Prognostic value of CD8+T cells related genes and exhaustion regulation of Notch signaling pathway in hepatocellular carcinoma.

Immunotherapy has emerged as the primary treatment modality for patients with advanced Hepatocellular carcinoma (HCC). However, its clinical efficacy remains limited, benefiting only a subset of patients, while most exhibit immune tolerance and face a grim prognosis. The infiltration of immune cells plays a pivotal role in tumor initiation and progression. In this study, we conducted an analysis of immune cell infiltration patterns in HCC patients and observed a substantial proportion of CD8+T cells. Leveraging the weighted gene co-expression network analysis (WGCNA), we identified 235 genes associated with CD8+T cell and constructed a risk prediction model. In this model, HCC patients were stratified into a high-risk and low-risk group. Patients in the high-risk group exhibited a lower survival rate, predominantly presented with intermediate to advanced stages of cancer, displayed compromised immune function, showed limited responsiveness to immunotherapy, and demonstrated elevated expression levels of the Notch signaling pathway. Further examination of clinical samples demonstrated an upregulation of the Notch1+CD8+T cell exhaustion phenotype accompanied by impaired cytotoxicity and cytokine secretion functions that worsened with increasing Notch activation levels. Our study not only presents a prognostic model but also highlights the crucial involvement of the Notch pathway in CD8+T cell exhaustion-a potential target for future immunotherapeutic interventions.

Effectiveness of adjuvant traditional Chinese medicine on macrovascular invasion in patients with hepatocellular carcinoma: a real-world propensity score-matched study.

The study aimed to investigate the potential of traditional Chinese medicine (TCM) in reducing the risk of macrovascular invasion (MVI) in Chinese patients with hepatocellular carcinoma (HCC). This retrospective analysis involved 2,267 HCC patients treated at our hospital. Propensity score (PS) matching was used to compare TCM users (n = 485) with non-users (n = 485) in terms of age, Barcelona Clinic Liver Cancer (BCLC) staging, type of treatment, and AFP. The impact of TCM on the hazard ratio (HR) of MVI was evaluated using a Cox multivariate regression model. The efficacy of TCM therapy on MVI was further examined using the log-rank test. The analysis revealed that TCM medication was a significant protective factor for MVI in HCC patients, as evidenced by the Cox analysis (adjusted HR = 0.496, 95% CI: 0.387-0.635, p < 0.001). After PS matching, the Kaplan-Meier curve demonstrated a lower occurrence rate of MVI in TCM users compared to non-users. The study findings suggest that TCM treatment has the potential to decrease the incidence of MVI in HCC patients, irrespective of etiology, BCLC staging, liver function, or treatment type. Notably, as the use of TCM increased, the percentage of MVI in patients showed a gradual decrease, indicating the potential of TCM therapy as a successful strategy for preventing MVI.

Asymmetric division of stem cells and its cancer relevance.

Asymmetric division is a fundamental process for generating cell diversity and maintaining the stem cell population. During asymmetric division, proteins, organelles, and even RNA are distributed unequally between the two daughter cells, determining their distinct cell fates. The mechanisms orchestrating this process are extremely complex. Dysregulation of asymmetric division can potentially trigger cancer progression. Cancer stem cells, in particular, undergo asymmetric division, leading to intra-tumoral heterogeneity, which contributes to treatment refractoriness. In this review, we delve into the cellular and molecular mechanisms that govern asymmetric division and explore its relevance to tumorigenesis.

TAMC-derived creatine sustains glioblastoma growth.

Tumor-associated myeloid cells (TAMCs) are the predominant immune population in glioblastoma (GBM), but the definite role of TAMCs in GBM tumorigenicity remains uncertain. In this issue of Cell Metabolism, Rashidi et al. identify a specific population of TAMCs surrounding hypoxic regions of GBM. These TAMCs provide creatine to nearby tumor cells to promote GBM progression.

A Nomogram Prognostic Model for Advanced Hepatocellular Carcinoma Based on the Interaction Between CD8+T Cell Counts and Age.

