Hepatocellular carcinoma (HCC) is one of the fastest growing cancers in the world, ranking fourth among the causes of cancer-induced death in the world. At present, the field of HCC treatment is developing rapidly, and immunotherapy has been recognized as a promising treatment method, in which T cells play a key role in HCC immunotherapy. However, in the case of virus infection or in tumor microenvironment (TME), T cells will be continuously stimulated by antigens and then fall into the state of T cell exhaustion (Tex). This state will not only reduce the immunity of patients but also lead to poor efficacy of immunotherapy. Therefore, to deeply analyze the mechanism of Tex and to explore effective strategies to reverse Tex is the key point in the immunotherapy for HCC. This review aims to summarize the mechanism of Tex in HCC patients, and the current situation and shortcomings of drug research and development to reverse Tex at this stage, in order to provide theoretical basis for the optimization of immunotherapy regimen for HCC patients.
Humans ; Carcinoma, Hepatocellular/therapy* ; Liver Neoplasms/therapy* ; Immunotherapy/methods* ; T-Lymphocytes/immunology* ; Tumor Microenvironment/immunology* ; Animals ; T-Cell Exhaustion

Tumor necrosis factor-α(TNF-α)is involved in the regulation of multiple biological processes such as the proliferation,invasion,migration,and chemotherapy resistance of hepatocellular carcinoma(HCC)cells through TNF receptor-mediated signaling pathways.At the same time,TNF-α also plays a role in inducing the apoptosis of HCC cells.Some TNF-α inhibitors have been shown to inhibit the progression of HCC and prolong survival time.At present,the potential mechanism of action of TNF-α in HCC remains unclear,and exploration of the interaction between TNF-α and HCC can help to determine the potential therapeutic targets for HCC.This article summarizes the latest research advances in the mechanism of action of TNF-α in HCC and introduces the possibility of targeting TNF-α as a treatment method for HCC,in order to provide a theoretical basis for the prevention and treatment of liver cancer and drug research and development.

Objective To explore the independent risk factors that affect the overall survival(OS)of elderly patients with hepatocellular carcinoma(HCC,≥60 years old)and build a nomogram prediction model.Methods Clinical data of all elderly patients with HCC from the SEER database from 2005 to 2020 were downloaded from SEER database.In accordance with the inclusion and exclusion criteria,the screened patients were randomly assigned to a training group(70%)and a validation group(30%).The independent risk factors of elderly patients with HCC were determined by univariate and multivariate Cox regression analyses and further validated by Kaplan-Meier survival analysis.On the basis of the determined variables,nomograms were developed and verified to predict the OS of elderly patients with HCC at 6,12,and 24 months.The consistency index(C index),calibration curve,receiver's operating characteristic(ROC)curve,and area under curve(AUC)were used to evaluate the prediction efficiency and discrimination ability of the prediction model,and decision curve analysis(DCA)was used to evaluate the potential clinical application value of the nomogram.Results A total of 1134 elderly patients with HCC were included,with 793 in the training group and 341 in the validation group.Seven variables,including age,clinical grade,clinical stage,M stage,tumor size classification,and radiotherapy,were identified as independent prognostic factors of this population.The constructed nomogram shows excellent prediction performance,with C indices of 0.745 in the training group and 0.704 in the validation group.The AUC values of the training group at 6,12,and 24 months were 0.785,0.788,and 0.798,respectively,and those of the validation group were 0.780,0.725,and 0.607,respectively.The calibration curve shows good consistency from the predicted survival probability to the actual probability.The ROC curve and DCA show that the nomogram proposed in this study has good prediction ability.Conclusion Age,clinical grade,clinical stage,M stage,tumor size classification,and radiotherapy are important influencing factors for the survival of elderly patients with HCC.The prediction model of prognosis nomogram constructed in this study has good predictive value,and it can be used to predict the OS of elderly patients with HCC,which could be helpful for individualized survival assessment and clinical management of these patients.

