Reassessing the Quantum Yield and Reactivity of Triplet-State Dissolved Organic Matter via Global Kinetic Modeling.

Measuring the quantum yield and reactivity of triplet-state dissolved organic matter (3DOM*) is essential for assessing the impact of DOM on aquatic photochemical processes. However, current 3DOM* quantification methods require multiple fitting steps and rely on steady-state approximations under stringent application criteria, which may introduce certain inaccuracies in the estimation of DOM photoreactivity parameters. Here, we developed a global kinetic model to simulate the reaction kinetics of the hv/DOM system using four DOM types and 2,4,6-trimethylphenol as the probe for 3DOM*. Analyses of residuals and the root-mean-square error validated the exceptional precision of the new model compared to conventional methods. 3DOM* in the global kinetic model consistently displayed a lower quantum yield and higher reactivity than those in local regression models, indicating that the generation and reactivity of 3DOM* have often been overestimated and underestimated, respectively. The global kinetic model derives parameters by simultaneously fitting probe degradation kinetics under different conditions and considers the temporally increasing concentrations of the involved reactive species. It minimizes error propagation and offers insights into the interactions of different species, thereby providing advantages in accuracy, robustness, and interpretability. This study significantly advances the understanding of 3DOM* behavior and provides a valuable kinetic model for aquatic photochemistry research.

Etiological characteristics of acute respiratory infections during the SARS-CoV-2 epidemic in Guizhou Province, China.

OBJECTIVE: Acute respiratory infections are a major global public health concern. However, there are few epidemiological studies investigating pathogens associated with respiratory tract infections in Guizhou Province, China. METHODS: We collected 17,850 blood samples from Guizhou Provincial People's Hospital between November 2018 and May 2023 to investigate the epidemiological characteristics of respiratory pathogens and their spread during the SARS-CoV-2 epidemic in Guizhou Province. RESULTS: We identified influenza virus and Mycoplasma pneumoniae as the predominant pathogens involved in acute respiratory infections in the study area. Immunoglobulin M positivity for respiratory syncytial virus, influenza virus, and M. pneumoniae showed a strong correlation with the clinical diagnosis of pneumonia. Seasonal epidemic patterns were observed for influenza A and B viruses. Following the SARS-CoV-2 outbreak, there was a significant decrease in the positive rates for most respiratory pathogens, particularly influenza A and B, Legionella pneumophila, and respiratory syncytial virus. CONCLUSION: This retrospective study contributes to the epidemiological evidence regarding respiratory pathogens in Guizhou Province, thereby enhancing the surveillance network for respiratory pathogens in China and providing valuable guidance for local hospitals.

UV-induced photodegradation of emerging para-phenylenediamine quinones in aqueous environment: Kinetics, products identification and toxicity assessments.

Substituted para-phenylenediamine quinones (PPD-quinones) are a class of emerging contaminants frequently detected in the aqueous environment. One of them, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q), was found to cause acute toxicities to aquatic species at extremely low environmental levels. The ubiquitousness and ecotoxicity of such pollutants underscore the importance of their transformation and elimination. In this work, we demonstrated effective removals of five PPD-quinones in aqueous environments under UV irradiation, with up to 94% of 6PPD-Q eliminated after a 40-min treatment. By applying high-resolution mass spectrometry (HRMS) non-targeted screening in combination with isotope labeling strategies, a total of 22 transformation products (TPs) were identified. Coupling with the time-based dynamic patterns, potential transformation mechanisms were identified as an •OH-induced photocatalysis reaction involving bond cleavage, hydroxylation, and oxidation. Computational toxicity assessment predicted lower aquatic toxicity of the TPs than their parent PPD-quinones. Our results in parallel evidenced an obvious reduction of PPD-quinones accompanied by the presence of their TPs in the effluent after UV disinfection in real municipal wastewater. This work builds a comprehensive understanding of the fate, transformation products, and related toxicological characteristics of emerging PPD-quinone contaminants in the aqueous environment.

Identification of SGMS2 as a molecule involved in natural killer cell recruitment and its in-deep analysis in the liver cancer microenvironment: Evidence from large populations cohort.