Objective: CD8+T cells are essential components of the adaptive immune system and are crucial in the body's immune system. This study aimed to investigate how the prognosis of patients with advanced hepatocellular carcinoma (HCC) was affected by their CD8+ T cell counts and age and established an effective nomogram model to predict the overall survival (OS). Methods: A total of 427 patients with advanced HCC from Beijing Ditan Hospital, Capital Medical University, were enrolled in this study and randomly divided into training and validation groups, with 300 and 127 individuals in each group, respectively. Cox regression analysis was used to screen for independent risk factors for advanced HCC, and the interactive relationship between CD8+T cells and patient age was examined to establish a nomogram prediction model. Results: Cox multivariate regression and interaction analyses indicated that tumor number, tumor size, aspartate aminotransferase (AST), C-reactive protein (CRP), relationship of CD8+T cell counts and age were independent predictors of 6-month OS in patients with advanced HCC, and the nomogram model was established based on these factors. The area under the receiver operating characteristic curve (AUC) of the nomogram model for predicting the 3-month, 6-month, and 12-month OS rates were 0.821, 0.802, and 0.756, respectively. Moreover, in clinical practice, patients with true-positive survival benefit more than true-positive death, therefore, we selected 25% as the clinical decision threshold probability based on probability density functions (PDFs) and clinical utility curves (CUCs), which can distinguish approximately 92% of patients who died and 37% of patients who survived. Conclusion: The nomogram model based on CD8+T cell counts and age accurately assessed the prognosis of patients with advanced HCC and suggested that high CD8+T cell levels are beneficial to the survival of patients with advanced HCC.

Biochar immobilized plant growth-promoting rhizobacteria enhanced the physicochemical properties, agronomic characters and microbial communities during lettuce seedling.

Spent mushroom substrate (SMS) is the by-products of mushroom production, which is mainly composed of disintegrated lignocellulosic biomass, mushroom mycelia and some minerals. The huge output and the lack of effective utilization methods make SMS becoming a serious environmental problem. In order to improve the application of SMS and SMS derived biochar (SBC), composted SMS (CSMS), SBC, combined plant growth-promoting rhizobacteria (PGPR, Bacillus subtilis BUABN-01 and Arthrobacter pascens BUAYN-122) and SBC immobilized PGPR (BCP) were applied in the lettuce seedling. Seven substrate treatments were used, including (1) CK, commercial control; (2) T1, CSMS based blank control; (3) T2, T1 with combined PGPR (9:1, v/v); (4) T3, T1 with SBC (19:1, v/v); (5) T4, T1 with SBC (9:1, v/v); (6) T5, T1 with BCP (19:1, v/v); (7) T6, T1 with BCP (9:1, v/v). The physicochemical properties of substrate, agronomic and physicochemical properties of lettuce and rhizospheric bacterial and fungal communities were investigated. The addition of SBC and BCP significantly (p < 0.05) improved the total nitrogen and available potassium content. The 5% (v/v) BCP addiction treatment (T5) represented the highest fresh weight of aboveground and underground, leave number, chlorophyll content and leaf anthocyanin content, and the lowest root malondialdehyde content. Moreover, high throughput sequencing revealed that the biochar immobilization enhanced the adaptability of PGPR. The addition of PGPR, SBC and BCP significantly enriched the unique bacterial biomarkers. The co-occurrence network analysis revealed that 5% BCP greatly increased the network complexity of rhizospheric microorganisms and improved the correlations of the two PGPR with other microorganisms. Furthermore, microbial functional prediction indicated that BCP enhanced the nutrient transport of rhizospheric microorganisms. This study showed the BCP can increase the agronomic properties of lettuce and improve the rhizospheric microbial community.