Immune checkpoint inhibitors(ICI),an immunotherapy,have an important role in the treatment of various cancers.However,ICIs induce several immune-related adverse events(irAEs).Interleukin(IL)-6 is an important inflammatory factor that promotes cancer progres-sion and modulates the clinical application of ICIs through various mechanisms.Herein,we postulate possible mechanisms that are involved in the ICI-regulatory effects mediated by the expression of the cytokine interleukin-6(IL-6),elucidate the effect of IL-6 on checkpoint-block-ade therapy and irAEs,and summarize the role of IL-6 signaling-targeted interventions in ICIs efficacy and irAEs management.

Objective To analyze the cellular senescence pathways and their associated genes with bioinformatic analysis by screening differentially expressed genes(DEGs)during embryonic kidney development with aid of transcriptomics in order to explore the relationship between cellular senescence and embryonic kidney development.Methods After the kidney tissues from mice at embryonic age of 14.5 days(E14.5 group)and 18.5 days(E18.5 group)were collected,the kidney tissue structure was observed with periodic acid Schiff(PAS)staining,the expression profiles of the related genes during embryonic kidney development were analyzed by transcriptomics,and the changes in the genes related to cellular senescence were further analyzed with bioinformatics.The expression levels of target genes were verified by real-time quantitative fluorescence PCR and Western blotting.Results With the development of the embryonic kidney,the kidney structure gradually matured.The results of transcriptomic and bioinformatic analyses revealed that cellular senescence-related genes played an important role in the development of embryonic kidney.The mRNA and protein levels of Cdkn1a(P21),which was correlated with cellular senescence,were significantly higher(P＜0.05),while the mRNA levels of Skp2,Ccne1,Ccnd2,and Cdk4 were decreased in the E1 8.5 group than the E14.5 group(P＜0.05).Conclusion Obvious changes in the expression levels of cellular senescence-related genes are observed during embryonic kidney development,suggesting that cellular senescence plays an important role in the development.

Objective To explore the biomechanical responses of the cupula of the human semicircular canal to three basic rotational perception processes.Methods A one-dimensional visual semicircular canal model was successfully fabricated using three-dimensional printing and hydrogel physical cross-linking technologies,and the response deformation of the cupula was explored by applying constant angular velocity,constant angular acceleration,and sinusoidal oscillation stimulations.Results The time constant of the biomimetic semicircular canal model was stable at approximately 3 s and close to the human time constant.The displacement deformation of the ampullary cupula was proportional to the angular acceleration applied.Under sinusoidal oscillation stimulation of 0.07-5.00 Hz,the gain of the semicircular canal increased from 1.54 um/° rises to 42.34 μm/°,but the phase difference decreased from 109.72° to 11.27°.Conclusions The biomimetic semicircular canal model prepared in this study can accurately simulate the working mechanism of the human semicircular canal and is expected to play a role in mechanism research and disease diagnosis of the human vestibular semicircular canal.

As an active hydroxyanthraquinone ingredient, emodin is abundant in Chinese medicine herbs, such as Rheum palmatum, Polygonum cuspidatum and Polygonum multiflorum.Modern pharmacological studies have shown that emodin has a variety of pharmacological activities including anti-tumor, anti-inflammatory and immunoregulatory, antibacterial and anti-viral effects, myocardial protection, neuroprotection, renal protection, bone protection, antifibrosis and so on, which indicate its high medicinal value and broad application prospects.This article aims to summarize the progress in the pharmacological activity and mechanism of action of emodin published in domestic and international journals over the last 5 years and highlight the potential targets and molecular signaling pathways linked with emodin, so as to provide some clues and references for further development and clinical application of emodin.

Because the work of administrative and logistics personnel in public hospitals is difficult to quantify and evaluate, its performance reform is difficult. A large public hospital in Wuhan has explored and established a distribution incentive mechanism that combines department performance appraisal, individual classification and grading, and secondary distribution within the department. Taking into account the completion of performance appraisal indicators of the national tertiary public hospital in the department, the results of the institutional " Excellent Management Team Ranking" , personal job grades, working years and other factors, a relatively mature and operable system has been formed, which could provide reference for the performance reform of other hospitals.

