Prognostic and therapeutic potential of imbalance between PD-1+CD8 and ICOS+Treg cells in advanced HBV-HCC.

Over 50% of patients with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) are diagnosed at an advanced stage, which is characterized by immune imbalance between CD8+ T cells and regulatory T (Treg) cells that accelerates disease progression. However, there is no imbalance indicator to predict clinical outcomes. Here, we show that the proportion of CD8+ T cells decreases and Treg cells increases in advanced HBV-HCC patients. During this stage, CD8+ T cells and Treg cells expressed the coinhibitory molecule PD-1 and the costimulatory molecule ICOS, respectively. Additionally, the ratio between PD-1+CD8 and ICOS+Tregs showed significant changes. Patients were further divided into high- and low-ratio groups: PD-1+CD8 and ICOS+Tregs high- (PD-1/ICOShi) and low-ratio (PD-1/ICOSlo) groups according to ratio median. Compared with PD-1/ICOSlo patients, the PD-1/ICOShi group had better clinical prognosis and weaker CD8+ T cells exhaustion, and the T cell-killing and proliferation functions were more conservative. Surprisingly, the small sample analysis found that PD-1/ICOShi patients exhibited a higher proportion of tissue-resident memory T (TRM) cells and had more stable killing capacity and lower apoptosis capacity than PD-1/ICOSlo advanced HBV-HCC patients treated with immune checkpoint inhibitors (ICIs). In conclusion, the ratio between PD-1+CD8 and ICOS+Tregs was associated with extreme immune imbalance and poor prognosis in advanced HBV-HCC. These findings provide significant clinical implications for the prognosis of advanced HBV-HCC and may serve as a theoretical basis for identifying new targets in immunotherapy.

Identification of Methamphetamine Abusers Can Be Supported by EEG-Based Wavelet Transform and BiLSTM Networks.

Methamphetamine (MA) is a neurological drug, which is harmful to the overall brain cognitive function when abused. Based on this property of MA, people can be divided into those with MA abuse and healthy people. However, few studies to date have investigated automatic detection of MA abusers based on the neural activity. For this reason, the purpose of this research was to investigate the difference in the neural activity between MA abusers and healthy persons and accordingly discriminate MA abusers. First, we performed event-related potential (ERP) analysis to determine the time range of P300. Then, the wavelet coefficients of the P300 component were extracted as the main features, along with the time and frequency domain features within the selected P300 range to classify. To optimize the feature set, F_score was used to remove features below the average score. Finally, a Bidirectional Long Short-term Memory (BiLSTM) network was performed for classification. The experimental result showed that the detection accuracy of BiLSTM could reach 83.85%. In conclusion, the P300 component of EEG signals of MA abusers is different from that in normal persons. Based on this difference, this study proposes a novel way for the prevention and diagnosis of MA abuse.

Redox-Inducible Radiomimetic Photosensitizers Selectively Suppress Cancer Cell Proliferation by Damaging DNA through Radical Cation Chemistry.

Radiotherapy leverages ionizing radiation to kill cancer cells through direct and indirect effects, and direct effects are considered to play an equal or greater role. Several photosensitizers have been developed to mimic the direct effects of radiotherapy, generating radical cations in DNA models, but none has been applied in cellular studies. Here, we design a radiomimetic photosensitizer, producing DNA radical cations in cells for the first time. To reduce adverse effects, several redox-inducible precursors are prepared as cancer cells have elevated levels of GSH and H2O2. These precursors respond to GSH or H2O2, releasing the active photosensitizer that captures DNA abasic (AP) sites and generates DNA radical cations upon photolysis, without disrupting the redox state of cells. DNA radical cations migrate freely and are eventually trapped by H2O and O2 to yield DNA lesions, thus triggering DNA damage response. Our study suggests that direct effects of radiotherapy suppress cancer cell proliferation mainly by inducing G2/M phase cell cycle arrest, rather than promoting apoptosis. Synergistic effects of the precursor and chemotherapeutic agents are also observed in combination phototherapy. Beyond highlighting an alternative strategy for phototherapy, this proof-of-concept study affords a facile cellular platform to study the direct effects of radiotherapy.

Prognostic Value of High-Density Lipoprotein Cholesterol in Patients with Overt Hepatic Encephalopathy.