Primary non-response to antiviral therapy affects the prognosis of hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND AND AIM: Although antiviral treatments have been shown to affect the recurrence and long-term survival of patients with hepatocellular carcinoma (HCC) who have high viral loads, the effect of different responses to antiviral therapy on the clinical outcomes remains unclear. This study aimed to assess the effect of primary non-response (no-PR) to antiviral therapy on the survival or prognosis of patients with HCC with a high load of hepatitis B virus (HBV) DNA. METHODS: A total of 493 HBV-HCC patients hospitalized at Beijing Ditan Hospital of Capital Medical University were admitted to this retrospective study. Patients were divided into two groups based on viral response (no-PR and primary response). Kaplan-Meier (KM) curves were used to compare the overall survival of the two cohorts. Serum viral load comparison and subgroup analysis were performed. Additionally, risk factors were screened and the risk score chart was created. RESULTS: This study consisted of 101 patients with no-PR and 392 patients with primary response. In the different categories based on hepatitis B e antigen and HBV DNA, no-PR group had a poor 1-year overall survival (OS). In addition, in the alanine aminotransferase < 50 IU/L and cirrhosis groups, primary nonresponse was related to poor overall survival and progression-free survival. Based on multivariate risk analysis, primary non-response (hazard ratio (HR) = 1.883, 95% CI 1.289-2.751, P = 0.001), tumor multiplicity (HR = 1.488, 95% CI 1.036-2.136, P = 0.031), portal vein tumor thrombus (HR = 2.732, 95% CI 1.859-4.015, P < 0.001), hemoglobin < 120 g/L (HR = 2.211, 95% CI 1.548-3.158, P < 0.001) and tumor size ≥ 5 cm (HR = 2.202, 95% CI 1.533-3.163, P < 0.001) were independent risk factors for 1-year OS. According to the scoring chart, patients were divided into three risk groups (high-, medium-, and low-risk groups) with mortality rates of 61.7%, 30.5%, and 14.1%, respectively. CONCLUSIONS: The level of viral decline at 3 months post-antiviral treatment may predict the OS of patients with HBV-related HCC, and primary non-response may shorten the median survival time of patients with high HBV-DNA levels.

Targeting intratumor heterogeneity suppresses colorectal cancer chemoresistance and metastasis.

Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.

The imbalance between NKG2A and NKG2D expression is involved in NK cell immunosuppression and tumor progression of patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Immunosuppression in a tumor microenvironment is associated with enhanced tumor progression. Natural killer group 2 (NKG2) family proteins, including inhibitory receptors and activators, can be used as attractive targets for immunotherapy of immune checkpoint inhibition. We further explore the expression level prognostic value of NKG2A and NKG2D in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). METHODS: This study was a prospective study involving 92 patients with HBV-HCC, 16 patients with HBV-related liver cirrhosis, 18 patients with CHB, and 38 healthy donors. We analyzed the expression and related functions of NKG2A, NKG2D, and the NKG2A/NKG2D ratio in the peripheral blood of patients with HBV-HCC and analyzed tumor progression. The tissue samples from patients with HBV-HCC were further used for multiple immunofluorescence and immunohistochemistry. RESULTS: In patients with HBV-HCC with tumor progression, the ratio of NKG2A/NKG2D is higher in NK cells and T cells. The Kaplan-Meier survival curve showed that the NKG2A/NKG2D ratio on NK cells could predict tumor progression in patients with HBV-HCC, and that an increase in this ratio was associated with inhibition of NK cell function. The Cancer Genome Atlas (TCGA) database was further used to verify that the higher the NKG2A/NKG2D ratio, the shorter the progression-free survival of patients with HCC, and the more likely the immune function was suppressed. CONCLUSIONS: The imbalance between NKG2A and NKG2D of NK cells is involved in NK cell immunosuppression, and the increase of the NKG2A/NKG2D ratio is related to the tumor progression of HBV-HCC.

Mechanisms and network pharmacological analysis of Yangyin Fuzheng Jiedu prescription in the treatment of hepatocellular carcinoma.

