Although activation of hepatic stellate cells (HSCs) plays a central role in the development of liver fibrosis, the mechanism underlying the activation of HSCs remains unclear. Keratin 17 (KRT17), a member of the intermediate filament family, can regulate tumor cell proliferation and migration. The current study aimed to elucidate the role of KRT17 in the activation of HSCs and the mechanisms underlying liver fibrosis.

The expression of KRT17 was determined using immunohistochemistry in tissue microarray. Western blotting and qRT-PCR assays were used to determine the KRT17 expression in fibrotic liver tissues obtained from human subjects and mice. LX-2 cells were treated with TGF-β1 recombinant protein and adipocyte differentiation mixture (MDI) mix to induce and reverse LX-2 cell activation, respectively, in order to explore the correlation between KRT17 and HSC activation. Additionally, cell proliferation and migration abilities of LX-2 cells transfected with KRT17-overexpressing plasmid or small interfering RNA were determined using CCK-8, flow cytometry, Transwell, and wound healing assays. Finally, rescue assay was used to explore the role of KRT17 in HSC activation and epithelial-mesenchymal transition (EMT).

The expression of KRT17 was higher in the human and mouse fibrotic liver tissues than in healthy liver tissues, and it was positively correlated with HSC activation. Upregulated KRT17 enhanced proliferation, migration, HSC activation and EMT in LX-2 cells, while knockdown of KRT17 reversed these effects. TGF-β1 recombinant protein accelerated KRT17-mediated EMT, HSC activation and proliferation, while TGF-β1 inhibitor counteracted the effect of KRT17 in vitro.

KRT17 promoted HSC activation, proliferation and EMT in hepatic fibrosis probably via TGF-β1 signaling, and KRT17 might serve as a therapeutic target for the treatment of liver fibrosis.

Endovascular implantation of iodine-125 (125I) seeds strand combined with stent is an effective method of treatment for portal vein tumor thrombosis. The aim of this study was to develop a novel endovascular brachytherapy stent (EVB-Stent) and to evaluate its feasibility of use.

An EVB-Stent was implanted into the main portal vein (MPV) in a live porcine model via the percutaneous transhepatic route. Blood samples were collected and tested before and after operation, as well as before euthanasia. Single-photon emission computed tomography (SPECT) combined with CT (SPECT/CT) scan were performed directly after operation and CT scan was performed 2 months after implantation. After the CT scan was performed, all animals were euthanized and histologically examined.

The novel stent was successfully positioned in all six pigs. No deterioration of liver function was observed during the 2-month follow-up period. SPECT/CT revealed the uniform distribution of radiation around the seeds strand, and the hottest spot was near the center of the MPV. The patency of the stented MPV was confirmed using CT scans. The tissue-accumulated absorbed dose was 31,822.11 mGy at 10 mm transversely away from the midpoint of the 125I seeds strand, with a half-life of 59.4 days. Pathological examination results showed no significant atrophy or inflammation of adjunct liver tissue, and no obvious intima thickening or thrombosis were detected in the stented MPV.

A liver porcine model was used to demonstrate that the transhepatic placement of a novel endovascular brachytherapy stent, EVB-Stent, is both technically feasible and safe.

Microvascular invasion (MVI) affects recurrence after treatment of small hepatocellular carcinoma (sHCC) of ≤3 cm in size. The present study aimed to investigate whether abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and intermuscular adipose tissue (IMAT) are associated with MVI in patients with sHCC.

A total of 124 patients with pathologically-confirmed sHCC diagnosed on surgical resection at the First Hospital Affiliated to Army Military University were recruited and divided into two groups according to MVI classification criteria (i.e., MVI-positive or MVI-negative). The SAT, VAT, and IMAT areas at the lumbar 3 vertebral level were imaged with abdominal computed tomography and measured using ImageJ software. Their association with MVI in sHCC was analyzed.

