Publications by authors named "Zeyang Ding"

25 Publications

  • Page 1 of 1

Construction and Validation of a Nomogram for Predicting the Risk of Deep Vein Thrombosis in Hepatocellular Carcinoma Patients After Laparoscopic Hepatectomy: A Retrospective Study.

J Hepatocell Carcinoma 2021 21;8:783-794. Epub 2021 Jul 21.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, People's Republic of China.

Background: The incidence of deep vein thrombosis (DVT) in hepatocellular carcinoma (HCC) patients after laparoscopic hepatectomy (LH) is unclear, and there is no effective method for DVT risk assessment in these patients.

Methods: The data from the total of 355 consecutive HCC patients who underwent LH were included. A DVT risk algorithm was developed using a training set (TS) of 243 patients, and its predictive performance was evaluated in both the TS and a validation set (VS) of 112 patients. The model was then used to develop a DVT risk nomogram (TRN).

Results: The incidence of DVT in the present study was 18.6%. Age, sex, body mass index (BMI), comorbidities and operative position were independent risk factors for DVT in the TS. The model based on these factors had a good predictive ability. In the TS, it had an area under the receiver operating characteristic (AUC) curve of 0.861, Hosmer-Lemeshow (H-L) goodness of fit value of 0.626, sensitivity of 44.4%, specificity of 96.5%, positive predictive value (PPV) of 74.1%, negative predictive value (NPV) of 88.4%, and accuracy of 86.8%. In the VS, it had an AUC of 0.818, H-L value of 0.259, sensitivity of 38.1%, specificity of 98.9%, PPV of 88.9%, NPV of 87.4%, and accuracy of 87.5%. The TRN performed well in both the internal and the external validation, indicating a good clinical application value. The TRN had a better predictive value of DVT than the Caprini score ( < 0.001).

Conclusion: The incidence of DVT after LH was high, and should not be neglected in HCC patients. The TRN provides an efficacious method for DVT risk evaluation and individualized pharmacological thromboprophylaxis.
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http://dx.doi.org/10.2147/JHC.S311970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312330PMC
July 2021

Pan-cancer analysis of the prognostic value of C12orf75 based on data mining.

Aging (Albany NY) 2021 06 1;13(11):15214-15239. Epub 2021 Jun 1.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.

The differential expression of chromosome 12 open reading frame 75 () is closely related with cancer progression. Here, we studied the expression levels of and investigated its prognostic value in various cancers across distinct datasets including ONCOMINE, PrognoScan, GEPIA, and TCGA. The correlation between genetic alteration of C12orf75 and immune infiltration was investigated using the cBioPortal and TIMER databases. RNA interference was used to verify the influence of knockdown on the biological phenotype of hepatocellular carcinoma cells. C12orf75 showed increased expression in most tested human cancers. The increased expression of was related with a poor prognosis in urothelial bladder carcinoma and hepatocellular liver carcinoma, but it was surprisingly converse in renal papillary cell carcinoma. In urothelial bladder carcinoma and hepatocellular liver carcinoma, we observed positive correlations between the expression of and the infiltration of immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The knockdown of in hepatocellular carcinoma cells suppressed the proliferation, migration, and invasion and arrested the cell cycle. This is the first report has potential as a prognostic biomarker and therapeutic target for molecularly targeted drugs in urothelial bladder carcinoma, hepatocellular liver carcinoma, and renal papillary cell carcinoma.
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http://dx.doi.org/10.18632/aging.203081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221310PMC
June 2021

Tuning Organic Microcrystal Morphologies through Crystal Engineering Strategies toward Anisotropic Optical Waveguide.

J Phys Chem Lett 2021 May 10;12(19):4585-4592. Epub 2021 May 10.

Engineering Research Center of Organic and Polymer Optoelectronic Materials, Ministry of Education, State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.

The construction of organic optoelectronic materials with desirable size and morphology remains a challenge now. Crystal engineering strategies (polymorphs and cocrystals) provide convenience for tailoring molecular packing and further controlling the growth morphology and photofunctionality of materials. Herein, we prepare polymorphic 2D plate crystals and 3D microhelixes by assembly of a cyanostilbene derivative (2-(3',5'-bis(trifluoromethyl)-biphenyl-4-yl)-3-(4-(pyridin-4-yl)phenyl)acrylonitrile, CF-CN-Py). The former emits blue emission, while the latter emits green emission. Different crystallization environments contribute to the adjustable morphologies. Then, novel cocrystals are fabricated with the introduction of 1,4-diiodotetrafluorobenzene (FDIB) to CF-CN-Py. Both molecular conformation and packing are totally changed in the cocrystal system. Such cocrystal displays a 1D sky-blue emissive rod shape on account of a long-range ordered π-stacking of molecules. In addition, the 2D plate crystal and 1D rod cocrystal are further applied to optical waveguides. In the plate crystal, a packing of transition dipole moment (μ) inclined to the upper surface leads to an anisotropic optical waveguide. In the cocrystal, owing to the nearly horizontal μ orientation, the cocrystal exhibits light propagation along the primary growth direction and a low optical loss coefficient. The present study supplies an effective way to construct materials with controlled morphology and optical waveguide.
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http://dx.doi.org/10.1021/acs.jpclett.1c00769DOI Listing
May 2021

Optimizing Management to Reduce the Mortality of COVID-19: Experience From a Designated Hospital for Severely and Critically Ill Patients in China.

Front Med (Lausanne) 2021 10;8:582764. Epub 2021 Mar 10.

Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The coronavirus disease 2019 (COVID-19) has swept through the world at a tremendous speed, and there is still limited data available on the treatment for COVID-19. The mortality of severely and critically ill COVID-19 patients in the Optical Valley Branch of Tongji Hospital was low. We aimed to analyze the available treatment strategies to reduce mortality. In this retrospective, single-center study, we included 1,106 COVID-19 patients admitted to the Optical Valley Branch of Tongji Hospital from February 9 to March 9, 2020. Cases were analyzed for demographic and clinical features, laboratory data, and treatment methods. Outcomes were followed up until March 29, 2020. Inflammation-related indices (hs-CRP, ESR, serum ferritin, and procalcitonin) were significantly higher in severe and critically ill patients than those in moderate patients. The levels of cytokines, including IL-6, IL2R, IL-8, and TNF-α, were also higher in the critical patients. Incidence of acute respiratory distress syndrome (ARDS) in the severely and critically ill group was 23.0% (99/431). Sixty-one patients underwent invasive mechanical ventilation. The correlation between SpO/FiO and PaO/FiO was confirmed, and the cut-off value of SpO/FiO related to survival was 134.43. The mortality of patients with low SpO/FiO (<134.43) at intubation was higher than that of patients with high SpO/FiO (>134.43) (72.7 vs. 33.3%). Among critical patients, the application rates of glucocorticoid therapy, continuous renal replacement therapy (CRRT), and anticoagulation treatment reached 55.2% (238/431), 7.2% (31/431), and 37.1% (160/431), respectively. Among the intubated patients, the application rates of glucocorticoid therapy, CRRT, and anticoagulation treatment were respectively 77.0% (47/61), 54.1% (33/61), and 98.4% (60/61). No vaccines or specific antiviral drugs for COVID-19 have been shown to be sufficiently safe and effective to date. Comprehensive treatment including ventilatory support, multiple organ function preservation, glucocorticoid use, renal replacement therapy, anticoagulation, and restrictive fluid management was the main treatment strategy. Early recognition and intervention, multidisciplinary collaboration, multi-organ function support, and personalized treatment might be the key for reducing mortality.
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http://dx.doi.org/10.3389/fmed.2021.582764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987780PMC
March 2021

Clinical characteristics and risk factors for mortality in cancer patients with COVID-19.

Front Med 2021 Apr 23;15(2):264-274. Epub 2021 Mar 23.

Hepatic Surgery Center, Liver Cancer Institute, and Hubei Key Laboratory of HPB Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Patients with cancer are at increased risk of severe infections. From a cohort including 3060 patients with confirmed COVID-19, 109 (3.4%) cancer patients were included in this study. Among them, 23 (21.1%) patients died in the hospital. Cancer patients, especially those with hematological malignancies (41.6%), urinary carcinoma (35.7%), malignancies of the digestive system (33.3%), gynecological malignancies (20%), and lung cancer (14.3%), had a much higher mortality than patients without cancer. A total of 19 (17.4%) cancer patients were infected in the hospital. The clinical characteristics of deceased cancer patients were compared with those of recovered cancer patients. Multivariate Cox regression analysis indicated that a Nutritional Risk Screening (NRS2002) score ⩾ 3 (adjusted hazard ratio (HR) 11.00; 95% confidence interval (CI) 4.60-26.32; P < 0.001), high-risk type (adjusted HR 18.81; 95% CI 4.21-83.93; P < 0.001), tumor stage IV (adjusted HR 4.26; 95% CI 2.34-7.75; P < 0.001), and recent adjuvant therapy (< 1 month) (adjusted HR 3.16; 95% CI 1.75-5.70; P < 0.01) were independent risk factors for in-hospital death after adjusting for age, comorbidities, D-dimer, and lymphocyte count. In conclusion, cancer patients showed a higher risk of COVID-19 infection with a poorer prognosis than patients without cancer. Cancer patients with high-risk tumor, NRS2002 score ⩾ 3, advanced tumor stage, and recent adjuvant therapy (< 1 month) may have high risk of mortality.
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http://dx.doi.org/10.1007/s11684-021-0845-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985225PMC
April 2021

H19 Promotes HCC Bone Metastasis Through Reducing Osteoprotegerin Expression in a Protein Phosphatase 1 Catalytic Subunit Alpha/p38 Mitogen-Activated Protein Kinase-Dependent Manner and Sponging microRNA 200b-3p.

Hepatology 2021 Jul 9;74(1):214-232. Epub 2021 May 9.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background And Aims: Bone is the second most frequent site of metastasis for HCC, which leads to an extremely poor prognosis. HCC bone metastasis is typically osteolytic, involving the activation of osteoclasts. Long noncoding RNA H19 plays an important role in the pathogenesis of human cancers. Nonetheless, the mechanism underlying the participation of H19 in HCC bone metastasis remains unclear.

Approach And Results: The current study established a mouse HCC bone metastasis model by using serial intracardiac injection and cell isolation to obtain cells with distinct bone metastasis ability. H19 was highly expressed in these cells and in clinical HCC bone metastasis specimens. Both osteoclastogenesis in vitro and HCC bone metastasis in vivo were promoted by H19 overexpression, whereas these processes were suppressed by H19 knockdown. H19 overexpression attenuated p38 phosphorylation and further down-regulated the expression of osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor. However, up-regulated OPG expression as well as suppressed osteoclastogenesis caused by H19 knockdown were recovered by p38 interference, indicating that p38 mitogen-activated protein kinase (MAPK)-OPG contributed to H19-promoted HCC bone metastasis. Furthermore, we demonstrated that H19 inhibited the expression of OPG by binding with protein phosphatase 1 catalytic subunit alpha (PPP1CA), which dephosphorylates p38. SB-203580-mediated inactivation of p38MAPK reversed the down-regulation of HCC bone metastasis caused by H19 knockdown in vivo. Additionally, H19 enhanced cell migration and invasion by up-regulating zinc finger E-box binding homeobox 1 through the sequestration of microRNA (miR) 200b-3p.