OBJECTIVE: To identify the key drugs of Yangyin Fuzheng Jiedu prescription (YFJP) and investigate their therapeutic effects against hepatocellular carcinoma (HCC) and the potential mechanism using network pharmacology. METHODS: The H22 tumor-bearing mouse model was established. Thirty male BALB/c mice were divided randomly into five groups. The mice were orally treated with either disassembled prescriptions of YFJP or saline solution continuously for 14 days. The mice were weighed every 2 days during treatment and the appearance of tumors was observed by photographing. The tumor inhibition rate and the spleen and thymus indexes were calculated. Hematoxylin and eosin and immunohistochemical staining were performed to observe the histological changes and tumor-infiltrating lymphocytes. Cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. The proportion of CD8+ T cells and the expression of programmed cell death protein 1 (PD-1), T cell immunoglobulin domain and mucin domain-3 (Tim-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were analyzed using flow cytometry. The production of serum cytokines was detected using the Milliplex® MAP mouse high sensitivity T cell panel kit. The active components of the key drugs and HCC-related target proteins were obtained from the corresponding databases. The putative targets for HCC treatment were screened by target mapping, and potential active components were screened by constructing a component-target network. The interactive targets of putative targets were obtained from the STRING database to construct the protein-protein interaction network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed based on potential targets. The gene-gene inner and component-target-pathway networks were constructed and analyzed to screen the key targets. Western blotting was used to evaluate the protein expression of the key targets in the tumor-bearing mouse model. The binding activity of the key targets and compounds was verified by molecular docking. RESULTS: Among the three disassembled prescriptions of YFJP, the Fuzheng prescription (FZP) showed significant antitumor effects and inhibited weight loss during the treatment of H22 tumor-bearing mice. FZP increased the immune organ index and the levels of CD8+ and CD3+ T cells in the spleen and peripheral blood of H22 tumor-bearing mice. FZP also reduced the expression of PD-1, TIGIT, and TIM3 in CD8+ T cells and the production of IL-10, IL-4, IL-6, and IL-1ß. Network pharmacology and experimental validation showed that the key targets of FZP in the treatment of HCC were PIK3CA, TP53, MAPK1, MAPK3, and EGFR. The therapeutic effect on HCC was evaluated based on HCC-related signaling pathways, including the PIK3-Akt signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. GO enrichment analysis indicated that FZP positively regulated the molecular functions of transferases and kinases on the cell surface through membrane raft, membrane microarea, and other cell components to inhibit cell death and programmed cell death. CONCLUSION: FZP was found to be the key disassembled prescription of YFJP that exerted antitumor and immunoregulatory effects against HCC. FZP alleviated T cell exhaustion and improved the immunosuppressive microenvironment via HCC-related targets, pathways, and biological processes.

Establishment of Nomogram Model for Minimally Invasive Treatment of Small Hepatocellular Carcinoma Based on CD8+T Cell Counts.

Purpose: Minimally invasive treatment of small hepatocellular carcinoma (HCC) is the main way of treatment, which can cause the change of HCC immune microenvironment. T lymphocytes are an important part of the immune microenvironment and may be powerful predictors of prognosis. The purpose of this study was to explore the effect of T lymphocytes on the prognosis of HCC and establish a prognostic model. Patients and Methods: We conducted a retrospective study of 300 patients with small HCC and developed a clinical prediction model. The selection of modeling variables was performed by combining backward stepwise Cox regression using Akaike's Information Criteria (AIC) and the Least Absolute Shrinkage and Selection Operator (LASSO) regression. Establish a dynamic nomogram model to predict 1-, 2-, and 3-year overall survival (OS). Receiver operating characteristic curve (ROC curve) was used to verify the model discriminative ability, calibration curve was used to examine the model calibration ability, and decision curve analysis (DCA) was used to evaluate the clinical value. Results: The nomogram to predict the OS of small HCC includes the following four variables: aspartate aminotransferase (AST), alpha fetoprotein (AFP), C-reactive protein (CRP) and CD8+T cell counts, represented liver function index, tumor-related index, Inflammatory index and immune-related index, respectively. The area under the receiver operating characteristic curves (AUC) of predicting 1-, 2-, and 3-year overall survival were 0.846, 0.824 and 0.812, and the model was excellent in discrimination, calibration and clinical applicability. Conclusion: Our study provides a nomogram based on CD8+T cell counts that can help predict the prognosis of small HCC after minimally invasive treatment, which suggests that T lymphocytes can be used as a prognostic factor for HCC. Larger trials are needed to verify our results.

Immunomodulatory Effect of Traditional Chinese Medicine Combined with Systemic Therapy on Patients with Liver Cancer: A Systemic Review and Network Meta-analysis.