Objective To establish a small liver cancer biobank with a standard operating procedure and the function of informationized management. Methods According to the inclusion and exclusion criteria, blood, tissue, and stool samples were collected from the patients with liver cancer who attended Liver Surgery Center, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, from August 2012 to December 2020 and signed the informed consent. In-and-out-of-storage management was performed based on the standard procedure for whole blood, serum, frozen tissue, paraffin-embedded tissue, and stool samples, and related clinical and follow-up data were collected. The frozen samples of liver cancer tissue and adjacent tissue in different years were randomly selected, and the concentration and completeness of total RNA were examined to ensure the quality of frozen samples stored in the biobank. Results The samples were collected from 4190 liver cancer patients who underwent surgery within a period of 101 natural months, and there were 41718 frozen tissue samples, 18950 paraffin-embedded tissue samples, 24389 whole blood samples, 20060 serum samples, and 5392 stool samples. The liver cancer patients had an age range of 13-88 years, and male patients accounted for 85.1%. The patients with hepatitis B accounted for 83.3%, and those with liver cirrhosis accounted for 73.5%. A standard operating procedure and an electronic data capture system were developed according to the collection, processing, storage, application, and informationized management of samples. Among the 18 frozen tissue samples randomly selected from the biobank, 16 samples had high RNA quality, which could meet the requirements of subsequent experiments. Conclusion A standardized and informationized biobank has been established for liver cancer, which provides high-quality samples for the basic research on liver cancer and helps to explore the research value of samples.

Objective:To investigate whether hepatitis B virus X protein (HBx) mediates the podocyte injury through reactive oxygen species (ROS) /nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) signaling pathway.Methods:HBx-overexpressing lentivirus was transfected into renal podocytes of mouse to mimic the pathogenesis of hepatitis B virus-associated glomerulonephritis. Podocytes were divided into the following five groups: blank control group (no special treatment), negative control group (transfected with control lentivirus), HBx overexpression group (transfected with HBx overexpression lentivirus), HBx overexpression+NLRP3 siRNA group (transfected with HBx overexpression lentivirus and NLRP3 siRNA), and HBx overexpression+ROS inhibitor group (transfected with HBx overexpression lentivirus and adding ROS inhibitor). The morphological changes of podocytes were observed with electron microscope. The generation of ROS was detected by dichlorodihydrofluorescein diacetate assay (DCFH-DA). Hoechst 33342 staining was used to observe the morphological and quantitative changes of podocyte nuclei. Enzyme-linked immunosorbent assay was used to detect caspase-1 activity, and the levels of lactate dehydrogenase, interleukin (IL)-1β and IL-18. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression levels of mRNA and protein of pyroptosis-related protein, such as NLRP3, apoptosis-associated speck-like protein containing card (ASC), caspase-1, IL-1β and IL-18. TUNEL staining and flow cytometer were used to detect the number of pyroptosis cells. Immunofluorescence staining was used to detect the expression levels of desmin and nephrin.Results:After successful infection of podocytes with HBx-overexpressing lentivirus, pyroptosis-related morphological changes in the cells were observed under electron microscope. The level of ROS in the HBx overexpression group was significantly higher compared to the negative control group ( P<0.05). Hoechst 33342 staining revealed condensed nuclei in the HBx overexpression group. TUNEL staining and flow cytometer demonstrated that podocytes underwent increased pyroptosis in the HBx overexpression group. The mRNA and protein expression levels of pyroptosis-related proteins such as NLRP3, ASC, caspase-1, IL-1β and IL-18 were up-regulated upon HBx overexpression (all P<0.05). Caspase-1 enzyme activity, lactate dehydrogenase and desmin expression levels were enhanced after HBx overexpression (all P<0.05). However, NLRP3 knockdown or addition of ROS inhibitors attenuated the pyroptosis and increased expression levels of pyroptosis-related proteins caused by HBx overexpression (all P<0.05). Conclusion:ROS/NLRP3 pathway plays an important role in HBx-induced podocyte pyroptosis.