Conclusions: H19 plays a critical role in HCC bone metastasis by reducing OPG expression, which is mediated by the PPP1CA-induced inactivation of the p38MAPK pathway; and H19 also functions as a sponge for miR-200b-3p.
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http://dx.doi.org/10.1002/hep.31673DOI Listing
July 2021

The emerging roles of IDO2 in cancer and its potential as a therapeutic target.

Biomed Pharmacother 2021 May 4;137:111295. Epub 2021 Feb 4.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

During the past decades, tryptophan metabolism disorder was discovered to play a vital and complex role in the development of cancer. Indoleamine 2,3-dioxygenase 2 (IDO2) is one of the initial and rate-limiting enzymes of the kynurenine pathway of tryptophan catabolism. Increasing evidence indicates that IDO2 is upregulated in some tumors and plays a role in the development of cancer. In spite of the growing body of research, few reviews focused on the role of IDO2 in cancer. Here, we review the emerging knowledge on the roles of IDO2 in cancer and its potential as a therapeutic target. Firstly, the main biological features and regulatory mechanisms are reviewed, after which we focus on the expression and roles of IDO2 in cancer. Finally, we discuss the potential of IDO2 as a therapeutic target for cancer treatment.
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http://dx.doi.org/10.1016/j.biopha.2021.111295DOI Listing
May 2021

The 14-3-3σ protein promotes HCC anoikis resistance by inhibiting EGFR degradation and thereby activating the EGFR-dependent ERK1/2 signaling pathway.

Theranostics 2021 1;11(3):996-1015. Epub 2021 Jan 1.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030, People's Republic of China.

Resistance to anoikis, cell death due to matrix detachment, is acquired during tumor progression. The 14-3-3σ protein is implicated in the development of chemo- and radiation resistance, indicating a poor prognosis in multiple human cancers. However, its function in anoikis resistance and metastasis in hepatocellular carcinoma (HCC) is currently unknown. Protein expression levels of 14-3-3σ were measured in paired HCC and normal tissue samples using western blot and immunohistochemical (IHC) staining. Statistical analysis was performed to evaluate the clinical correlation between 14-3-3σ expression, clinicopathological features, and overall survival. Artificial modulation of 14-3-3σ (downregulation and overexpression) was performed to explore the role of 14-3-3σ in HCC anoikis resistance and tumor metastasis and . Association of 14-3-3σ with epidermal growth factor receptor (EGFR) was assayed by co-immunoprecipitation. Effects of ectopic 14-3-3σ expression or knockdown on EGFR signaling, ligand-induced EGFR degradation and ubiquitination were examined using immunoblotting and co-immunoprecipitation, immunofluorescence staining, and flow cytometry analysis. The levels of EGFR ubiquitination, the interaction between EGFR and 14-3-3σ, and the association of EGFR with c-Cbl after EGF stimulation, in 14-3-3σ overexpressing or knockdown cells were examined to elucidate the mechanism by which 14-3-3σ inhibits EGFR degradation. Using gain-of-function or loss-of-function strategies, we further investigated the role of the EGFR signaling pathway and its downstream target machinery in 14-3-3σ-mediated anoikis resistance of HCC cells. We demonstrated that 14-3-3σ was upregulated in HCC tissues, whereby its overexpression was correlated with aggressive clinicopathological features and a poor prognosis. and experiments indicated that 14-3-3σ promoted anoikis resistance and metastasis of HCC cells. Mechanistically, we show that 14-3-3σ can interact with EGFR and significantly inhibit EGF-induced degradation of EGFR, stabilizing the activated receptor, and therefore prolong the activation of EGFR signaling. We demonstrated that 14-3-3σ downregulated ligand-induced EGFR degradation by inhibiting EGFR-c-Cbl association and subsequent c-Cbl-mediated EGFR ubiquitination. We further verified that activation of the ERK1/2 pathway was responsible for 14-3-3σ-mediated anoikis resistance of HCC cells. Moreover, EGFR inactivation could reverse the 14-3-3σ-mediated effects on ERK1/2 phosphorylation and anoikis resistance. Expression of 14-3-3σ and EGFR were found to be positively correlated in human HCC tissues. Our results indicate that 14-3-3σ plays a pivotal role in the anoikis resistance and metastasis of HCC cells, presumably by inhibiting EGFR degradation and regulating the activation of the EGFR-dependent ERK1/2 pathway. To our best knowledge, this is the first report of the role of 14-3-3σ in the anoikis resistance of HCC cells, offering new research directions for the treatment of metastatic cancer by targeting 14-3-3σ.
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http://dx.doi.org/10.7150/thno.51646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738881PMC
July 2021

Immunological Role and Prognostic Value of APBB1IP in Pan-Cancer Analysis.