Of the 124 patients with sHCC, 67 were MVI-positive and 57 were MVI-negative. Univariate analysis revealed a significant difference in the abdominal VAT and SAT between the MVI-positive and MVI-negative groups (p<0.05), with an area under the receiver operating characteristic curve of 0.76 and 0.65, respectively.

The results of this study suggest that the areas of abdominal SAT and VAT are of significant clinical value because they can effectively predict the MVI status in patients with sHCC.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy that causes a poor survival. We aimed to identify its prognostic factors and to develop a nomogram that will predict survival of ICC patients among all stages.

A total of 442 patients with pathology-proven ICC registered at the Fifth Medical Center of PLA General Hospital between July 2007 and December 2019 were enrolled. Subjects were followed for survival status until June 30, 2020. A prognostic model visualized as a nomogram was constructed in the training cohort using multivariate cox model, and was then validated in the validation cohort.

The median age was 55 years. With a median follow-up of 50.4 months, 337 patients died. The median survival was 11.6 months, with 1-, 3- and 5-year survival rates of 48.3%, 22.7% and 16.2%, respectively. Factors associated with overall survival were multiple tumors, lymph node involvement, vascular invasion, distant metastasis, decreased albumin, elevated lactate dehydrogenase (LDH), decreased iron, elevated fibrinogen, elevated CA125 and elevated CA19-9. A nomogram predicting survival of ICC patients at the time of diagnosis achieved a Harrel’s c-statistic of 0.758, significantly higher than the 0.582 of the TNM stage alone. Predicted median survivals of those within the low, mid and high-risk subgroups were 35.6, 12.1 and 6.2 months, respectively.

A nomogram based on imaging data and serum biomarkers at diagnosis showed good ability to predict survival in patients with all stages of ICC. Further studies are needed to validate the prognostic capability of our new model.

This study aimed to evaluate the diagnostic performance of high frame rate contrast-enhanced ultrasound (H-CEUS) of focal liver lesions (FLLs).

From July 2017 to June 2019, conventional contrast-enhanced ultrasound (C-CEUS) and H-CEUS were performed in 78 patients with 78 nodules. The characteristics of C-CEUS and H-CEUS in malignant and benign groups and the differences between different lesion sizes (1–3 cm, 3–5 cm, or >5 cm) of C-CEUS and H-CEUS were examined. The diagnostic performance of C-CEUS and H-CEUS was analyzed. The chi-square test or Fisher’s exact test was used to assess inter-group differences. The receiver operating characteristic curve was plotted to determine the diagnostic performance of C-CEUS and H-CEUS.

There were significant differences in the enhancement area, fill-in direction and vascular architecture between C-CEUS and H-CEUS for both benign and malignant lesions (all p=0.000–0.008), but there were no significant differences in washout results (p=0.566 and p=0.684, respectively). For lesions 1–3 cm in size, the enhancement area, fill-in direction, and vascular architecture on C-CEUS and H-CEUS were significantly different (all p=0.000), unlike for lesions 3–5 cm or >5 cm in size. For differentiation of malignant from benign FLLs in the 1–3 cm group, H-CEUS showed sensitivity, specificity, accuracy, and positive and negative predictive values of 92.86%, 95.0%, 96.3%, 90.48% and 93.75%, respectively, which were higher than those for C-CEUS (75.0%, 70.0%, 77.78%, 66.67% and 72.91%, respectively).

H-CEUS provided more vascular information which could help differentiate malignant from benign FLLs, especially for lesions 1–3 cm in size.

Long non-coding RNA small nucleolar RNA host genes (SNHGs) play a critical role in the occurrence and development of tumors. In this study, we aimed to investigate the role of SNHG4 in hepatocellular carcinoma (HCC) and its underlining mechanism.