BACKGROUND: Liver cancer, a common malignancy within the digestive system, presents with a particularly grim prognosis. Within the immune microenvironment, the role of natural killer (NK) cells in liver cancer remains unclear. METHODS: We sourced data on clinical parameters and gene expressions for liver cancer patients from The Cancer Genome Atlas Program database and carried out all analyses using R software and its relevant codes. RESULTS: In our research, we delved into the genes intertwined with NK cells in hepatocellular carcinoma (HCC). Leveraging the QUANTISEQ and MCPCOUNTER algorithms to quantify NK cells, we spotlighted genes vital to the recruitment of NK cells. Among these genes, GDE1, WDFY3, DNAJB14, PKD2, DGAT2, SGMS2 and MKNK2 showed a strong correlation with patient outcomes. We also mapped out the single-cell expression trajectories of these genes within the HCC milieu. From our findings, SGMS2 emerged as a key gene warranting further scrutiny. Our in-depth analysis of SGMS2 shed light on its influence over specific biological pathways, its contribution to the immune landscape and its role in genomic instability within HCC. Drawing from this, we formulated a predictive model rooted in SGMS2-associated genes. This model showcased remarkable precision across both training and validation cohorts. CONCLUSIONS: Overall, our investigation underscored the profound implications of SGMS2, a gene pivotal to NK cell infiltration, in the landscape of HCC, thereby positioning it as a potential linchpin in oncological strategies.

Photo-transformation of wastewater effluent organic matter reduces the formation potential and toxicity of chlorinated disinfection byproducts.

Sunlight exposure can degrade and transform discharged wastewater effluent organic matter (EfOM) in aquatic systems, potentially enhancing the feasibility of reusing wastewater for drinking purposes. However, there remains a lack of comprehensive understanding regarding the sunlight-induced changes in the molecular-level composition, characteristics, and chlorine reactivity of EfOM. Herein, we investigated the impact of sunlight on the optical properties, chemical composition, and formation of disinfection byproducts of EfOM using multiple spectroscopic analyses, high-resolution mass spectrometry, chlorination experiments, and in vitro bioassays. Upon natural sunlight exposure, we observed significant decreases in ultraviolet-visible absorbance and fluorescence intensity of EfOM, indicating the destruction of chromophores and fluorophores. Photolysis generally yields products with lower molecular weight and aromaticity, and with higher saturation and oxidation levels. Moreover, a shift within the EfOM from condensed aromatic-like compounds to tannin-like components was observed. Furthermore, sunlight exposure reduced the reactivity of EfOM toward the formation of trihalomethanes and haloacetonitriles during chlorination, while there was a slight increase in the specific formation potential of haloketones. Importantly, the disinfection byproducts resulting from chlorination of the irradiated EfOM exhibited reduced microtoxicity. Overall, this study provides new insights into alterations in EfOM under sunlight exposure and aids in predicting the health risks of effluent discharge in water environments.

Modeling cross-talk of RNA modification enzymes reveals tumor microenvironment-associated clinical significance and immunotherapy prediction in hepatobiliary malignancy.

RNA modification includes four main types, N6-methyladenosine, N1-methyladenosine, alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing, involving 41 enzymes that serve as "writers", "readers" and "erasers". By collecting RNA modifying enzyme information in 1759 hepatobiliary malignancy (HBM) samples from 11 datasets, an RNA modification HBM Score (RH_score) was established based on unsupervised cluster analysis of RNA modification-associated differentially expressed genes (DEGs). We identified the imbalanced expression of 41 RNA modification enzymes in HBM, which was scientifically categorized into two groups: RH_Score high and RH_Score low. A high RH_Score was associated with a worse prognosis and more immature immune cells in the tumor microenvironment (TME), while a low RH_Score was associated with a better prognosis and more mature immune cells in the TME. Further analysis using single-cell databases showed that the high RH_Score was immune exhaustion in the TME. RH_Score was involved in transcriptional regulation and post-transcriptional events in HBM. Additionally, resistant and sensitive drugs were selected based on RNA modification, and anti-PD-L1 therapy responded better with low RH_Score. In conclusion, our study comprehensively analyzes RNA modification in HBM, which induces TME changes and transcriptional and posttranscriptional events, implying potential guiding significance in prognosis prediction and treatment options.

Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma.