J Cancer 2021 1;12(2):595-610. Epub 2021 Jan 1.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

APBB1IP is a Rap1-binding protein that mainly acts as a regulator of leukocyte recruitment and pathogen clearance through complement-mediated phagocytosis. However, the role of in tumor immunity remains unclear. This study was carried out to evaluate the prognostic landscape of in pan-cancer analysis and investigate the relationship between expression and immune infiltration. We explored the expression pattern and prognostic value of in pan-cancer analysis through Kaplan-Meier Plotter and multiple databases, including TCGA, Oncomine. We then assessed the correlation between expression and immune cell infiltration using the TIMER database. Furthermore, we identified the proteins that interact with APBB1IP and performed epigenetic and transcriptional analyses. Multivariate Cox regression analyses were applied to construct a prognostic model, which consisted of APBB1IP and its interacting proteins, based on the lung cancer cohorts from the Gene Expression Omnibus (GEO) database. The expression of APBB1IP was correlated with the prognosis of several types of cancer. APBB1IP upregulation was found to be associated with increased immune cell infiltration, especially for CD8 T cells, natural killer (NK) cells, and immune regulators. A link was found between APBB1IP and immune-related proteins including RAP1A/B, TLN1/2 and VCL in the interaction network. APBB1IP can serve as a prognostic biomarker in pan-cancer analysis. APBB1IP upregulation was correlated with increased immune-cell infiltration, and the expression APBB1IP in different tumors might be related to the tumor immune microenvironment.
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http://dx.doi.org/10.7150/jca.50785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738982PMC
January 2021

Comprehensive analysis of TGF-β-induced mRNAs and ncRNAs in hepatocellular carcinoma.

Aging (Albany NY) 2020 Oct 4;12(19):19399-19420. Epub 2020 Oct 4.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Transforming growth factor β (TGF-β) is a potent inducer of epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), and plays a critical role in its tumorigenesis and progression. Accumulating evidence indicates that protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), may play key roles in the tumorigenesis and progression of HCC. In this study, we first report on the differential expression of lncRNAs, mRNAs, miRNAs, and circRNAs in Huh7 cells treated with TGF-β or DMSO for 7 days. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for significantly differentially expressed RNAs (DE RNAs). Then the competing endogenous RNA (ceRNA) network based on these DE RNAs was predicted and constructed. Among them, we identified that lncRNA SLC7A11-AS1 and hsa_circ_0006123 are involved in the EMT process induced by TGF-β and may promotes the metastasis of HCC. This knowledge may pave the way to develop novel clinical diagnostics and therapeutic approaches. Our study might open a new avenue for future investigations of the molecular mechanisms driving the EMT process induced by TGF-β in HCC.
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http://dx.doi.org/10.18632/aging.103826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732333PMC
October 2020

Development and validation of a CpG island methylator phenotype-related prognostic signature for cholangiocarcinoma.

J Cell Physiol 2021 Apr 29;236(4):3143-3156. Epub 2020 Sep 29.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Cholangiocarcinoma (CCA) still has a very unfavorable prognosis with a very high mortality, which is complicated by a lack of prognostic biomarkers. In this study, CCA patients in the Gene Expression Omnibus (GEO) cohort were categorized into two subtypes. Differentially expressed and methylated genes were identified, and the impact of DNA methylation in the trans-regulation of gene expression was investigated. Finally, a CIMP-related methylation signature specific for CCA (CMSC) was trained in GEO and validated in the Tongji cohort. A subset of patients with CIMP-H was identified, which was correlated with an unfavorable prognosis. Gene enrichment analysis implied the potential mechanism of CIMP as a promoter of carcinogenesis by regulating proliferation. The trans-regulation among differentially methylated CpG sites and genes with the same change trends was positively correlated, while the converse situation showed a negative correlation. Notably, CMSC based on four genes could significantly classify CCA patients into low- and high-risk groups in the GEO cohort, and the robustness of CMSC was validated in the Tongji cohort. The results of receiver operating characteristic analysis further indicated that CMSC was capable of highly sensitive and specific prediction of the patient outcomes in CCA. In conclusion, our work highlights the clinical significance of CMSC in the prognosis of CCA.
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http://dx.doi.org/10.1002/jcp.30082DOI Listing
April 2021

White-light-emitting hydrogels with self-healing properties and adjustable emission colors.

J Colloid Interface Sci 2021 Jan 25;582(Pt B):825-833. Epub 2020 Aug 25.

Engineering Research Center of Organic and Polymer Optoelectronic Materials, Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, PR China; State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, PR China. Electronic address:

White-light-emitting soft materials with self-healing properties show extensive applications in many fields. Herein, a novel self-healing hydrogel is successfully fabricated using oxidized dextran (Odex) and dithiodipropionate dihydrazide (TPH). Carbon dots (CDs), Riboflavin (Ri) and Rhodamine B (RhB) are incorporated into the gel matrix to produce white light emission through fluorescence resonance energy transfer (FRET) process, thus achieving excellent Commission Internationale de L'eclairage (CIE) coordinate value of (0.30, 0.33). The emission colors can be easily tuned via changing proportions of three emitters or the excitation wavelength. When the hydrogels are coated on an ultraviolet light-emitting diodes (UV LED), the hydrogel coating converts UV light to white light and repairs itself in 20 h while a hole is dug from it. Thanks to reversible exchanging reactions of acylhydrazone and disulfide bonds in hydrogel networks, the hydrogel coating exhibits perfect self-healing property in a wide range of pH (from 5 to 9 except for 7). The excellent emission and self-healing properties of hydrogels have great value in practical applications.
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http://dx.doi.org/10.1016/j.jcis.2020.08.080DOI Listing
January 2021

Integrative analysis of scRNA-seq and GWAS data pinpoints periportal hepatocytes as the relevant liver cell types for blood lipids.