Overt hepatic encephalopathy (OHE), a serious complication of liver cirrhosis, is associated with alterations in lipid and lipoprotein metabolism. We evaluated the correlation between high-density lipoprotein cholesterol (HDL-C) levels and transplant-free (TF) mortality in patients with OHE. Patients with OHE admitted to Beijing Ditan Hospital between January 2010 and August 2016 (n = 821) and between September 2016 and December 2020 (n = 480) were included in the training and validation sets, respectively. Independent predictors were explored by a multivariate Cox regression analysis, and the area under the receiver operating characteristic curve (AUC) was used to assess the prognostic value of these factors. The prognostic value of HDL-C was good (AUC at 1 year: 0.745) and was equivalent to that of the Model for End-Stage Liver Disease (MELD) score (AUC at 1 year: 0.788). The optimal threshold values for HDL-C and MELD were 0.5 mmol/L and 17, respectively. The 1-year TF mortality rates in the low-risk (HDL-C ≥ 0.5 mmol/L and MELD < 17) and high-risk (HDL-C < 0.5 mmol/L and MELD ≥ 17) groups were 7.5% and 51.5% in the training set and 10.1% and 48.2% in the validation set, respectively. HDL-C level < 0.5 mmol/L and MELD score > 17 can facilitate the identification of high-risk patients and provide a basis for timely treatment.

Effects of adjuvant huaier granule therapy on survival rate of patients with hepatocellular carcinoma.

Objective: Clinical trials have reported that Huaier granule inhibits the recurrence of hepatocellular carcinoma (HCC) after resection. However, its efficacy in patients at different clinical stages of HCC remains unknown. We investigated the effects of Huaier granule on the 3-year overall survival (OS) rate of patients at different clinical stages. Design: This cohort study included 826 patients with HCC, screened between January 2015 and December 2019. The patients were divided into Huaier (n = 174) and control groups (n = 652), and the 3-year OS rates were compared between the two groups. To eliminate bias caused by confounding factors, propensity score matching (PSM) was performed. We used the Kaplan-Meier method to estimate OS rate and tested the difference using the log-rank test. Results: Multivariable regression analysis revealed that Huaier therapy was an independent protective factor for 3-year survival rate. After PSM (1:2), the Huaier and control groups comprised 170 and 340 patients, respectively. The 3-year OS rate was remarkably higher in the Huaier group than in the control group (adjusted hazard ratio [aHR]: 0.36; 95% confidence interval: 0.26-0.49; p < 0.001). The aHR for Huaier use for 3-12, 12-24, and >24 months was 0.48, 0.23, and 0.16, respectively, indicating a dose-response pattern. For the 3-12-, 12-24-, and >24-month groups, the 3-year OS rate was 54.1%, 68.6%, and 90.4%, respectively. Multivariate stratified analysis confirmed that the mortality risk in Huaier users was lower than that in non-Huaier users in most subgroups. Conclusion: Adjuvant Huaier therapy improved the OS rate in patients with HCC. However, these findings require further verification through prospective clinical studies.

Neutrophil-to-high-density-lipoprotein-cholesterol ratio and mortality among patients with hepatocellular carcinoma.

Background: Inflammatory responses and lipid metabolism disorders contribute to the development and prognosis of hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic value of lipid-related inflammatory parameters in patients with HCC. Methods: From January 2010 to June 2017, we enrolled 1,639 patients with HCC at Beijing Ditan Hospital. Multivariate Cox regression analysis and area under the receiver operating characteristic (AUC) analysis were used to evaluate and compare the predictability and reliability of high-density lipoprotein cholesterol (HDL-C), neutrophil-to-HDL-C ratio (NHR), monocyte-to-HDL-C ratio (MHR), and lymphocyte-to-HDL-C ratio (LHR) values. A restricted cubic spline was used to explore the association between the NHR and 3-year mortality in patients with HCC. Differences in survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. The results were validated in an internal cohort between July 2017 and October 2019 (n = 373). Results: After adjusting for confounding variables, NHR was independently associated with 3-year mortality, both as a continuous and categorical variable (both p < 0.05). The correlation between the mortality and the MHR and LHR was not statistically significant. The NHR showed a suitable prognostic value (AUC at 3 years: 0.740), similar to that of the Model for End-stage Liver Disease (MELD) (AUC at 3 years: 0.761). In the validation cohort, the AUC of the NHR was 0.734 at 3 years. The optimal cut-off values of NHR and MELD were 3.5 and 9, respectively. The 3-year survival rates in the low- (NHR < 3.5 and MELD <9) and high-risk (NHR ≥ 3.5 and MELD ≥9) groups were 81.8 and 19.4%, respectively, in the training cohort, and 84.6 and 27.5%, respectively, in the validation cohort. Conclusion: Baseline NHR is a promising prognostic parameter for mortality in patients with HCC and patients with NHR ≥ 3.5 and MELD ≥9 have a high mortality rate.