Objective: As immune combination therapy in the treatment of liver cancer made significant achievements, and the modulating effect of traditional Chinese medicine (TCM) on immunity gradually appeared. The main purpose of this study was to study the effect of different TCM combined with systemic therapy (ST) on immune regulation in patients with liver cancer, as well as the efficacy and safety of combined therapy, and to find the best combined application scheme by ranking. Methods: Nine electronic databases were searched from January 1, 2010, to November 12, 2021, to search for RCTs of TCM combined ST in the field of liver cancer for literature screening, quality evaluation and data extraction. STATA 15.0 and RevMan 5.3 software were used to conduct network meta-analysis to analyze and explore the significance of TCM combined ST in immune regulation, efficacy and safety in clinical application. The probability value of the surface under the cumulative ranking curve was used to rank the processing studied. Results: A total of 25 studies involving 2,152 participants were included in the network meta-analysis, including six traditional Chinese medicine injections and seven proprietary Chinese medicines. The results showed that Dahuang Zhechong Wan and Kangai injection combined with ST were the best choices for immune regulation. Moreover, the Huaier granule was the best choice to reduce vascular endothelial growth factors. Conclusion: For patients with liver cancer, TCM combined with ST was better than that of ST alone and can significantly improve the immune function of patients as well as the efficacy and safety of treatment. However, given the limited sample size and methodological quality of the trials that we included in our study, more centralized and randomized controlled trials with a large sample size are required to verify our findings.

Glycometabolism-related gene signature of hepatocellular carcinoma predicts prognosis and guides immunotherapy.

Hepatocellular carcinoma (HCC) is a severe cancer endangering human health. We constructed a novel glycometabolism-related risk score to predict prognosis and immunotherapy strategies in HCC patients. The HCC data sets were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, and the glycometabolism-related gene sets were obtained from the Molecular Signature Database. The least absolute contraction and selection operator (LASSO) regression model was used to construct a risk score based on glycometabolism-related genes. A simple visual nomogram model with clinical indicators was constructed and its effectiveness in calibration, accuracy, and clinical value was evaluated. We also explored the correlation between glycometabolism-related risk scores and molecular pathways, immune cells, and functions. Patients in the low-risk group responded better to anti-CTLA-4 immune checkpoint treatment and benefited from immune checkpoint inhibitor (ICI) therapy. The study found that glycometabolism-related risk score can effectively distinguish the prognosis, molecular and immune-related characteristics of HCC patients, and may provide a new strategy for individualized treatment.

Changes of serofast status in HIV negative asymptomatic neurosyphilis patients after treatment.

Serofast status after therapy in syphilis patients is a common phenomenon. A proportion of patients who have serofast status exhibit abnormal cerebrospinal fluid test results, which can be defined as asymptomatic neurosyphilis (ANS); however, it remains unclear whether ANS patients can achieve serological cure after anti-neurosyphilis treatment as quickly as other serofast patients. In this study, non-treponemal pallidum antibody serological responses were studied in ANS and serofast control patients, and the cumulative rates of serological cure in the ANS group were 9.6, 22.1, 25.9, and 30.2% in 3, 6, 9, and 12 month after treatment, which were statistically higher than those of the serofast control group. The change gap in serological cure rates was even more pronounced within 6 months after treatment, but the majority of ANS patients had no change in serofast status at 12 months after treatment. Our study indicates that anti-neurosyphilis therapy can partially change the serofast status. As serofast status cannot easily be changed even under neurosyphilis treatment in the majority of patients, the pathogenesis of this condition needs further research.

Dynamic Nomogram for Predicting Macrovascular Invasion of Patients with Unresectable Hepatocellular Carcinoma after Transarterial Chemoembolization.