Hum Mol Genet 2020 11;29(18):3145-3153

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health.

Liver, a heterogeneous tissue consisting of various cell types, is known to be relevant for blood lipid traits. By integrating summary statistics from genome-wide association studies (GWAS) of lipid traits and single-cell transcriptome data of the liver, we sought to identify specific cell types in the liver that were most relevant for blood lipid levels. We conducted differential expression analyses for 40 cell types from human and mouse livers in order to construct the cell-type specifically expressed gene sets, which we refer to as construction of the liver cell-type specifically expressed gene sets (CT-SEGS). Under the assumption that CT-SEGS represented specific functions of each cell type, we applied stratified linkage disequilibrium score regression to determine cell types that were most relevant for complex traits and diseases. We first confirmed the validity of this method (of delineating functionally relevant cell types) by identifying the immune cell types as relevant for autoimmune diseases. We further showed that lipid GWAS signals were enriched in the human and mouse periportal hepatocytes. Our results provide important information to facilitate future cellular studies of the metabolic mechanism affecting blood lipid levels.
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http://dx.doi.org/10.1093/hmg/ddaa188DOI Listing
November 2020

MicroRNA-148a-3p inhibits progression of hepatocelluar carcimoma by repressing SMAD2 expression in an Ago2 dependent manner.

J Exp Clin Cancer Res 2020 Aug 4;39(1):150. Epub 2020 Aug 4.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent common cancer worldwide with high mortality. Transforming growth factor-β (TGF-β) signaling pathway was reported dysregulated during liver cancer formation and progression. As a key component of TGF-β signaling, the role of SMAD2 and its regulatory mechanisms in HCC remain unclear.

Methods: SMAD2 expression in paired HCC specimens were determined by western blot and immunohistochemistry (IHC). quantitative real-time PCR (qRT-PCR) was used to measure mRNA and microRNA (miRNA) expression level. Cell migration, invasion and proliferation ability were evaluated by transwell, CCK8 and EdU assay. In silico websites were used to manifest overall survival rates of HCC patients or to predict miRNAs targeting SMAD2. Dual luciferase reporter assay and anti-Ago2 immunoprecipitation assay were performed to confirm the binding between SMAD2 mRNA and miRNA-148a-3p (miR-148a). Tumorigenesis and lung metastasis mouse model were used to explore the role of miR-148a in vivo. In situ hybridization (ISH) was conducted to determine the expression of miR-148a in liver tissues.

Results: In this study, we found that SMAD2 was highly expressed in HCC and elevated SMAD2 expression predicted shorter overall survival (OS) time for HCC patients. SMAD2 promoted mobility and proliferation of HCC cells in vitro. We further revealed that the expression of miR-148a was negatively correlated with SMAD2 and found that miR-148a repressed SMAD2 expression by downregulating its mRNA through binding with Argonaute 2 (Ago2) in HCC. Transwell, CCK8 and animal experiments exhibited miR-148a inhibited metastasis and proliferation of HCC in vitro and in vivo. Moreover, the phenotype changes caused by miR-148a manipulation were recovered by rescuing SMAD2 expression in HCC cells. ISH assay indicated miR-148a was downregulated in HCC and low expression of miR-148a associated with more aggressive clinic features and poor prognosis.

Conclusion: miR-148a was identified as a repressor of HCC progression by downregulating SMAD2 in an Ago2 dependent manner.
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http://dx.doi.org/10.1186/s13046-020-01649-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401232PMC
August 2020

Organ function support in patients with coronavirus disease 2019: Tongji experience.

Front Med 2020 Apr 14;14(2):232-248. Epub 2020 May 14.

Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Coronavirus disease 2019 (COVID-19) is a highly contagious disease and a serious threat to human health. COVID-19 can cause multiple organ dysfunction, such as respiratory and circulatory failure, liver and kidney injury, disseminated intravascular coagulation, and thromboembolism, and even death. The World Health Organization reports that the mortality rate of severe-type COVID-19 is over 50%. Currently, the number of severe cases worldwide has increased rapidly, but the experience in the treatment of infected patients is still limited. Given the lack of specific antiviral drugs, multi-organ function support treatment is important for patients with COVID-19. To improve the cure rate and reduce the mortality of patients with severe- and critical-type COVID-19, this paper summarizes the experience of organ function support in patients with severe- and critical-type COVID-19 in Optical Valley Branch of Tongji Hospital, Wuhan, China. This paper systematically summarizes the procedures of functional support therapies for multiple organs and systems, including respiratory, circulatory, renal, hepatic, and hematological systems, among patients with severe- and critical-type COVID-19. This paper provides a clinical reference and a new strategy for the optimal treatment of COVID-19 worldwide.
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http://dx.doi.org/10.1007/s11684-020-0774-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220847PMC
April 2020

Multi-color tunable circularly polarized luminescence in one single AIE system.

