Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

Humans ; COVID-19 ; Consensus ; SARS-CoV-2 ; China

Schizophrenia is a serious mental disease. The diagnosis of schizophrenia so far relies heavily on subjective evidence, including self-reported experiences by patients, manifestations described by relatives, and abnormal behaviors assessed by psychiatrists. The diagnosis, monitoring of the disease progression and therapy efficacy assessment are challenging due to the lack of established laboratory biomarkers. Based on the current literature, clinical consensus, guidelines, and expert recommendations, this review highlighted evidence-based potential laboratory biomarkers for the diagnosis of schizophrenia, including genetic biomarkers, neurotransmitters, neurodevelopmental-related proteins, and intestinal flora, and discussed the potential future directions for the application of these biomarkers in this field, aiming to provide an objective basis for the use of these biomarkers in the early and accurate diagnosis, treatment, and prognosis and rehabilitation assessment of schizophrenia.

Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-γ, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery.
Animals ; Carcinoma, Non-Small-Cell Lung ; immunology ; therapy ; Cell Line, Tumor ; ErbB Receptors ; immunology ; metabolism ; Female ; Humans ; Immunotherapy, Adoptive ; methods ; Lung Neoplasms ; immunology ; therapy ; Mice ; Mice, Inbred NOD ; Receptors, Chimeric Antigen ; immunology ; T-Lymphocytes ; immunology ; Xenograft Model Antitumor Assays

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma. Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research.
Adoptive Transfer ; methods ; Carcinoma, Hepatocellular ; immunology ; therapy ; Humans ; Immunotherapy, Adoptive ; methods ; Liver Neoplasms ; immunology ; therapy ; Lymphocytes, Tumor-Infiltrating ; cytology ; Randomized Controlled Trials as Topic ; Receptors, Chimeric Antigen ; T-Lymphocytes ; cytology

Objective To retrospectively analysis the clinical effect of temporary hemiepiphysiodesis for treatment of genu varus and valgus with pathologic physis in children.Methods All of 31 children (52 knees) were included in the study from January 2008 to December 2014,20 boys and 11 girls,the age at the time of surgery from 2 year 4 month to 13 year 4 month,mean 6 year 5 month.12 varus and 19 valgus,10 unilateral and 21 bilateral,41 femurs and 44 tibias.The Mechanichal Axis Deviation (MAD) was evaluated and the mechanical lateral distal femur angle (mLDFA) and medial proximal tibia angle (mMPTA) pre-operation and post-surgery was measured.Judging the efficacy with zone system for assessing mechanical axis based on Stevens,we think the results was satisfactory if the mechanical axis falls in zone ± 1 when removed the eightplate and other was unsatisfactory.We made statistical analysis of children who were corrected satisfactory and observed the change of the width and appearance of the physis.We also made the univariate analysis and Logistical multivariate regression analysis about sex,unilateral or bilateral,surgery age,femur or tibia,varus or valgus and severity of deformity to judge the influencing factors between satisfactory and unsatisfactory.We recorded the knee function and deformity recurrence at last follow up.Results The follow-up period was 2 year 6 month to 9 year 5 month,mean 4 year 1 month,44 knees (84.6％) were corrected satisfactory.The mean value of MAD at pre-surgery and at the time when the plate was removed were (-33.3t7.2) mm and (2.1 ±4.3) mm,mean mLDFA were 102.9°±4.9° and 85.3°±3.8°,mean mMPTA were 81.2°±3.4° and 90.5° ±4.4° in genu varus (21 knees);The meam value of MAD at pre-surgery and at the time when the plate was removed were 29.3±6.8 mm and-4.1±6.5 mm,and the mean mLDFA were 79.5o±5.7° and 88.1°±3.5°,mean mMPTA was 97.0°±4.3° and 87.1°±5.2° in genu valgus (23 knees),which were significant difference.There were 28 knees with physis width asymmetry in the 44 knees pre-operation and improved obviously after-surgery and the appearance became normally.8 knees corrected unsatisfactory included 2 varus and 6 valgus.The severity of deformity was a risk factor that affects efficacy with univariate analysis(t=5.124,P=0.000).Regarding the range of the age,we also did the logistic multivariate regression analysis with results showing that surgery age (OR=1.032) and se verity of deformity (OR=1.335) were related to the outcome.There were 8 knees in the 44 knees which had deformity recurrence and the rate was 19.5％ (8/41,3 knees excluded due to doing the limb lengthening surgery when removing the plate) at last follow up,and the knees function were normal.Conclusion Temporary hemiepiphysiodesis is a minimally invasive and effective method for treatment of genu varus or valgus with pathologic physis in children and could improve the appearance of the physis.The age at surgery and severity of deformity are the risk factors that affect efficacy.The pathological changes persisted could cause complication and deformity recurrence which need follow-up after removal of the plate.

Objective: To investigate the clinical effect and safety of Wanfeile in the treatment of erectile dysfunction (ED). METHODS: Totally 100 ED patients received oral Wanfeile at 100 mg, once every 3 days, for a course of 3 months. We compared the IIEF-5 scores of the patients before and after medication and among the patients with different degrees of ED. We evaluated the total clinical effectiveness of Wanfeile and analyzed adverse reactions. RESULTS: The total effectiveness rate of Wanfeile was 95.6%. All the patients showed significant improvement in the IIEF-5 scores after treatment as compared with the baseline (P <0.05). Adverse reactions were observed in 5 cases (5.50%), all mild and transient. CONCLUSIONS Wanfeile is safe and efficacious for the treatment of ED.
Double-Blind Method ; Drug Administration Schedule ; Erectile Dysfunction ; drug therapy ; Humans ; Male ; Phosphodiesterase 5 Inhibitors ; administration & dosage ; adverse effects ; Sildenafil Citrate ; administration & dosage ; adverse effects ; Surveys and Questionnaires ; Treatment Outcome