Understanding the details of metabolic reprogramming in hepatocellular carcinoma (HCC) is critical to improve stratification for therapy. Both multiomics analysis and cross-cohort validation were performed to investigate the metabolic dysregulation of 562 HCC patients from 4 cohorts. On the basis of the identified dynamic network biomarkers, 227 substantial metabolic genes were identified and a total of 343 HCC patients were classified into 4 heterogeneous metabolic clusters with distinct metabolic characteristics: cluster 1, the pyruvate subtype, associated with upregulated pyruvate metabolism; cluster 2, the amino acid subtype, with dysregulated amino acid metabolism as the reference; cluster 3, the mixed subtype, in which lipid metabolism, amino acid metabolism, and glycan metabolism are dysregulated; and cluster 4, the glycolytic subtype, associated with the dysregulated carbohydrate metabolism. These 4 clusters showed distinct prognoses, clinical characteristics and immune cell infiltrations, which was further validated by genomic alterations, transcriptomics, metabolomics, and immune cell profiles in the other 3 independent cohorts. Besides, the sensitivity of different clusters to metabolic inhibitors varied depending on their metabolic features. Importantly, cluster 2 is rich in immune cells in tumor tissues, especially programmed cell death protein 1 (PD-1)-expressing cells, which may be due to the tryptophan metabolism disorders, and potentially benefiting more from PD-1 treatment. In conclusion, our results suggest the metabolic heterogeneity of HCC and make it possible to treat HCC patients precisely and effectively on specific metabolic characteristics.

Dual role of soil-derived dissolved organic matter in the sulfamethoxazole oxidation by manganese dioxide.

Manganese dioxide (MnO2) can mediate organic pollutant oxidation in aquatic environments, which has been reported to be inhibited or promoted by dissolved organic matter (DOM) in different studies. It remains unresolved why conflicting results have been observed and whether such results depend on the type and concentration of DOM. Here, we used three types of well-characterized DOM derived from soil heated at 50, 250, or 400 °C (DOM_50, DOM_250, and DOM_400, respectively) to evaluate the impacts of DOM type and concentration and environmental pH on MnO2-mediated oxidation of sulfamethoxazole, a widely detected and ecotoxic emerging pollutant. We observed that the degradation rate of sulfamethoxazole was possibly promoted by DOM_250 (pH 6‒8), while it was generally inhibited by DOM_50 and DOM_400. Furthermore, it was initially inhibited and then promoted with increasing DOM concentrations and was consistently less inhibited at a higher pH. The inter-DOM variations of sulfamethoxazole degradation could be explained by the more enriched polyphenolics in DOM_250 than in DOM_50 and DOM_400, whereas the weak promoting effect of DOM_400 indicates that high DOM aromaticity may not necessarily promote pollutant degradation. Our results reconcile the debate on the role of DOM in the oxidation of sulfamethoxazole by MnO2 and highlight the decisiveness of the molecular composition and concentration of DOM and the reaction pH in the overall promoting or inhibiting role of DOM.

A Novel Thoracoabdominal Aorta CTA-based Nomogram Model to Identify Ideal Candidates for Transradial Approach Chemoembolization in Patients with Liver Cancer.

Background: High technical complexity limits the wide use of transradial approach (TRA) chemoembolization in the management of liver cancer. We sought to construct a thoracoabdominal aorta CTA-based nomogram model to identify ideal candidates for TRA chemoembolization in patients with liver cancer. Methods: Patients who had received thoracoabdominal aorta CTA before TRA chemoembolization from 2018 to 2020 were retrospectively enrolled and randomly divided into a training set and a validation set. The clinical characteristics and CTA features were collected to build a clinical model. Univariate and multivariate analyses were used to identify significant clinical-radiological variables. A CTA-based nomogram model was constructed by using multivariate logistic regression analysis. The predictive performance, as well as discrimination efficacy of the model, was evaluated by ROC analysis and calibration plot. Results: Vascular variation (P=0.028), Myla classification (P=0.030), length from left subclavian artery to the left subclavian artery (P=0.017), and angle between common hepatic artery and abdominal aorta (P=0.017) were identified as important factors associated with the technical complexity of TRA chemoembolization, indicated by fluoroscopy time of the total procedure. The CTA-based nomogram model was established by these abovementioned variables, which demonstrated good predictive ability in both the training cohort (AUC=0.929) and validation cohort (AUC= 0.769), with a high C-index of 0.928 and 0.827 respectively. Moreover, satisfactory calibrations were confirmed by the Hosmer-Lemeshow test with P values of 0.618 and 0.299 in the training cohort and validation cohort. Conclusion: Our study constructs a novel CTA-based nomogram, which can serve as a useful tool to identify ideal candidates for TRA chemoembolization in patients with liver cancer.