Datasets were acquired from The Cancer Genome Atlas (TCGA) database. lncLocator 2.0 was used to identify the distribution of SNHG4 in HCC cells. Gene expression, Kaplan-Meier survival, microRNA and transcription factor target analyses were performed with the University of Alabama Cancer (UALCAN) Database, Kaplan-Meier Plotter, LinkedOmics, WebGestalt and gene set enrichment analysis, respectively. Gene Ontology and pathway enrichment analyses and assessment of RNA binding proteins were performed by R software, circlncRNAnet and Encyclopedia of RNA Interactomes (ENCORI). In addition, CirclncRNAnet and ENCORI were used to find the correlation between SNHG4 and important proteins, while the prognostic value was assessed with the Human Protein Atlas database and Kaplan-Meier Plotter.

Expression of SNHG4 in HCC is higher in HCC tissue than in normal healthy liver tissues and is mainly distributed in the nucleus. SNHG4 positively correlated with poor prognosis (p<0.01 for overall survival and recurrence-free survival). Functional enrichment analysis revealed SNHG4 involvement with regulation of ribosomal RNA synthesis and the RNA processing and surveillance pathway. SNHG4 is closely associated with miR-154 and miR-206, transcription factor target E2F family and the signaling pathway for MAPK/ERK and mTOR. U2 auxiliary factor 2 (U2AF2) showed strong correlation with SNHG4, while low-expression of U2AF2 showed good prognosis.

Based on our findings, we infer SNHG4 may play a role in the formation of HCC via regulation of tumor-related pathways.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new concept, proposed in 2020; however, its applicability in Asia populations has yet to be evaluated. Therefore, we aimed to compare the difference in epidemiological and clinical characteristics between MAFLD and non-alcoholic fatty liver disease (NAFLD) among Asian populations.

Based on the Jinchang cohort, 30,633 participants were collected. The prevalence and incidence of MAFLD and NAFLD were used to analyze the epidemic characteristics and its overlapping effects. In addition, the corresponding clinical characteristics of the two diagnostic criteria populations were compared.

The prevalence rates of MAFLD and NAFLD were 21.03% and 18.83%, respectively. After an average 2.28-year follow-up, the incidence densities of MAFLD and NAFLD were 41.58 per 1,000 person-years and 37.69 per 1,000 person-years, respectively. With the increase of baseline age, body mass index (BMI), and waist circumference (WC) levels, the prevalence and incidence of MAFLD and NAFLD were on the rise (all ptrend<0.05). Among the total patients diagnosed at baseline or follow-up, most patients had both MAFLD and NAFLD, accounting for 78.84% and 82.88%, respectively. Compared with NAFLD, MAFLD patients had greater proportions of males and metabolic diseases (diabetes, dyslipidemia), and had higher BMI, WC, liver enzymes, blood glucose, and lipid levels in the baseline diagnosis patients (p<0.05). Additionally, lean MAFLD patients had higher metabolic disorders than lean NAFLD patients (p<0.05).

Compared with NAFLD, the newly proposed definition of MAFLD is more practical and accurate, and it can help identify more fatty liver patients with high-risk diseases.

Infectious diseases have always been a difficult clinical problem, especially severe infections and those infections of unknown origin. The invention of a new detection method is particularly important and urgent. Metagenomic next-generation sequencing (mNGS) is a high-throughput sequencing method that sequences microbial DNA and RNAs from fluid or solid tissue samples in hours. All important sequence data that is present in a specimen can be used for pathogen identification after a series of bioinformatics analysis. Recently, mNGS has been used in preclinical trials to find and identify pathogens from the respiratory system, central nervous system, bloodstream, and other infections. mNGS technology has advantages of being faster, accurate, and detection of unknown pathogens over conventional laboratory methods for microbial identification and detection of antimicrobial resistance and virulence markers. However, mNGS has limitations that include human source DNA and RNA removal, intracellular bacteria extraction difficulties, and background pollution. mNGS technologies are innovative methods, especially when a bacterial culture is negative; however, a comprehensive collection of clinical evidence is required before they move from research into clinical laboratories.

