
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http://dx.doi.org/10.7150/jca.50371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890316PMC
January 2021

Automatic Detection and Classification of Focal Liver Lesions Based on Deep Convolutional Neural Networks: A Preliminary Study.

Front Oncol 2020 29;10:581210. Epub 2021 Jan 29.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

With the increasing daily workload of physicians, computer-aided diagnosis (CAD) systems based on deep learning play an increasingly important role in pattern recognition of diagnostic medical images. In this paper, we propose a framework based on hierarchical convolutional neural networks (CNNs) for automatic detection and classification of focal liver lesions (FLLs) in multi-phasic computed tomography (CT). A total of 616 nodules, composed of three types of malignant lesions (hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and metastasis) and benign lesions (hemangioma, focal nodular hyperplasia, and cyst), were randomly divided into training and test sets at an approximate ratio of 3:1. To evaluate the performance of our model, other commonly adopted CNN models and two physicians were included for comparison. Our model achieved the best results to detect FLLs, with an average test precision of 82.8%, recall of 93.4%, and F1-score of 87.8%. Our model initially classified FLLs into malignant and benign and then classified them into more detailed classes. For the binary and six-class classification, our model achieved average accuracy results of 82.5 and73.4%, respectively, which were better than the other three classification neural networks. Interestingly, the classification performance of the model was placed between a junior physician and a senior physician. Overall, this preliminary study demonstrates that our proposed multi-modality and multi-scale CNN structure can locate and classify FLLs accurately in a limited dataset, and would help inexperienced physicians to reach a diagnosis in clinical practice.
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http://dx.doi.org/10.3389/fonc.2020.581210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878526PMC
January 2021

polymorphisms and hepatoblastoma susceptibility in Chinese children.

J Cancer 2021 1;12(5):1373-1378. Epub 2021 Jan 1.

Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China.

Hepatoblastoma (HB) is the most prevalent primary hepatic cancer in children aged 6 months to 3 years. is recurrently mutated in various diseases, and critically involved in tumorigenesis. However, a limited number of studies have examined the involvement of polymorphisms in HB risk. We used the TaqMan assay to genotype four polymorphisms (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) in 275 Chinese children with HB and 1018 cancer-free controls from five medical centers in China. Their association with HB risk was evaluated on the basis of odds ratio (OR) and corresponding 95% confidence interval (CI). Overall, no significant associations were found in single locus and combine analysis. Interestingly, in the stratified analysis, we found that subjects with 1-3 risk genotypes were more likely to develop HB in patients ≥17 months of age (adjusted OR=1.76, 95% CI=1.04-2.98, =0.034). The rs3811464 GA/AA genotypes were associated with decrease HB risk in patients with clinical stage III+IV disease (adjusted OR=0.50, 95% CI=0.26-0.96, =0.038). Our results suggest that the polymorphisms have a weak association with HB susceptibility in the Chinese children. rs3811464 G>A may decrease HB risk in stage III+IV patients which need further validations with larger samples and different ethnicities.
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http://dx.doi.org/10.7150/jca.52621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847658PMC
January 2021

Iodine-125 Seeds Combined With Biliary Stent Placement Versus Stent Placement Alone For Unresectable Malignant Biliary Obstruction: A Meta-Analysis Of Randomized Controlled Trials.

J Cancer 2021 1;12(5):1334-1342. Epub 2021 Jan 1.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009.

Malignant biliary obstruction is always caused by tumors which are unresectable so that palliative stent placement is conducted for drainage of bile duct tree. Recently, irradiation stent with I seeds has been used to improve the stent patency and survival time of patients. We conducted this meta-analysis to evaluate the therapeutic efficacy and safety of biliary stent placement with I seeds compared with stent placement alone in patients with malignant biliary obstruction. We searched Pubmed, Web of Science, ClinicalTrials.gov, Cochrane Library, Embase and CNKI databases for all relevant studies up to 1 May 2020. Patient survival, stent patency, and adverse events were the primary outcome measured. Also, Review Manager 5.3 and Stata/SE15.0 were used to perform the analysis. Eleven randomized controlled trials with a total of 767 patients were included for meta-analysis. Stent combined with I seeds showed lower risk of stent occlusion at 3 month (Odds Ratios(OR) = 0.15; 95%CI: 0.05-0.49, =0.002), 6 month (OR = 0.18; 95%CI: 0.08-0.44, = 0.0001), 9 month (OR = 0.10; 95%CI: 0.05-0.20, < 0.00001) and 1 year (OR = 0.15; 95%CI: 0.07-0.31, < 0.00001) and better mean survival (MD = 125days; 95% CI 91-159 days; P < 0.00001) compared with stent placement alone. Also, reconstructed Kaplan-Meier data demonstrated improved survival in patients treated with stent plus I seeds (hazard ratio(HR)= 1.886; 95% CI: 1.609 to 2.210; P < 0.0001) Moreover, our analysis did not show significant difference between the two groups about the risk of adverse events including abdominal pain, hemobilia, pancreatitis, cholangitis and cholecystitis. I seeds combined with stent demonstrated superior stent patency and improved survival time compared to stent alone with acceptable complications.
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http://dx.doi.org/10.7150/jca.49663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847662PMC
January 2021

The Role of Tumor Associated Macrophages in Hepatocellular Carcinoma.