Chem Sci 2020 Jan 15;11(8):2169-2174. Epub 2020 Jan 15.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University Changchun 130012 P. R. China

Circularly polarized luminescence (CPL) materials with a large luminescence dissymmetry factor ( ) and multi-color properties are very attractive. While multi-color tunable CPL can be realized by different organic dyes, the challenge of realizing both a higher and multiple colors using a single component remains. Here, we design an aggregation-induced emission (AIE) fluorophore, which is a pyridine functionalized cyanostilbene attached to a chiral unit, and realize multi-color tunable CPL with a high . The compound can self-assemble into a nanohelix and form both gel and xerogel films, exhibiting blue CPL with large values of -3.0 × 10 and -1.7 × 10, respectively. With the assistance of pyridine protonation, the xerogel films exhibit red-shifted CPL signals from 480 nm to 530 nm, covering from blue green and yellow to orange. Additionally, the remains constant during the process. This work paves a simple and convenient way to construct multi-color tunable CPL materials using a single molecule.
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http://dx.doi.org/10.1039/c9sc05643bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150103PMC
January 2020

Tunable morphologies and emission of photosensitive supramolecular self-assemblies through positional and trans-cis isomerization.

Nanoscale 2020 Jan;12(3):2071-2080

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, 2699 Qianjin Avenue, Changchun 130012, P. R. China.

Cyanostilbene units are widely attractive as photoresponsive supramolecular building blocks whose structures and emission can be modulated by trans-cis isomerization. Generally, the change of properties is related to the molecular structure of cyanostilbene, which is still unpredictable and needs to be explored. Herein, two benzene-1,3,5-tricarboxamide (BTA) based cyanostilbene derivatives with different cyano positions have been designed to investigate the emission as well as structural changes during the trans-cis photoisomerization process in monomer and aggregation states, respectively. In the monomer state, the derivative with cyano groups at the outer position, β-BTTPA, exhibits obvious emission enhancement upon UV irradiation, while the other derivative (α-BTTPA) shows emission quenching. In addition, upon the formation of aggregates, β-BTTPA forms nano-level fibers with blue-green emission, but α-BTTPA forms micron-level flat ribbons with blue emission. More importantly, also driven by the trans-cis photoisomerization, the self-assemblies show morphological transitions (ribbons/fibers to spheres) due to the fact that the equilibrium of the system is broken by the photoreactions. Such changes further contribute to emission switching as well as enhanced hydrophobic properties.
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http://dx.doi.org/10.1039/c9nr09155fDOI Listing
January 2020

PTPRε Acts as a Metastatic Promoter in Hepatocellular Carcinoma by Facilitating Recruitment of SMAD3 to TGF-β Receptor 1.

Hepatology 2020 09 3;72(3):997-1012. Epub 2020 Sep 3.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background And Aims: Transforming growth factor beta (TGF-β) suppresses early stages of tumorigenesis, but contributes to the migration and metastasis of cancer cells. However, the role of TGF-β signaling in invasive prometastatic hepatocellular carcinoma (HCC) is poorly understood. In this study, we investigated the roles of canonical TGF-β/mothers against decapentaplegic homolog 3 (SMAD3) signaling and identified downstream effectors on HCC migration and metastasis.

Approach And Results: By using in vitro trans-well migration and invasion assays and in vivo metastasis models, we demonstrated that SMAD3 and protein tyrosine phosphatase receptor epsilon (PTPRε) promote migration, invasion, and metastasis of HCC cells in vitro and in vivo. Further mechanistic studies revealed that, following TGF-β stimulation, SMAD3 binds directly to PTPRε promoters to activate its expression. PTPRε interacts with TGFBR1/SMAD3 and facilitates recruitment of SMAD3 to TGFBR1, resulting in a sustained SMAD3 activation status. The tyrosine phosphatase activity of PTPRε is important for binding with TGFBR1, recruitment and activation of SMAD3, and its prometastatic role in vitro. A positive correlation between pSMAD3/SMAD3 and PTPRε expression was determined in HCC samples, and high expression of SMAD3 or PTPRε was associated with poor prognosis of patients with HCC.

Conclusions: PTPRε positive feedback regulates TGF-β/SMAD3 signaling to promote HCC metastasis.
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http://dx.doi.org/10.1002/hep.31104DOI Listing
September 2020

The Roles of TIF1γ in Cancer.

Front Oncol 2019 2;9:979. Epub 2019 Oct 2.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Transcriptional intermediary factor 1 γ (TIF1γ), also known as TRIM33, RFG7, PTC7, or Ectodermin, is an E3 ubiquitin-ligase family member with a ring-box-coiled-coil region. It can regulate TGF-β/Smad signaling in two different ways in different cellular contexts. On one hand, TIF1γ can monoubiquitinate Smad4 to inhibit the formation of Smad2/3/4 nuclear complexes. On the other hand, TIF1γ can function as a cofactor of phosphorylated (p)-Smad2/3, competing with Smad4 to inhibit the formation of the Smad2/3/4 complex. In addition, TIF1γ has been reported to play a role in transcription elongation, cellular differentiation, embryonic development, and mitosis. As transforming growth factor-β (TGF-β) superfamily signaling plays an important role in the occurrence and development of cancer, and TIF1γ was reported to be involved in the regulation of TGF-β superfamily signaling, studies on TIF1γ during the last decade have focused on its role in the development of cancer. However, TIF1γ can function either as a tumor suppressor or promoter in different cellular contexts, yet there are few reviews focusing on the roles of TIF1γ in cancer. Hence, in this paper we systematically review and discuss the roles of TIF1γ in cancer. Firstly, we review the biological features, the regulatory mechanisms and the related signaling pathways of TIF1γ. Next, we illustrate the roles of TIF1γ in different tumors. We then provide a tentative hypothesis that explains the dual roles of TIF1 γ in cancer. Finally, we provide our viewpoint regarding the future developments of cancer research focusing on TIF1γ, especially in relation to the effects of TIF1γ on tumoral immunity.
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http://dx.doi.org/10.3389/fonc.2019.00979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783507PMC
October 2019

Development and validation of a CIMP-associated prognostic model for hepatocellular carcinoma.