Gallbladder polyp (GBP) assessment aims to identify the early stages of gallbladder carcinoma. Many studies have analyzed the risk factors for malignant GBPs. In this retrospective study, we aimed to establish a more accurate predictive model for potential neoplastic polyps in patients with GBPs.

We developed a nomogram-based model in a training cohort of 233 GBP patients. Clinical information, ultrasonographic findings, and blood test findings were analyzed. Mann-Whitney U test and multivariate logistic regression analyses were used to identify independent predictors and establish the nomogram model. An internal validation was conducted in 225 consecutive patients. Performance and clinical benefit of the model were evaluated using receiver operating characteristic curves and decision curve analysis (DCA), respectively.

Age, cholelithiasis, carcinoembryonic antigen, polyp size, and sessile shape were confirmed as independent predictors of GBP neoplastic potential in the training group. Compared with five other proposed prediction methods, the established nomogram model presented better discrimination of neoplastic GBPs in the training cohort (area under the curve [AUC]: 0.846) and the validation cohort (AUC: 0.835). DCA demonstrated that the greatest clinical benefit was provided by the nomogram compared with the other five methods.

Our developed preoperative nomogram model can successfully be used to evaluate the neoplastic potential of GBPs based on simple clinical variables that maybe useful for clinical decision-making.

Continuous release and transmission of hepatitis B virus (HBV) is one of the main factors leading to chronic hepatitis B (CHB) infection. However, the mechanism of HBV-host interaction for optimal viral transport is unclear. Hence, we aimed to explore how HBV manipulates microtubule-associated protein 1S (MAP1S) and microtubule (MT) to facilitate its transport and release.

The expression of MAP1S or acetylated MT was investigated by immunofluorescence, RT-PCR, immunoblotting, and plasmid transfection. MAP1S overexpression or knockdown was performed by lentiviral infection or sh-RNA transfection, respectively. HBV DNA was quantified using q-PCR.

Significantly higher level of MAP1S in HepG2215 cells compared with HepG2 cells was detected using RT-PCR (p<0.01) and immunoblotting (p<0.001). Notably, stronger MAP1S expression was observed in the liver tissues of patients with CHB than in healthy controls. MAP1S overexpression or knockdown demonstrated that MAP1S promoted MT acetylation and reduced the ratio of HBV DNA copies inside to outside cells. Further, transfection with the hepatitis B virus X protein (HBx)-expressing plasmids induced significantly higher level of MAP1S than that in controls (p<0.0001), whereas HBVX− mutant-encoding HBV proteins (surface antigen, core protein, and viral DNA polymerase) hardly affected its expression.

These results demonstrate that HBx induces the formation of stable MTs to promote the release of HBV particles through upregulating MAP1S. Thus, our studies delineate a unique molecular pathway through which HBV manipulates the cytoskeleton to facilitate its own transportation, and indicate the possibility of targeting MAP1S pathway for treatment of patients with CHB.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has alarmed people worldwide as an emerging coronavirus, which to date remains a major global public health challenge. Patients are being treated with different therapies; however, no evidence of a single therapy has been found to improve the clinical outcomes significantly; therefore, there is currently no single effective treatment against COVID-19. The research related to virus-specific T cell therapy has provided positive results when treating Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Therefore, when facing a new virus, it is necessary to continue innovating the therapeutic strategies that have worked to treat viral infections previously, adapting to the pathogenesis of this new disease, to treat patients infected with SARS-CoV-2 effectively and safely. This proposal presents the research idea of creating SARS-CoV-2 specific interferon-gamma (IFN-γ) and interleukin-10 (IL-10) co-producing CD4 T cells to determine the cytokine secretion and viability of their production for virus-specific T cell therapy.

The incidence of diabetes has been increasing dramatically in recent years, and diabetes remains a severe threat to global health. Herein, the updated viewpoint regarding the potential impact of gut microbiota on type 2 diabetes mellitus (T2DM) is discussed, and it is emphasized that standardized methods are essential for future studies.