Background: The purpose of our dynamic nomogram is to help clinical select hepatocellular carcinoma (HCC) patients with transarterial chemoembolization (TACE) treatment advantages. Methods: In total, 1,135 patients with HCC admitted to the Beijing Ditan Hospital of Capital Medical University were enrolled in this study. We used a 7:3 random splits between a training set (n=796) and a validation set (n=339). The dynamic nomogram was established by multiple logistic regression and evaluated by the C-indices. We generated calibration plots, decision analysis curve and a clinical impact curve to assess the clinical usefulness of the nomogram. Macrovascular invasion (MVI) incidence curves were constructed using the Kaplan-Meier method and compared by the log-rank test. Results: Multivariate logistic regression analysis identified six risk factors independently associated with MVI: BCLC staging B vs 0-A (hazard ratio (HR): 2.350, 95% confidence interval (CI): 1.222-4.531; P = 0.010) and staging C vs 0-A (HR: 3.652, 95% CI: 1.212-11.184; P = 0.022), treatment -TACE (HR: 2.693, 95%CI: 1.824-3.987; P < 0.001), tumour size ≥3cm (HR: 2.239, 95%CI: 1.452-3.459; P < 0.001), É£-GGT ≥60 (HR: 1.685, 95%CI: 1.100-2.579; P = 0.016), AFP ≥400 (HR: 2.681, 95%CI: 1.692-4.248; P < 0.001) and CRP ≥5 (HR: 3.560, 95%CI: 2.361-5.388; P < 0.001). The C-indices was 0.817 and 0.829 in the training and validation sets, respectively. The calibration curves showed good agreement between the predicted probability and the actual probability by the dynamic nomogram. Conclusions: Our study developed and validated a dynamic nomogram including BCLC staging, treatment modality, tumour size, and three laboratory parameters (É£-GGT, AFP and CRP). It has good discrimination and accuracy, and provides a simple and reliable basis for clinical decision-making.

The survival strength of younger patients in BCLC stage 0-B of hepatocellular carcinoma: basing on competing risk model.

BACKGROUND: The number of young patients with hepatocellular carcinoma (HCC) is increasing, but whether patients of different ages have a survival advantage is unclear. This study was conducted to investigate whether age differences in the Barcelona Clinic Liver Cancer (BCLC) classification system contribute to the long-term survival outcomes of patients with HCC. METHODS: A total of 1602 patients with HCC admitted to the Beijing Ditan Hospital was included in this study. Patients were divided into younger (≤45 years) and older (> 45 years) groups. Factors determining overall survival and progression-free survival were analyzed using univariate and multivariate analyses with the Kaplan-Meier method and Cox proportional hazard regression model. We calculated the cumulative incidence function using the Fine-Gray model. The effect of mortality on age was also estimated using a restricted cubic spline. RESULTS: After matching, overall survival and progression-free survival were significantly better in younger patients than in older patients with BCLC stage 0-B (p = 0.015 and p = 0.017, respectively). In BCLC stage 0-B, all-cause mortality increased with age and increased rapidly around the age of 40 years (non-linear, p < 0.05). In BCLC stages 0-B, HCC-related and non-HCC-related deaths significantly differed between younger and older individuals (p = 0.0019). CONCLUSION: In stage BCLC 0-B, age affects the long-term prognosis of patients.

Nomogram for prediction of long-term survival with hepatocellular carcinoma based on NK cell counts.

INTRODUCTION: Among all immune cells, natural killer (NK) cells play an important role as the first line of defense against tumor. The purpose of our study is to observe whether the NK cell counts can predict the overall survival of patients with hepatocellular carcinoma (HCC). METHODS: To develop a novel model, from January 2010 to June 2015, HCC patients enrolled in Beijing Ditan hospital were divided into training and validation cohort. Cox multiple regression analysis was used to analyze the independent risk factors for 1-year, 3-year and 5-year overall survival (OS) of patients with HCC, and the nomogram was used to establish the prediction model. In addition, the decision tree was established to verify the contribution of NK cell counts to the survival of patients with HCC. RESULTS: The model used in predicting overall survival of HCC included six variables (namely, NK cell counts, albumin (ALB) level, alpha-fetoprotein (AFP) level, portal vein tumor thrombus (PVTT), tumor number and treatment). The C-index of nomogram model in HCC patients predicting 1-year, 3-year and 5-year overall survival was 0.858, 0.788 and 0.782 respectively, which was higher than tumor-lymph node-metastasis (TNM) staging system, Okuda, model for end-stage liver disease (MELD), MELD-Na, the Chinese University Prognostic Index (CUPI) and Japan Integrated Staging (JIS) scores (p < 0.001). The decision tree showed the specific 5-year OS probability of HCC patients under different risk factors, and found that NK cell counts were the third in the column contribution. CONCLUSIONS: Our study emphasizes the utility of NK cell counts for exploring interactions between long-term survival of HCC patients and predictor variables.

Cytoplasmic NEAT1 Suppresses AML Stem Cell Self-Renewal and Leukemogenesis through Inactivation of Wnt Signaling.