The E3 ubiquitin ligase SOCS-7 reverses immunosuppression via Shc1 signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies and is the third leading cause of tumor-related mortality worldwide. Despite advances in HCC treatment, diagnosis at the later stages, and the complex mechanisms relating to the cause and pathogenesis, results in less than 40% of HCC patients being eligible for potential therapy. Prolonged inflammation and resulting immunosuppression are major hallmarks of HCC; however, the mechanisms responsible for these processes have not been clearly elucidated. In this study, we identified SOCS-7, an inhibitor of cytokine signaling, as a novel regulator of immunosuppression in HCC. We found that SOCS-7 mediated E3 ubiquitin ligase activity on a signaling adaptor molecule, Shc1, in Huh-7 cells. Overexpression of SOCS-7 reduced the induction of immunosuppressive factors, TGF-ß, Versican, and Arginase-1, and further reduced STAT3 activation. Furthermore, using an in vivo tumor model, we confirmed that SOCS-7 negatively regulates immunosuppression and inhibits tumor growth by targeting Shc1 degradation. Together, our study identified SOCS-7 as a possible therapeutic target to reverse immunosuppression in HCC.

Polycyclic aromatic hydrocarbon occurrence in forest soils in response to fires: a summary across sites.

Forest fires are important sources of polycyclic aromatic hydrocarbons (PAHs) in soils. However, factors controlling PAH production in soils subjected to fires in different sites are poorly understood. Here, we analyzed 143 sets of previously published data to evaluate the concentrations and composition profiles of PAHs in ash and soils associated with forest fires and to assess the impacts of soil depth, fire intensity, post-fire duration, and vegetation type on their occurrence. Compared to unburned soils, the total PAH concentrations increased by 205% (95% confidential interval of 152-269%; n = 136) in soils associated with fires. This increase surpassed that of PAH toxic equivalents (73%) because fires produce dominantly low-ring PAHs with relatively low toxicity. PAH concentrations in fire-impacted sites increased by 684%, 258%, and 155% in the ash, 0-5 cm soil depth interval, and >5 cm soil depth interval, respectively. The increases in PAH concentrations associated with mild-intensity fires (412%) exceeded those associated with moderate-intensity (163%) and high-intensity (168%) fires, which is possibly due to pyromineralization or volatilization of organic matters at high burning temperatures. These increases were highest within a month after the fire (280%), gradually decreasing over time, and showed no significant difference compared to the reference sites after 24 months. The concentration increases exhibit no major difference between various vegetation types (broad-leaved forest vs. coniferous forest vs. shrub). Assessments reveal that exposure to post-fire soil PAHs involves no serious human health risk. However, potential adverse effects of soil PAHs on other organisms (e.g., microbes and plants) and ecosystems should be further examined. The present study highlights the strong impacts of soil depth, fire intensity, and post-fire duration, and the relatively weak impact of the vegetation type on PAH concentrations in soils associated with fires in different areas.

Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization.

Background: Transarterial chemoembolization (TACE) stands for the most commonly utilized therapy for hepatocellular carcinoma (HCC) worldwide. This study was to explore the potential predictive and prognostic roles of LAG-3 and PD-L1 as serum biomarkers in HCC patients underwent TACE treatment. Methods: A total of 100 HCC patients receiving TACE as well as 30 healthy controls were enrolled in the study. Serum LAG-3 and PD-L1 levels were determined at baseline and 3 day after TACE using enzyme-linked immunosorbent assay (ELISA). Results: We found serum levels of LAG-3 and PD-L1 were significantly elevated in HCC patients compared with healthy controls. Interestingly, patients with low pre-TACE and post-TACE levels of LAG-3 but not PD-L1 had a high probability of achieving an objective response (OR) after TACE treatment. Additionally, high pre-TACE LAG-3 level was correlated with poor disease outcome, and the patients with both high serum LAG-3 and PD-L1 level had the shorter overall survival (OS) than patients who are either PD-L1 or LAG-3 high or both PD-L1 and LAG-3 low. High pre-TACE serum LAG-3 level was positively associated with more cirrhosis pattern, advanced BCLC stage, pre-TACE alanine aminotransferase (ALT) level, and pre-TACE aspartate aminotransferase (AST) level. Furthermore, in 50 patients who underwent TACE, the serum LAG-3 level was significantly decreased at 3 day after TACE. Conclusion: Both pre-TACE and post-TACE serum LAG-3 levels could serve as powerful predictors for tumor response of TACE, and high pre-TACE serum LAG-3 level was an indicator for poor prognosis in HCC.