Exertional heatstroke (EHS) is associated with strenuous physical activity in hot environments. The present study aimed to investigate dynamic changes of hepatic function indices in EHS patients and determine risk factors for death.

This single-center retrospective cohort study considered all patients with EHS admitted to the intensive care unit at the General Hospital of Southern Theater Command of PLA from October 2008 to May 2019. Data on general characteristics, organ function parameters, and the 90-day outcome of enrolled patients were collected. Hepatic indices were collected dynamically, and patients with acute hepatic injury (AHI) were identified by plasma total bilirubin (TBIL) ≥34.2 µmol/L and an international normalized ratio ≥1.5, or with any grade of hepatic encephalopathy.

In patients who survived, TBIL, alanine aminotransferase and aspartate aminotransferase were increased at 24 h, peaked at 2–3 days, and began to decrease at 5 days. In non-survivors, TBIL continuously increased post-admission. The area under the receiver operating characteristic curve for the prediction of mortality based on sequential organ failure assessment (SOFA) scores was 89.8%, and the optimal cutoff value was 7.5. Myocardial injury and infection were identified as independent risk factors for death in EHS patients with AHI.

In EHS patients, hepatic dysfunction usually occurred within 24 h. Patients with AHI had more severe clinical conditions, and significantly increased 90-day mortality rates. SOFA scores over 7.5, complicated with myocardial injury or infection, were found to be risk factors for death in EHS patients with AHI.

Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions.

Cell damage caused by ionizing radiation is very complex, and has generalities and specificities regarding different ionizing radiation types, characters and radiating methods. These specificities have a complicated molecular mechanism and result in various radiobiological responses; however, the details remain unclear. Ionizing radiation can impair biological macromolecules in cells, such as DNA, RNA, signal proteins. Moreover, different radiation doses, as well as linear energy transfer (LET), cause various effects. Cells show a certain adaptive response to low-dose ionizing radiation (LDIR) when they receive a secondary larger dose of radiation. By contrast, high-dose or LET ionizing radiation can lead a much more serious attack on macromolecules, especially to the molecules involved in gene mutations, DNA single strand breaks (SSBs), DNA double strand breaks (DSBs) and DNA damage repair responses. Under extreme conditions, such as space radiation during a space mission, a large amount of abnormally repaired DNA may vastly affect the cell signal transduction pathway, initiate apoptosis, uncontrolled cell proliferation, and even carcinogenesis. In this mini-review, the molecular mechanism of carcinogenesis induced by high-dose and LET ionizing radiation in cell lifespan is elucidated.

The relationship between quantitative magnetic resonance imaging (MRI) imaging features and gene-expression signatures associated with the recurrence of hepatocellular carcinoma (HCC) is not well studied.

In this study, we generated multivariable regression models to explore the correlation between the preoperative MRI features and Golgi membrane protein 1 (GOLM1), SET domain containing 7 (SETD7), and Rho family GTPase 1 (RND1) gene expression levels in a cohort study including 92 early-stage HCC patients. A total of 307 imaging features of tumor texture and shape were computed from T2-weighted MRI. The key MRI features were identified by performing a multi-step feature selection procedure including the correlation analysis and the application of RELIEFF algorithm. Afterward, regression models were generated using kernel-based support vector machines with 5-fold cross-validation.

The features computed from higher specificity MRI better described GOLM1 and RND1 gene-expression levels, while imaging features computed from lower specificity MRI data were more descriptive for the SETD7 gene. The GOLM1 regression model generated with three features demonstrated a moderate positive correlation (p<0.001), and the RND1 model developed with five variables was positively associated (p<0.001) with gene expression levels. Moreover, RND1 regression model integrating four features was moderately correlated with expressed RND1 levels (p<0.001).

The results demonstrated that MRI radiomics features could help quantify GOLM1, SETD7, and RND1 expression levels noninvasively and predict the recurrence risk for early-stage HCC patients.