J Cancer 2021 1;12(5):1284-1294. Epub 2021 Jan 1.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and represents a classic paradigm of inflammation-related cancer. Various inflammation-related risk factors jointly contribute to the development of chronic inflammation in the liver. Chronic inflammation, in turn, leads to continuous cycles of destruction-regeneration in the liver, contributing to HCC development and progression. Tumor associated macrophages are abundant in the tumor microenvironment of HCC, promoting chronic inflammation and HCC progression. Hence, better understanding of the mechanism by which tumor associated macrophages contribute to the pathogenesis of HCC would allow for the development of novel macrophage-targeting immunotherapies. This review summarizes the current knowledge regarding the mechanisms by which macrophages promote HCC development and progression, as well as information from ongoing therapies and clinical trials assessing the efficacy of macrophage-modulating therapies in HCC patients.
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http://dx.doi.org/10.7150/jca.51346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847664PMC
January 2021

Efficacy of licartin combined with transcatheter hepatic arterial chemoembolization in the treatment of middle-advanced primary liver cancer.

J BUON 2020 Nov-Dec;25(6):2584-2591

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.

Purpose: To explore the clinical efficacy and safety of Licartin combined with transcatheter hepatic arterial chemoembolization (TACE) in the treatment of middle-advanced primary liver cancer.

Methods: The clinical data of 112 patients with middle-advanced primary liver cancer treated in our hospital from March 2015 to March 2017 were collected. Fifty-six patients underwent TACE combined with Licartin (Licartin+TACE group), while the remaining 56 patients were treated with TACE alone (TACE group). The short-term efficacy, peripheral hemogram, liver function, alpha fetoprotein (AFP) level, count of circulating tumor cells (CTCs) and cluster of differentiation (CD)147 phenotype before and after treatment were assessed in both groups, the incidence of adverse reactions was compared, and the postoperative survival and disease development were recorded during follow-up.

Results: At 2 weeks after treatment, the levels of ALT and AST were significantly higher in Licartin + TACE group than those in TACE group (p<0.05). After treatment, the white blood cell count (WBC) and platelet count (PLT) obviously declined in both groups, and they were obviously lower in Licartin + TACE group than those in TACE group (p<0.05). After treatment, the count of CTCs evidently declined in both groups compared with that before treatment (p<0.05), and it was evidently lower in Licartin + TACE group than in TACE group (p<0.001). All patients were followed up for 3-36 months. In Licartin + TACE group and TACE group, the mean overall survival (OS) was 13.1±3.6 months and 11.3±2.8 months, respectively, and the mean progression-free survival (PFS) was 7.9±1.4 months and 6.1±1.2 months, respectively. At the end of follow-up, the Kaplan-Meier survival curves were plotted and log-rank test found that the OS rate was remarkably superior in Licartin + TACE group to that in TACE group (p=0.047), but the PFS rate had no statistically significant difference between the two groups (p=0.372).

Conclusions: Licartin combined with TACE has better efficacy than TACE alone in the treatment of middle-advanced primary liver cancer, with tolerable adverse reactions, which prolongs patients' survival time.
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January 2021

Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition).

Liver Cancer 2020 Dec 11;9(6):682-720. Epub 2020 Nov 11.

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people.

Summary: Since the publication of in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years.

Key Messages: Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People's Republic of China in December 2019.
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http://dx.doi.org/10.1159/000509424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768108PMC
December 2020

A self-designed liver circle for on-demand Pringle's manoeuver in laparoscopic liver resection.

J Minim Access Surg 2021 Jan-Mar;17(1):120-126

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: Laparoscopic liver resection (LLR) allows minimal incisions and relatively quicker post-operative recovery, while intraoperative massive haemorrhage led to conversion to laparotomy. This study aimed to introduce a new, safe and convenient device to serve as Pringle's manoeuver according to the demand in LLR.

Methods: A liver circle consisting of a hole and a round stem with an obtuse small head was made by medical silica gel. It was applied in LLR to perform on-demand Pringle's manoeuver and developed its function in inferior vena cava (IVC) occlusion. The time of performing Pringle's manoeuver by liver circle, extracorporeal tourniquet and endo intestinal clip under laparoscopic simulator and LLR was compared.