Development of a nomogram to predict the risk of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis on antivirals.

Objective: Patients with compensated hepatitis B-related cirrhosis receiving antivirals are at the risk of hepatocellular carcinoma (HCC). This study aimed to develop and validate a nomogram for predicting the incidence of HCC in patients with hepatitis-B related cirrhosis. Design: A total of 632 patients with compensated hepatitis-B related cirrhosis treated with entecavir or tenofovir between August 2010 and July 2018 were enrolled. Cox regression analysis was used to identify independent risk factors for HCC and a nomogram was developed using these factors. The area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analyses were used to evaluate the nomogram performance. The results were validated in an external cohort (n = 324). Results: In the multivariate analysis, age per 10 years, neutrophil-lymphocyte ratio > 1.6, and platelet count < 86×109/L were independent predictors of HCC occurrence. A nomogram was developed to predict HCC risk using these three factors (ranging from 0 to 20). The nomogram showed better performance (AUC: 0.83) than that of the established models (all P < 0.05). The 3-year cumulative HCC incidences in the low- (scores < 4), medium- (4-10), and high-risk (> 10) subgroups were 0.7%, 4.3%, and 17.7%, respectively, in the derivation cohort, and 1.2%, 3.9%, and 17.8%, respectively, in the validation cohort. Conclusion: The nomogram showed good discrimination and calibration in estimating HCC risk in patients with hepatitis-B related cirrhosis on antivirals. High-risk patients with a score > 10 points require close surveillance.

Dual-responsive probe and DNA interstrand crosslink precursor target the unique redox status of cancer cells.

Elevated GSH and H2O2 in cancer cells is sometimes doubted due to their contrary reactivities. Here, we construct a dual-responsive fluorescent probe to confirm the conclusion, and employ this to exploit a redox-inducible DNA interstrand crosslink (ICL) precursor. It crosslinks DNA upon activation by GSH and H2O2, affording an alternative dual-responsive strategy.

Association between probiotic therapy and the risk of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis.

Objective: Probiotics may offer cancer-prevention benefits, based on experimental investigation results. This study aimed to determine the potential association between probiotics and hepatocellular carcinoma (HCC) in patients with hepatitis B-related cirrhosis (HBC) receiving antiviral therapy. Design: This retrospective study included 1267 patients with HBC treated with entecavir or tenofovir between January 2013 and December 2017. The risk of developing HCC was compared between two cohorts of 449 probiotic users (taking a cumulative defined daily doses [cDDD] of ≥ 28) and 818 non-probiotic users (< 28 cDDD). To eliminate the bias caused by confounding factors, propensity score matching (PSM) was used. Results: On multivariate regression analysis, probiotic consumption was an independent protective factor for HCC occurrence. After PSM, the incidence of HCC was significantly lower in the probiotic users than that in the nonusers (adjusted hazard ratio [aHR]: 0.70, 95% confidence interval: 0.59-0.83, P < 0.001). The aHRs for probiotics with 28-89, 90-180, and >180 cDDD were 0.58, 0.28, and 0.12, respectively, indicating a dose-response pattern. In 28-89, 90-180, and >180 cDDD, the 3-year cumulative incidence of HCC was 8.7%, 4.7%, and 3.0%, respectively. A multivariate stratified analysis confirmed that the administration of probiotics could help patients. Conclusion: Adjuvant probiotic therapy may reduce the risk of HCC in patients receiving antiviral medication for HBC. However, further clinical research is required to confirm these findings.