Perivascular epithelioid cell neoplasms (PEComas) are a rare type of mesenchymal neoplasm and their preoperative diagnosis is challenging. In this study, we summarized the experience from a single medical center to study the examinations, clinical presentations, and pathological and histological characteristics of PEComas in the liver in order to optimize overall understanding of the diagnosis and treatment of these neoplasms.

We conducted a retrospective analysis to investigate the clinical and pathological characteristics as well as imaging presentations of 75 patients diagnosed with hepatic PEComa in The First Affiliated Hospital of Zhejiang University between April 2010 and April 2020.

Among the 75 patients, 52 were women, and the median age was 48 years. Most patients had no specific symptoms, and two were admitted to the hospital for a second time owing to relapse. All patients underwent surgical resection. Histologically, 38 patients had classical angiomyolipoma (AML) and 37 had epithelioid AML. The PEComas were accompanied by positive immunohistochemical expression of HMB45, Melan-A, and smooth muscle actin. Follow-up data were obtained from 47 of the total 75 patients, through October 2020. Two patients had metastasis after surgery.

AML is the most common type of hepatic PEComa. There are no specific symptoms of hepatic PEComa, and serological examinations and imaging modalities for accurate preoperative diagnosis are lacking. Epithelioid AML should be considered a tumor of uncertain malignant potential; however, the prognosis of PEComa after resection is promising.

Ras-related nuclear (RAN) protein is a small GTP-binding protein that is indispensable for the translocation of RNA and proteins through the nuclear pore complex. Recent studies have indicated that RAN plays an important role in virus infection. However, the role of RAN in hepatitis C virus (HCV) infection is unclear. The objective of this study was to investigate the role and underlying mechanisms of RAN in HCV infection.

Huh7.5.1 cells were infected with the JC1-Luc virus for 24 h and then were incubated with complete medium for an additional 48 h. HCV infection and RAN expression were determined using luciferase assay, quantitative reverse transcription-PCR and western blotting. Small interfering RNA was used to silence RAN. Western blotting and immunofluorescence were used to evaluate the cytoplasmic translocation of polypyrimidine tract-binding (PTB), and coimmunoprecipitation was used to examine the interaction between RAN and PTB.

HCV infection significantly induced RAN expression and cytoplasmic redistribution of PTB. Knockdown of RAN dramatically inhibited HCV infection and the cytoplasmic accumulation of PTB. Colocalization of RAN and PTB was determined by immunofluorescence, and a direct interaction of RAN with PTB was demonstrated by coimmunoprecipitation.

PTB in the host cytoplasm is directly associated with HCV replication. These findings demonstrate that the involvement of RAN in HCV infection is mediated by influencing the cytoplasmic translocation of PTB.

Coronaviruses are enveloped positive-strand RNA viruses that belong to the Coronaviridae family. According to the World Health Organization, this virus family has led to an international public health emergency. On the basis of existing clinical outcomes of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, it is hypothesized that quercetin can play a potential role in alleviating various symptoms of coronavirus disease 2019 (COVID-19) infection and serve as a supplement to other prescribed anti-viral drugs currently used for the treatment of COVID-19. Quercetin containing medicinal plants can become attractive agents for alleviating various side effects of COVID-19 infection and may potentially affect COVID-19 replication. In this article, we estimated quercetin content, using a RP-HPLC method, in various medicinal plants and propose the possible use of these extracts as health supplements for alleviating different clinical symptoms reported in COVID-19 patients. Also, this article describes the development of a dry powder inhaler (DPI) of quercetin using lactose as a carrier molecule. Moringa oleifera and Glycyrrhiza glabra extracts contain quercetin and can be potentially useful as health supplements for COVID-19 affected patients. The DPI of pure quercetin was found to supply a fine particle fraction of almost 40%, revealing the efficacy of the formulation in the discharge of quercetin into the lungs. Nevertheless, the suggested idea of using quercetin for alleviating side effects of COVID-19 infection does not have any direct experimental evidence. It is therefore believed that these therapeutic strategies may help clinicians to better treat COVID-19 affected patients.