Results: The liver circle was successfully applied to perform Pringle's manoeuver, IVC exposure and occlusion. It took less time in the occluding step of Pringle's manoeuver than the extracorporeal tourniquet (4.15 ± 0.35 s vs. 9.90 ± 1.15 s, P < 0.05) and the endo intestinal clip (4.15 ± 0.35 s vs. 47.91 ± 3.98 s, P < 0.05) under LLR. The total manipulating time for Pringle's manoeuver with liver circle remained the shortest, and the advantages were more obvious with increased frequencies of intermittent Pringle's manoeuver.

Conclusion: The new-designed liver circle is more convenient compared to other techniques in performing Pringle's manoeuver, especially the intermittent Pringle's manoeuver in LLR. It can be used to perform on-demand hepatic blood inflow occlusion in every LLR by pre-circling the hepatoduodenal ligament to control bleeding during surgery. It can also be applied to expose the surgical field of vision and perform IVC occlusion to reduce intraoperative blood loss.
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http://dx.doi.org/10.4103/jmas.JMAS_130_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945630PMC
December 2020

Reversibility of hAT-MSCs phenotypic and metabolic changes after exposure to and withdrawal from HCC-conditioned medium through regulation of the ROS/MAPK/HIF-1α signaling pathway.

Stem Cell Res Ther 2020 11 27;11(1):506. Epub 2020 Nov 27.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.

Background: Mesenchymal stem cells (MSCs) play an important role in tumor progression; concomitantly, MSCs also undergo profound changes in the tumor microenvironment (TME). These changes can directly impact the application and efficacy of MSC-based anti-tumor therapy. However, few studies have focused on the regulation of MSC fate in TME, which will limit the progress of MSC-based anti-tumor therapy. Herein, we investigated the effects of conditioned medium from human hepatocellular carcinoma cells (HCC-CM) on the phenotype and glucose metabolism of human adipose tissue-derived MSCs (hAT-MSCs).

Methods: The passage 2 (P2) to passage 3 (P3) hAT-MSCs were exposed to conditioned medium from Hep3B, Huh7 and HCCLM3 cells for 4-8 weeks in vitro. Then, immunofluorescent, CCK-8 assay, EdU assay, Transwell assay, and flow cytometry were used to assess the alterations in cell phenotype in terms of cell morphology, secretory profiles, proliferation, migration, invasion, cell cycle, and apoptosis. In addition, glucose metabolism was evaluated by related kits. Next, the treated hAT-MSCs were subjected to withdrawal from HCC-CM for 2-4 weeks, and alterations in phenotype and glucose metabolism were reevaluated. Finally, the molecular mechanism was clarified by Western blotting.

Results: The results revealed that after exposure to HCC-CM, hAT-MSCs developed a stellate-shaped morphology. In association with cytoskeleton remodeling, hAT-MSCs showed enhanced capacities for migration and invasion, while cell proliferation was inhibited by regulating the cell cycle by downregulating cyclins and cyclin-dependent kinases and activating the mitochondrial apoptosis pathway. In terms of glucose metabolism, our results showed mitochondrial dysfunction and elevated glycolysis of hAT-MSCs. However, interestingly, when the treated hAT-MSCs were subjected to withdrawal from HCC-CM, the alterations in phenotype and glucose metabolism could be reversed, but secretory phenotype and tumor-promoting properties appear to be permanent. Further studies showed that these changes in hAT-MSCs may be regulated by the ROS/MAPK/HIF-1α signaling pathway.

Conclusion: Taken together, the effects of long-term HCC-CM treatment on phenotype and glucose metabolism in hAT-MSCs are modest and largely reversible after withdrawal, but HCC-CM endow hAT-MSCs with permanent secretory phenotype and tumor-promoting properties. This is the first report on the reversal of phenotype and glucose metabolism in tumor-associated MSCs (TA-MSCs), it is anticipated that new insights into TA-MSCs will lead to the development of novel strategies for MSC-based anti-tumor therapy.
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http://dx.doi.org/10.1186/s13287-020-02010-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694319PMC
November 2020

A DM9-containing protein from oyster Crassostrea gigas (CgDM9CP-3) mediating immune recognition and encapsulation.

Dev Comp Immunol 2021 Mar 24;116:103937. Epub 2020 Nov 24.

Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Functional Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China. Electronic address:

DM9 domain containing protein (DM9CP) is a recently identified pattern recognition molecules exiting in most organisms except plants. In the present study, a novel DM9-containing protein (CgDM9CP-3) was identified from Pacific oyster Crassostrea gigas with an open reading frame of 438 bp, encoding a polypeptide of 145 amino acids containing two tandem DM9 repeats. The deduced amino acid sequence of CgDM9CP-3 shared 52.4% and 58.6% identity with CgDM9CP-1 and CgDM9CP-2, respectively. The mRNA transcripts of CgDM9CP-3 were highest expressed in oyster gills and its protein was mainly distributed in cytomembrane of haemocytes. After the stimulations with Vibrio splendidus and mannose, the mRNA expression of CgDM9CP-3 in oyster gills was significantly up-regulated and reached the peak level at 12 h and 24 h (p < 0.05), which was 7.80-fold (p < 0.05) and 42.82-fold (p < 0.05) of that in the control group, respectively. The recombinant CgDM9CP-3 protein (rCgDM9CP-3) was able to bind LPS, PGN and d-Mannose, fungi Pichia pastoris and Yarrowia lipolytica, as well as gram-negative bacteria Escherichia coli, Vibrio anguillarum and V. splendidus in a Ca-dependent manner. Moreover, it could enhance the encapsulation of haemocytes and exhibited agglutination activity towards fungi P. pastoris and Y. lipolytica in vitro with Ca. These results suggested that CgDM9CP-3 not only acted as a PRR involved in the pathogen recognition, but also enhanced cellular encapsulation in oyster C. gigas.
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http://dx.doi.org/10.1016/j.dci.2020.103937DOI Listing
March 2021

A truncated intracellular Dicer-like molecule involves in antiviral immune recognition of oyster Crassostrea gigas.

Dev Comp Immunol 2021 Mar 18;116:103931. Epub 2020 Nov 18.

Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Southern Laboratory of Ocean Science and Engineering (Guangdong,Zhuhai), Zhuhai, 519000, China; Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China. Electronic address:

The enzyme Dicer is best known for its role as an endoribonuclease in the small RNA pathway, playing a crucial role in recognizing viral double-stranded RNA (dsRNA) and inducing down-stream cascades to mediate anti-virus immunity. In the present study, a truncated Dicer-like gene was identified from oyster Crassostrea gigas, and its open reading frame (ORF) encoded a polypeptide (designed as CgDCL) of 530 amino acids. The CgDCL contained one N-terminal DEAD domain and a C-terminal helicase domain, but lack the conserved PAZ domain, ribonuclease domain (RIBOc) and dsRNA binding domain. The mRNA transcripts of CgDCL were detected in all the examined tissues with high expression levels in lip, gills and haemocytes, which were 62.06-fold, 48.91-fold and 47.13-fold (p < 0.05) of that in mantle, respectively. In the primarily cultured oyster haemocytes, the mRNA transcripts of CgDCL were significantly induced at 12 h after poly(I:C) stimulation, which were 4.04-fold (p < 0.05) of that in control group. The expression level of CgDCL mRNA in haemocytes was up-regulated significantly after dsRNA and recombinant interferon-like protein (rCgIFNLP) injection, which was 12.87-fold (p < 0.01) and 3.22-fold (p < 0.05) of that in control group, respectively. CgDCL proteins were mainly distributed in the cytoplasm of haemocytes. The recombinant CgDCL protein displayed binding activity to dsRNA and poly(I:C), but no obvious dsRNA cleavage activity. These results collectively suggest that truncated CgDCL from C. gigas was able to be activated by poly(I:C), dsRNA and CgIFNLP, and functioned as an intracellular recognition molecule to bind nucleic acid of virus, indicating a potential mutual cooperation between RNAi and IFN-like system in anti-virus immunity of oysters.
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http://dx.doi.org/10.1016/j.dci.2020.103931DOI Listing
March 2021

Identification of snoRNA SNORA71A as a Novel Biomarker in Prognosis of Hepatocellular Carcinoma.

Dis Markers 2020 26;2020:8879944. Epub 2020 Sep 26.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.

Background: Small nucleolar RNAs (snoRNAs) have been proved to play important roles in various cellular physiological process. Recently, dysregulation of snoRNA SNORA71A has been found involved in tumorigenesis of various malignant cancers. However, the emerging effects of SNORA71A in hepatocellular carcinoma (HCC) remain largely unclear. In this study, we aimed to explore the SNORA71A expression and its underlying significance in HCC.

Methods: Expression of SNORA71A in cell lines and clinical specimens was measured by quantitative real-time PCR. Then, all enrolled HCC patients were divided into low and high SNORA71A expression subgroups and then they were compared in the aspects of clinical features as well as survival outcome by respective statistical analysis methods.

Results: SNORA71A was significantly downexpressed in SK-HEP-1 ( = 0.001), Huh-7 ( < 0.001), Hep3B ( < 0.001), and clinical HCC specimens ( = 0.006). Comparing the clinical features between SNORA71A expression subgroups, it showed that low SNORA71A expression was significantly associated with large tumor diameter, multiple lesions, capsular invasion, bad tumor differentiation, and TNM stage ( < 0.05). Furthermore, it was found that HCC patients with lower SNORA71A expression had higher risk in postoperative tumor relapse (median time: 9.5 vs. 35.2 months; low vs. high; < 0.001) and poor overall survival (median time: 36.8 vs. 52.9 months; low vs. high; < 0.001). Besides, SNORA71A expression served as independent risk factors for tumor-free (HR = 0.450; 95% CI [0.263-0.770]; = 0.004) and long-term survival (HR = 0.289; 95% CI [0.127-0.657]; = 0.003).