EBioMedicine 2019 Sep 4;47:128-141. Epub 2019 Sep 4.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: CpG island methylator phenotype (CIMP), a common biological phenomenon characterized by a subset of concurrently methylated genes, can have an influence on the progression of multiple cancers. However, the potential mechanism of CIMP in hepatocarcinogenesis and its clinical relevance remains only partially understood.

Methods: We used a methylation array from the cancer genome atlas (TCGA) to stratify HCC patients into different CIMP subtypes, and evaluated their correlation with clinical characteristics. In addition, mutation, CNV, and transcriptome profiles were also utilized to evaluate the distinctive genomic patterns correlated with CIMP. Finally, a CIMP-associated prognostic model (CPM) was trained and validated using four independent datasets.

Findings: A subgroup of patients was identified as having CIMP-H, which was associated with worse OS and DFS. Gene enrichment analysis indicated that the terms "liver cancer with EPCAM up", "tumor invasiveness up", "methyltransferase complex", and "translational initiation" were enriched in CIMP-H subgroup. Notably, somatic mutation analysis indicated that CIMP-H patients presented with a higher mutation burden of BRD4, DDIAS and NOX1. Moreover, four CPM associated genes could significantly categorize patients into low- and high-risk groups in the training dataset and another 3 independent validation datasets. Finally, a nomogram incorporating a classifier based on four mRNAs, pathological M stage and CIMP status was established, which showed a favorable discriminating ability and might contribute to clinical decision-making for HCC.

Interpretation: Our work highlights the potential clinical application value of CPM in predicting the overall survival of HCC patients and the mechanisms underlying the role of CIMP in hepatocarcinogenesis. FUND: This work was supported by the State Key Project on Infectious Diseases of China (2018ZX10723204-003), the National Nature Science Foundation of China (Nos. 81874065, 81500565, 81874149, 81572427, and 81401997), the Hepato-Biliary-Pancreatic Malignant Tumor Investigation Fund of Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province (CXPJJH11800001-2018356).
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http://dx.doi.org/10.1016/j.ebiom.2019.08.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796541PMC
September 2019

Genome-wide identification of a competing endogenous RNA network in cholangiocarcinoma.

J Cell Biochem 2019 11 3;120(11):18995-19003. Epub 2019 Jul 3.

Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cholangiocarcinoma (CCA) is the second widespread liver tumor with relatively poor survival. Increasing evidence in recent studies showed long noncoding RNAs (lncRNAs) exert a crucial impact on the development and progression of CCA based on the mechanism of competing endogenous RNAs (ceRNAs). However, functional roles and regulatory mechanisms of lncRNA-regulated ceRNA in CCA, are only partially understood. The expression profile of messenger RNAs (mRNAs), lncRNAs, and microRNAs (miRNAs) downloaded from The Cancer Genome Atlas were comprehensively investigated. Differential expression of these three types of RNA between CCA and corresponding precancerous tissues were screened out for further analysis. On the basis of interactive information generated from miRDB, miRTarBase, TargetScan, and miRcode public databases, we then constructed an mRNA-miRNA-lncRNA regulatory network. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses were conducted to identify the biological function of the ceRNA network involved in CCA. As a result, 2883 mRNAs, 136 miRNAs, and 993 lncRNAs were screened out as differentially expressed RNAs in CCA. In addition, a ceRNA network in CCA was constructed, composing of 50 up and 27 downregulated lncRNAs, 14 up and 7 downregulated miRNAs, 29 up and 25 downregulated mRNAs. Finally, gene set enrichment and pathway analysis indicated our CCA-specific ceRNA network was related with cancer-related pathway and molecular function. In conclusion, our research identified a novel lncRNA-related ceRNA network in CCA, which might act as a potential therapeutic target for patients with CCA.
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http://dx.doi.org/10.1002/jcb.29222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771781PMC
November 2019

Multi-stimuli responsive supramolecular gels based on a D-π-A structural cyanostilbene derivative with aggregation induced emission properties.

Soft Matter 2019 Feb;15(7):1658-1665

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, 2699 Qianjin Avenue, Changchun 130012, P. R. China.

Developing multi-stimuli responsive fluorescent gel materials in a single system remains challenging. Gelator molecules with classical fluorophores suffer from the aggregation-caused quenching (ACQ) effect, limiting their applications further. Herein, a novel V-shaped cyanostilbene-based molecule (BAPBIA) with aggregation induced emission (AIE) characteristics and great gelation ability was synthesized and was found to exhibit multi-stimuli responsive behaviors. Reversible gel-sol phase transitions together with emission quenching are realized in response to external stimuli including heat, light and fluoride ions. Especially, the introduction of a dimethylaniline group (donor) and a cyano group (acceptor) generates a D-π-A structure, further leading to an intramolecular charge transfer (ICT) effect, which enlarges the emission contrast with the variation of the distribution of charge. Thus, upon trifluoroacetic acid (TFA) triggered protonation of the dimethylaniline group, not only a gel-sol transition but also emission color switching (yellow-to-blue) is achieved due to the loss of the ICT effect. This work paves an easy way to construct fully reversible multi-stimuli responsive fluorescence modulation smart materials.
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http://dx.doi.org/10.1039/c8sm02434kDOI Listing
February 2019

Fluorescence Regulation and Photoresponsivity in AIEE Supramolecular Gels Based on a Cyanostilbene Modified Benzene-1,3,5-Tricarboxamide Derivative.