As an essential component of paraspeckles, nuclear paraspeckle assembly transcript 1 (NEAT1) localizes in the nucleus, promoting progression of various malignant solid tumors. Herein, an adverse effect of NEAT1 is reported, showing that the short isoform, NEAT1_1 suppresses acute myeloid leukemia (AML) development. NEAT1_1 is downregulated in leukemia stem cells (LSCs) and its decreased expression correlates with recurrence in AML patients. It is demonstrated that NEAT1_1 suppresses leukemogenesis and LSC function but is dispensable for normal hematopoiesis. Mechanistically, NEAT1_1 is released from the nucleus into the cytoplasm of AML cells, regulated by transcription factor C/EBPß and nuclear protein NAP1L1. Cytoplasmic NEAT1_1 interacts with Wnt component DVL2 and E3 ubiquitin ligase Trim56, facilitates Trim56-mediated DVL2 degradation, and thus suppresses Wnt signaling. Collectively, the findings show NEAT1_1 is translocated from the nucleus to the cytoplasm and acts as a tumor suppressor in AML.

Antiviral Therapy Reduces Mortality in Hepatocellular Carcinoma Patients with Low-Level Hepatitis B Viremia.

BACKGROUND AND AIMS: Although antiviral treatment has been shown to reduce mortality in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients with high HBV-DNA levels, it is still unclear whether it is useful in reducing mortality in patients with low HBV-DNA levels. METHODS: A retrospective analysis of 756 HBV-associated HCC patients at the Beijing Ditan Hospital with HBV-DNA levels < 500 IU/mL was conducted between January 2008 and June 2017. Patients were divided into antiviral and non-antiviral groups based on whether they received nucleos(t)ide analogue (NA) treatment when they were diagnosed with HCC in our hospital for the first time. We used 1:4 frequency matching by age, gender, tumor size, Barcelona Clinic Liver Cancer (BCLC) staging, anti-tumor therapy, cirrhosis, diabetes, and hyperlipoidemia to compare the antiviral (n = 366) and non-antiviral (n = 100) groups. A Cox multivariate regression analysis was employed to evaluate the effects of NA therapy on the hazard ratio (HR), and the Kaplan-Meier survival curve was used to determine the mortality risk in patients with HCC. A Log rank test was performed to analyze the effects of NA therapy on the survival rate of patients with HCC. RESULTS: After propensity score matching, the 1-, 3-, and 5-year overall survival (OS) rates for the antiviral and non-antiviral groups were 82.5%, 68.6%, and 52.2%, and 61.0%, 51.0%, and 38.0%, respectively. The l-year progression-free survival (PFS) rates for the two groups were 68.0% and 47.0%, respectively. The OS of the antiviral group was significantly higher than that of the control group (P < 0.001, P = 0.001, and P = 0.013, respectively). The 1-year PFS for the antiviral group was also significantly better than that for the non-antiviral groups (P = 0.005). After adjusting for confounding prognostic factors in the Cox model, the HR of 5-year death after antiviral treatment was 0.721 (95% confidence interval [CI], 0.530-0.980, P = 0.037). Antiviral therapy is an independent protective factor for 5-year mortality in patients with HCC and low-level viremia. CONCLUSION: Antiviral therapy significantly reduced mortality in HCC patients with low HBV-DNA levels.

CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses in mice.

Initiation of T cell receptor (TCR) signaling involves the activation of the tyrosine kinase LCK; however, it is currently unclear how LCK is recruited and activated. Here, we have identified the membrane protein CD146 as an essential member of the TCR network for LCK activation. CD146 deficiency in T cells substantially impaired thymocyte development and peripheral activation, both of which depend on TCR signaling. CD146 was found to directly interact with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain. Interestingly, we found CD146 to be present in both monomeric and dimeric forms in T cells, with the dimerized form increasing after TCR ligation. Increased dimerized CD146 recruited LCK and promoted LCK autophosphorylation. In tumor models, CD146 deficiency dramatically impaired the antitumor response of T cells. Together, our data reveal an LCK activation mechanism for TCR initiation. We also underscore a rational intervention based on CD146 for tumor immunotherapy.