Conclusions: Our study for the first time demonstrated that downregulation of SNORA71A could serve as a novel biomarker for clinical assessment and prognostic prediction of HCC patients.
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http://dx.doi.org/10.1155/2020/8879944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537701PMC
September 2020

Long Non-coding RNA CASC15 Promotes Intrahepatic Cholangiocarcinoma Possibly through Inducing PRDX2/PI3K/AKT Axis.

Cancer Res Treat 2021 Jan 5;53(1):184-198. Epub 2020 Oct 5.

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Purpose: Intrahepatic cholangiocarcinoma (ICC) is one of the most common liver primary tumors but its treatments are limited. Bioinformatics showed that the expression level of long non-coding RNA cancer-associated susceptibility 15 gene (CASC15) is correlated with ICC progression, but its functional mechanism remains unclear.

Materials And Methods: Tissues from ICC patients, tumor and adjacent tissue, were used for detection of the expression of CASC15. Clinical data were also collected for clinicopathologic and survival analysis. Short interfering RNA and lentiviral short hairpin RNA were used to knock down CASC15 and PRDX2 expression in ICC cell lines, for the analysis of changes of cell function and xenografts. RNA-pulldown and RNA immunoprecipitation assays were used to detect RNA-binding protein, PRDX2. Male nude mice were used for ICC xenografts, and livers were collected after 4 weeks for immunohistochemistry.

Results: CASC15 is highly expressed in ICC tissues and is related to higher TNM stage. Knockdown of CASC15 in ICC cells reduced cell proliferation, migration, invasiveness and increased apoptosis, and G1/S block. PRDX2 bound to CASC15. Knockdown of CASC15 decreased PRDX2 expression which was rescued by the inhibition of proteasome formation. Downregulation of PRDX2 resulted in G1/S block, reduced ICC cell invasion. Downregulation of CASC15 inhibited phosphoinositide 3-kinase (PI3K)/AKT/c-Myc pathway through downregulating of PRDX2 and overexpressed PRDX2 rescued the block. CASC15 knockout in ICC xenografts suppressed tumor development in vivo, decreased the expression of PRDX2 and Ki67 and inhibited PI3K/AKT pathway.

Conclusion: CASC15 promotes ICC possibly by targeting PRDX2 via the PI3K/AKT pathway, indicating poor prognosis and high degree of malignancy of ICC.
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http://dx.doi.org/10.4143/crt.2020.192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812017PMC
January 2021

A Nanomedicine Fabricated from Gold Nanoparticles-Decorated Metal-Organic Framework for Cascade Chemo/Chemodynamic Cancer Therapy.

Adv Sci (Weinh) 2020 Sep 14;7(17):2001060. Epub 2020 Jun 14.

Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310009 China.

The incorporation of new modalities into chemotherapy greatly enhances the anticancer efficacy combining the merits of each treatment, showing promising potentials in clinical translations. Herein, a hybrid nanomedicine () is fabricated using metal-organic framework (MOF) nanoparticles and gold nanoparticles (Au NPs) as building blocks for cancer chemo/chemodynamic therapy. MOF NPs are used as vehicles to encapsulate camptothecin (CPT), and the hybridization by Au NPs greatly improves the stability of the nanomedicine in a physiological environment. Triggered by the high concentration of phosphate inside the cancer cells, effectively collapse after internalization, resulting in the complete drug release and activation of the cascade catalytic reactions. The intracellular glucose can be oxidized by Au NPs to produce hydrogen dioxide, which is further utilized as chemical fuel for the Fenton reaction, thus realizing the synergistic anticancer efficacy. Benefitting from the enhanced permeability and retention effect and sophisticated fabrications, the blood circulation time and tumor accumulation of are significantly increased. In vivo results demonstrate that the combination of chemotherapy and chemodynamic therapy effectively suppresses the tumor growth, meantime the systemic toxicity of this nanomedicine is greatly avoided.
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http://dx.doi.org/10.1002/advs.202001060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507500PMC
September 2020

Extensive germline genome engineering in pigs.

Nat Biomed Eng 2021 02 21;5(2):134-143. Epub 2020 Sep 21.

Qihan Bio Inc, Hangzhou, China.