Chemistry 2019 Jan 4;25(1):315-322. Epub 2018 Dec 4.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, 130012, P. R. China.

Supramolecular interactions play an important role in regulating the optical properties of molecular materials. Different arrangements of identical molecules can afford a more straightforward insight into the contributions of supramolecular interactions. Herein, a novel gelator, BTTPA, composed of a benzene-1,3,5-tricarboxamide (BTA) central unit functionalized with three cyanostilbenes is designed, which forms two kinds of gels in DMSO/water mixtures. Depending on the water volume content, the gels exhibit quite different aggregation-induced emission enhancement (AIEE) properties, with one emitting a green emission (G-gel), and the second emitting a blue emission (B-gel). The main reason for this difference is that water affects H-bonding and π-π interactions, further resulting in disparate packing modes of gelators. In addition, only the G-gel displays gel-to-sol transition accompanied with fluorescence switching according to the trans-cis photoisomerization of cyanostilbene under UV light irradiation. The B-gel does not exhibit any change because of its tight hexagonal packing arrangement. Such packing modes restricted the space in which molecules were located and inhibited the transformation of configuration of cyanostilbene. These phenomena underline the incomparable status of packing modes and molecular configuration in regulating fluorescence properties and photoresponse behavior in organic solid-state luminescent materials.
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http://dx.doi.org/10.1002/chem.201804135DOI Listing
January 2019

Safety and efficacy of n-3 fatty acid-based parenteral nutrition in patients with obstructive jaundice: a propensity-matched study.

Eur J Clin Nutr 2018 08 13;72(8):1159-1166. Epub 2018 Jul 13.

Institute of Hepato-Pancreato-Biliary Surgery center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Background: It is reported that lipid emulsion enriched in n-3 fatty acids (FAs) helps us to improve postoperative recovery for surgical patients with biliary tract disease. Its role for postoperative patients with obstructive jaundice is as yet unclear. The object of this study was to evaluate the safety and efficacy of n-3 fatty acid-based parenteral nutrition (PN) for patients with obstructive jaundice following surgical procedures.

Methods: Data were collected from patients with obstructive jaundice who received PN, including n-3 PUFA-enriched lipid emulsions and standard non-enriched lipid emulsions (e.g., soybean oil). We then calculated a propensity score, the probability of receiving different PN, by the propensity score matched (PSM) method. After matching, we compared isonitrogenous total PN with 20% Structolipid and 10% n-3 fatty acid (Omegaven, Fresenius-Kabi, Germany) (treatment group) to Structolipid alone (control group) for 5 days postoperatively, in the absence of enteral nutrition.

Results: Before the propensity score matching, there were 226 patients enrolled. After propensity score stratification, 108 cases remained, and all covariates were balanced. Among matched patients with PN, patients in the control group were at a higher risk for long-term jaundice recovery (12.9 ± 8.5 VS 16.4 ± 7.9 P = 0.029), lower velocity of reduction in jaundice (P = 0.045), and lower pre-albumin (P = 0.002). No significant difference as found in terms of comorbidities, white blood cell (WBC), albumin and other aspects.

Conclusion: PN with n-3 PUFA-enriched lipid emulsions was safe and effective in accelerating jaundice recovery for patients after surgical procedures. This trial was registered at clinicaltrials.gov as NCT03376945.
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http://dx.doi.org/10.1038/s41430-018-0256-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085574PMC
August 2018

CD2-Associated Protein Contributes to Hepatitis C, Virus Propagation and Steatosis by Disrupting Insulin Signaling.

Hepatology 2018 11;68(5):1710-1725

Center for Molecular Virology, Wuhan Institute of Virology, State Key Laboratory of Virology, Chinese Academy of Sciences, Wuhan, China.

Chronic hepatitis C virus (HCV) infection can result in steatosis, a condition displaying aberrant accumulation of neutral lipid vesicles, the component of lipid droplets (LDs), which are essential for HCV assembly. However, the interplay between HCV infection and steatosis remains unclear. Here, we show that HCV-infected cells have higher levels of CD2-associated protein (CD2AP), which plays two distinct, yet tightly linked, roles in HCV pathogenesis: Elevated CD2AP binds to nonstructural protein 5A (NS5A) and participates in the transport of NS5A to LDs to facilitate viral assembly; Up-regulated CD2AP also interacts with casitas B-lineage lymphoma (b) (Cbl/Cbl-b) E3 ligases to degrade insulin receptor substrate 1 (IRS1), which, in turn, disrupts insulin signaling and increases LD accumulation through the IRS1/protein kinase B (Akt)/adenosine monophosphate-activated protein kinase (AMPK)/hormone-sensitive lipase (HSL) signaling axis to accommodate viral assembly. In the HCV-infected mouse model, CD2AP expression is up-regulated during the chronic infection stage and this up-regulation correlates well with liver steatosis. Importantly, CD2AP up-regulation was also detected in HCV-infected human liver biopsies showing steatosis compared to non-HCV-infected controls. Conclusion: CD2AP is indicated as a protein up-regulated by HCV infection, which, in turn, stimulates HCV propagation and steatosis by disrupting insulin signaling; targeting CD2AP may offer an opportunity for alleviating HCV infection and its associated liver pathology. (Hepatology 2018;XX:XXX-XXX.).
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http://dx.doi.org/10.1002/hep.30073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220802PMC
November 2018
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