The clinical applicability of porcine xenotransplantation-a long-investigated alternative to the scarce availability of human organs for patients with organ failure-is limited by molecular incompatibilities between the immune systems of pigs and humans as well as by the risk of transmitting porcine endogenous retroviruses (PERVs). We recently showed the production of pigs with genomically inactivated PERVs. Here, using a combination of CRISPR-Cas9 and transposon technologies, we show that pigs with all PERVs inactivated can also be genetically engineered to eliminate three xenoantigens and to express nine human transgenes that enhance the pigs' immunological compatibility and blood-coagulation compatibility with humans. The engineered pigs exhibit normal physiology, fertility and germline transmission of the 13 genes and 42 alleles edited. Using in vitro assays, we show that cells from the engineered pigs are resistant to human humoral rejection, cell-mediated damage and pathogenesis associated with dysregulated coagulation. The extensive genome engineering of pigs for greater compatibility with the human immune system may eventually enable safe and effective porcine xenotransplantation.
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http://dx.doi.org/10.1038/s41551-020-00613-9DOI Listing
February 2021

Down-regulation of small nuclear RNA (snRNA) RNU5E-1 in hepatocellular carcinoma presents with vital clinical significance.

J Gastrointest Oncol 2020 Aug;11(4):738-746

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: For lack of accurate diagnosis and ideal prognosis assessment, hepatocellular carcinoma (HCC) has become the fourth cancers-related death malignant diseases. Small nuclear RNAs (snRNAs) have been investigated as a new class of regulators associated with pathogenesis and clinical evaluation of tumors such as HCC. As for RNU5E-1, one newly identified snRNA, may have similar functions. However, the relationship between RNU5E-1 expression and HCC tumorigenesis remains unclear.

Methods: The relative RNU5E-1 expression was measured in several HCC cell lines and HCC tissues of 100 patients using quantitative real-time PCR. All patients were grouped according to individual RNU5E-1 expression. Then, the potential association between RNU5E-1 expression in HCC clinical characteristics and prognostic information of patients was evaluated.

Results: Compared to human normal hepatocyte cell line QSG-7701, the RNU5E-1 expression in HCC cell lines (fold change: SK-HEP-1, 0.417; Hep 3B, 0.313; Huh-7, 0.189) were significantly down-regulated (P<0.05). Similarly, its expression levels were remarkably lower in HCC tissue than that in corresponding adjacent liver tissues (average fold change: 0.322, P=0.002). Besides, the expression level of RNU5E-1 was remarkably related to tumor size, vessel carcinoma embolus, differentiation level, TNM stages and tumor recurrence rate as well as long-term survival in HCC patients (P<0.05). Moreover, in Kaplan-Meier and Cox regression analysis, RNU5E-1 expression was remarkably correlated to postoperative tumor-free as well as long-term survival in HCC patients as independent factors (P<0.05).

Conclusions: The research revealed that RNU5E-1 was down-regulated in HCC and it could be one of indicators for diagnosis and prognostic prediction of HCC patients.
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http://dx.doi.org/10.21037/jgo-20-49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475331PMC
August 2020

Altered mRNA and lncRNA expression profiles in the striated muscle complex of anorectal malformation rats.

Pediatr Surg Int 2020 Nov 11;36(11):1287-1297. Epub 2020 Sep 11.

Department of Pediatric Surgery, Shengjing Hospital, China Medical University, 36 Sanhao Street, Shenyang, Liaoning, 110004, People's Republic of China.

Background: Striated muscle complex (SMC) dysplasia has been confirmed to contribute to postoperative defecation dysfunction of patients with anorectal malformations (ARMs). To date, the potential molecular mechanisms of SMC dysplasia underlying the development of ARMs have not been clearly explained. This study examined the expression profiles of mRNAs and lncRNAs in the malformed SMC of ARM rats using RNA sequencing (RNA-seq).

Methods: A rat model of ARMs was established by the intragastric administration of 1% ethylene thiourea (ETU) on an embryonic day 10 (E10). The rats were subjected to euthanasia and the SMC samples were collected on E19. The expression of mRNAs and lncRNAs was analyzed by RNA-seq on the Illumina HiSeq2500 platform. qRT-PCR was used to confirm the results of RNA-seq.

Results: Compared with the levels in control rats, 1408 mRNAs and 472 lncRNAs were differentially expressed in the SMC of E19 ARM rats. GO and KEGG pathway analyses showed that the top enriched GO terms were mainly related to muscle development and the enriched pathways were associated with muscle and synaptic development. Protein-protein interaction network analysis was also performed using the STRING database. The network map revealed the interaction between the WNT3 protein and NTRK1, NTF4, MUSK, and BMP5 proteins. Finally, the qRT-PCR results further confirmed the RNA-seq data.

Conclusion: Our findings indicate the involvement of these dysregulated mRNAs and lncRNAs in the pathogenesis of SMC dysplasia in ARMs, providing a theoretical foundation for developing interventions to improve postoperative defecation function.
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http://dx.doi.org/10.1007/s00383-020-04741-wDOI Listing
November 2020

The Members of the Highly Diverse Integrin Family Cooperate for the Generation of Various Immune Responses.

Front Immunol 2020 23;11:1420. Epub 2020 Jul 23.

Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.

Studies on invertebrate immune receptors can provide insights into characteristics specific to innate immune system. Here, eight α and three β integrins are identified from an invertebrate, the Pacific oyster , and their possible immune functions are studied. Oyster α/β integrins exhibit a higher degree of sequence and structural variability than the members from and . The analysis reveals that oyster RGD- and laminin-binding receptor homologs are present in the phylogenetic tree of α integrins, but the other six oyster α integrins mainly form a species-specific branch; meanwhile, oyster β integrins are clustered with insect β integrins but distinct from a member from the mollusk . Although phylogenetically lacking the important α integrin branches of LDV-binding, PS3-type, and αI-containing integrins, oyster integrins can bind to most ECM ligands, including RGDCP, LDVCP, GFOGERCP, and laminin protein in a distinct binding pattern. Besides, oyster integrins are distributed in different hemocyte subpopulations, while only specific integrins are selectively involved in hemocyte phagocytosis, migration, and encapsulation, and some of them participate in more than one immune response in a sophisticated pattern. Especially, oyster β integrins are arranged in the core to mediate complex immune responses, unlike the counterparts in humans that mainly depend on αI-containing integrins to incite immune reactions. This study represents the first comprehensive attempt to reveal the structural and evolutionary features of the integrin family and their involvement in cellular immune responses in the non-model invertebrate and sheds light on the characteristics specific to the innate immune system in the integrin family.
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http://dx.doi.org/10.3389/fimmu.2020.01420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390872PMC
April 2021

A CD63 Homolog Specially Recruited to the Fungi-Contained Phagosomes Is Involved in the Cellular Immune Response of Oyster .

Front Immunol 2020 22;11:1379. Epub 2020 Jul 22.

Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, China.

Cluster of differentiation 63 (CD63), a four-transmembrane glycoprotein in the subfamily of tetraspanin, has been widely recognized as a gateway from the infection of foreign invaders to the immune defense of hosts. Its role in Pacific oyster is, however, yet to be discovered. This work makes contributions by identifying CD63H, a CD63 homolog with four transmembrane domains and one conservative CCG motif, and establishing its role as a receptor that participates in immune recognition and hemocyte phagocytosis. The presence of CD63H messenger RNA (mRNA) in hepatopancreas, labial palps, gill, and hemocytes is confirmed. The expression level of mRNA in hemocytes is found significantly ( < 0.01) upregulated after the injection of . CD63H protein, typically distributed over the plasma membrane of oyster hemocytes, is recruited to the -containing phagosomes after the stimulation of . The recombinant CD63H protein expresses binding capacity to glucan (GLU), peptidoglycan (PGN), and lipopolysaccharide (LPS) in the presence of lyophilized hemolymph. The phagocytic rate of hemocytes toward and is significantly inhibited ( < 0.01) after incubation with anti-CgCD63H antibody. Our work further suggests that CD63H functions as a receptor involved in the immune recognition and hemocyte phagocytosis against invading pathogen, which can be a marker candidate for the hemocyte typing in .
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http://dx.doi.org/10.3389/fimmu.2020.01379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387653PMC
April 2021

Spatiotemporal expression of neurogenic locus notch homolog protein 1 in developing caudal spinal cord of fetuses with anorectal malformations from ETU-fed rats.

J Mol Histol 2020 Oct 11;51(5):519-530. Epub 2020 Aug 11.

Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Weilin Wang. 36, Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.

Complications, such as fecal soiling, incontinence, and constipation, are major health issues for patients with anorectal malformations (ARMs) after surgery. Dysplasia of the caudal spinal cord is an increasingly pivotal area in the field of postoperative complications for patients with ARMs. However, the existing research has not fully defined the mechanism underlying ARMs development. The neurogenic locus notch homolog (Notch) signaling pathway comprises several highly conserved proteins that are involved in spinal cord developmental processes. In the present study, the emerging role of Notch1 in fetal lumbosacral spinal cords was investigated in a rat model of ARMs using ethylene thiourea. Immunohistochemical staining, western blot and quantitative reverse transcription real-time polymerase chain reaction were utilized to analyze spatiotemporal expression of Notch1 on embryonic days (E) 16, E17, E19, and E21. The expression levels of the neuronal marker neurofilament and recombination signal-binding protein-J protein were evaluated for temporal correlations to Notch1 expression. The results implied that Notch1 expression was reduced in lumbosacral spinal cord neurons of ARMs embryos compared to control embryos. These results showed that, in ARMs embryos decreased Notch1 expression is related to the dysplasia of the caudal spinal cord during embryogenesis, indicating that Notch signaling may participate pathogenic embryonic lumbosacral spinal development and may be associated with postoperative complications of ARMs.
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http://dx.doi.org/10.1007/s10735-020-09900-wDOI Listing
October 2020

Bromo- and extraterminal domain protein inhibition improves immunotherapy efficacy in hepatocellular carcinoma.

Cancer Sci 2020 Oct 17;111(10):3503-3515. Epub 2020 Aug 17.

Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.

Hepatocellular carcinoma (HCC) represents the majority of liver cancer and is the fourth most common cause of cancer-related death. Although advances in molecular targeted therapy have shown promise, none of these agents has yet demonstrated significant clinical benefit. Bromo- and extraterminal domain (BET) protein inhibitors have been considered potential therapeutic drugs for HCC but the biological activity remains unclear. This study found that BET protein inhibition did not effectively suppress the progression of HCC, using a transgenic HCC mouse model. Mechanistically, the BET protein inhibitor JQ1 upregulated the expression of programmed cell death-ligand 1 (PD-L1) on the plasma membrane in vivo and in vitro. Moreover, JQ1 enhanced the expression of Rab8A, which upregulated the expression of PD-L1 on the plasma membrane. This study also showed that JQ1 combined with anti-PD-L1 Ab effectively suppressed HCC progression, and this benefit was obtained by enhancing the activation and cytotoxic capabilities of CD8 T cells. These results revealed the crucial role and regulation of BET protein inhibition on the expression of PD-L1 in HCC. Thus, combining BET protein inhibition with immune checkpoint blockade offers an efficient therapeutic approach for HCC.
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http://dx.doi.org/10.1111/cas.14588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540980PMC
October 2020

Revealing the clinical significance and prognostic value of small nucleolar RNA SNORD31 in hepatocellular carcinoma.

Biosci Rep 2020 07;40(7)

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.

Background: For lack of accurate early diagnosis and prognostic assessment, hepatocellular carcinoma (HCC) becomes severe challenge with the fourth cancer-related mortality. Recently, non-coding RNA (ncRNA) was identified to make functions in progression of various tumors. Among that, a novel ncRNA, small nucleolar RNA C/D box 31 (SNORD31) was suggested in previous study to function as potential tumor suppressing role. In the present study, we aimed to investigate the expression patterns and clinical significance of SNORD31 in HCC.

Methods: SNORD31 expression was calculated in HCC cell lines as well as clinical specimens by RT-PCR. HCC patients were subdivided into high and low SNORD31 expression groups and their clinical characteristics were compared. Besides, the association between SNORD31 expression and postoperative prognosis was evaluated using Kaplan-Meier and Cox regression analysis.

Results: Compared with corresponding normal reference, expression levels of SNORD31 were significantly down-regulated in both HCC cell lines and clinical specimens (P<0.01). Moreover, low SNORD31 expression was remarkably correlated with large tumor diameter, high incidence of vessel carcinoma embolus and capsular invasion, severe tumor differentiation and tumor-node-metastasis (TNM) stage (P<0.05). In the following analysis, HCC patients with low SNORD31 expression were independently inclined with poor tumor-free (median time: 9.17 vs 48.8 months, low vs high, P<0.001) as well as long-term survival (LTS; median time: 40.26 vs 55.41 months, low vs high, P=0.002).

Conclusions: The ncRNA SNORD31 was proved to be commonly down-regulated in HCC and was independently associated with multiple malignant characteristics and long-term prognosis of HCC patients, which implied that SNORD31 possessed potential as a novel HCC biomarker.
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http://dx.doi.org/10.1042/BSR20201479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376641PMC
July 2020

Transamniotic mesenchymal stem cell therapy for neural tube defects preserves neural function through lesion-specific engraftment and regeneration.

Cell Death Dis 2020 07 13;11(7):523. Epub 2020 Jul 13.

Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang, China.

Neural tube defects (NTDs) lead to prenatal mortality and lifelong morbidity. Currently, surgical closure of NTD lesions results in limited functional recovery. We previously suggested that nerve regeneration was critical for NTD therapy. Here, we report that transamniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for NTDs during early development may achieve beneficial functional recovery. In our ex vivo rat embryonic NTD model, BMSCs injected into the amniotic cavity spontaneously migrated into the defective neural tissue. Hepatocyte growth factor and its receptor c-MET were found to play critical roles in this NTD lesion-specific migration. Using the in vivo rat fetal NTD model, we further discovered that the engrafted BMSCs specifically differentiated into the cell types of the defective tissue, including skin and different types of neurons in situ. BMSC treatment triggered skin repair in fetuses, leading to a 29.9 ± 5.6% reduction in the skin lesion area. The electrophysiological functional recovery assay revealed a decreased latency and increased motor-evoked potential amplitude in the BMSC-treated fetuses. Based on these positive outcomes, ease of operation, and reduced trauma to the mother and fetus, we propose that transamniotic BMSC administration could be a new effective therapy for NTDs.
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http://dx.doi.org/10.1038/s41419-020-2734-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354991PMC
July 2020