Tumor Mutation Burden-Associated LINC00638/miR-4732-3p/ULBP1 Axis Promotes Immune Escape via PD-L1 in Hepatocellular Carcinoma.

Tumor mutation burden (TMB) is associated with immune infiltration, while its underlying mechanism in hepatocellular carcinoma (HCC) remains unclear. A long noncoding RNA (lncRNA)-related competitive endogenous RNA (ceRNA) network can regulate various tumor behaviors, and research about its correlation with TMB and immune infiltration is warranted. Data were downloaded from TCGA and ArrayExpress databases. Cox analysis and machine learning algorithms were employed to establish a lncRNA-based prognostic model for HCC. We then developed a nomogram model to predict overall survival and odds of death for HCC patients. The association of this prognostic model with TMB and immune infiltration was also analyzed. In addition, a ceRNA network was constructed by using DIANA-LncBasev2 and the starBase database and verified by luciferase reporter and colocalization analysis. Multiplex immunofluorescence was applied to determine the correlation between ULBP1 and PD-L1. An eight-lncRNA (SLC25A30-AS1, HPN-AS1, LINC00607, USP2-AS1, HCG20, LINC00638, MKLN1-AS and LINC00652) prognostic score model was constructed for HCC, which was highly associated with TMB and immune infiltration. Next, we constructed a ceRNA network, LINC00638/miR-4732-3p/ULBP1, that may be responsible for NK cell infiltration in HCC with high TMB. However, patients with high ULBP1 possessed a poorer prognosis. Using multiplex immunofluorescence, we found a significant correlation between ULBP1 and PD-L1 in HCC, and patients with high ULBP1 and PD-L1 had the worst prognosis. In brief, the eight-lncRNA model is a reliable tool to predict the prognosis of HCC patients. The LINC00638/miR-4732-3p/ULBP1 axis may regulate immune escape via PD-L1 in HCC with high TMB.

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors.

The discovery that mutations in the EGFR gene are detected in up to 50% of lung adenocarcinoma patients, along with the development of highly efficacious epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of this frequently occurring lung malignancy. Indeed, the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy. Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). The first-generation TKIs include erlotinib, gefitinib, lapatinib, and icotinib; the second-generation ErbB family blockers include afatinib, neratinib, and dacomitinib; whereas osimertinib, approved by the FDA on 2015, is a third-generation TKI targeting EGFR harboring specific mutations. Compared with the first- and second-generation TKIs, third-generation EGFR inhibitors display a significant advantage in terms of patient survival. For example, the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months. Unfortunately, however, like other targeted therapies, new EGFR mutations, as well as additional drug-resistance mechanisms emerge rapidly after treatment, posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance. In this review, we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance. We also discuss the current status of fourth-generation EGFR inhibitors, which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.

Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway.

BACKGROUND: Recurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumor-repopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance. METHODS: Suppression of TRCs may thus be an effective therapeutic strategy for treating this fatal disease. We evaluated the pharmacology and mechanism of sulfarotene, a new type of synthetic retinoid, on the cancer stem cell-like properties of HCC TRCs, and assessed its preclinical efficacy in models of HCC patient-derived xenografts (PDXs). RESULTS: Sulfarotene selectively inhibited the growth of HCC TRCs in vitro and significantly deterred TRC-mediated tumor formation and lung metastasis in vivo without apparent toxicity, with an IC50 superior to that of acyclic retinoid and sorafenib, to which the recurrent HCC exhibits significant resistance at advanced stage. Sulfarotene promoted the expression and activation of RARα, which down-regulated SOS2, a key signal mediator associated with RAS activation and signal transduction involved in multiple downstream pathways. Moreover, sulfarotene selectively inhibited tumorigenesis of HCC PDXs with high expression for SOS2. CONCLUSIONS: Our study identified sulfarotene as a selective inhibitor for the TRCs of HCC, which targets a novel RARα-SOS2-RAS signal nexus, shedding light on a new, promising strategy of target therapy for advanced liver cancer.

Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway.

OBJECTIVE: Protein convertase subtilisin/Kexin type 9 (PCSK9) has been found to be closely associated with the occurrence and development of numerous tumors. However, the precise role of PCSK9 and its relationship to the development of hepatocellular carcinoma (HCC) remain largely unknown. This study aimed to clarify these issues. METHODS: The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by the quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemical analyses, and the effects of PCSK9 expression on HCC cell biological traits were investigated by overexpressing and downregulating PCSK9 expression in vivo and in vitro. Additionally, the mechanism by which PCSK9 mediated dissociation of glutathione S-transferase Pi 1 (GSTP1) dimers and phosphorylation of the Jun N-terminal kinase (JNK) pathway components were investigated. RESULTS: PCSK9 expression levels were significantly lower in HCC tissues than in adjacent non-tumor samples. In vivo and in vitro experiments suggested that PCSK9 inhibited HCC cell proliferation and metastasis. Further analysis showed that PCSK9 interacted with GSTP1 and promoted GSTP1 dimer dissociation and JNK signaling pathway inactivation in HCC cells. Moreover, the relationships between PCSK9 protein expressions and clinical outcomes were investigated. The PCSK9-lo group displayed a significantly shorter overall survival (OS; median OS: 64.2 months vs. 83.2 months; log-rank statistic: 4.237; P = 0.04) and recurrence-free survival (RFS; median RFS: 26.5 months vs. 46.6 months; log-rank statistic: 10.498; P = 0.001) time than the PCSK9-hi group. CONCLUSIONS: PCSK9 inhibited HCC cell proliferation, cell cycle progression, and apoptosis by interacting with GSTP1 and suppressing JNK signaling, suggesting that PCSK9 might act as a tumor suppressor and be a therapeutic target in HCC patients.

Albumin-to-alkaline phosphatase ratio as a predictor of tumor recurrence and prognosis in patients with early-stage hepatocellular carcinoma undergoing radiofrequency ablation as initial therapy.

OBJECTIVE: Albumin-to-alkaline phosphatase ratio (AAPR), a newly developed blood biomarker, has been reported to have prognostic value in several types of cancer. This study aimed to investigate the predictive value of AAPR in patients with early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) as initial therapy. METHODS: This retrospective study analyzed 445 patients with newly diagnosed HCC undergoing RFA as initial therapy. A series of survival analyses were performed to evaluate the prognostic value of AAPR. Univariate and multivariate analyses were performed to identify independent prognostic factors. An AAPR-based nomogram was constructed, and its predictive performance was validated. RESULTS: Patients with a low AAPR had a significantly reduced recurrence-free survival (RFS) and overall survival (OS) compared with those with a high AAPR. AAPR was found to be an independent prognostic indicator and showed superior discrimination efficacy than other liver function indices. The AAPR-based nomogram had a concordance index value of 0.72 (95% confidence interval [CI]: 0.65-0.79) in the training cohort and 0.72 (95% CI: 0.63-0.81) in the validation cohort, which significantly outperformed other existing staging systems. CONCLUSIONS: AAPR serves as a promising indicator of prognosis in patients with early-stage HCC undergoing RFA. The AAPR-based nomogram might contribute to individualized prognosis prediction and clinical decision making.

Sulfiredoxin-1 is a promising novel prognostic biomarker for hepatocellular carcinoma.

Identifying novel prognostic biomarkers for hepatocellular carcinoma (HCC) and then, develop an effective individualized treatment strategy remain extremely warranted. The prognostic role of sulfiredoxin-1(SRXN1), an antioxidant enzyme, remains unknown in HCC. This study aimed to explore the prognostic implications of SRXN1 in HCC patients after partial hepatectomy. The expression of SRXN1 in HCC and normal tissue were analyzed using the patients from the public databases and Zhongshan Hospital. The Cox regression, Kaplan-Meier survival analysis, and time-dependent receiver operating characteristic curves were performed to identify the predictive role of SRXN1 expression on HCC patients. A prognostic nomogram based on SRXN1 expression was constructed and validated to further confirm the predictive power of SRXN1 as a prognostic biomarker. Finally, functional enrichment analysis and protein-protein interaction network analysis of SRXN1 and its associated genes were conducted. The results showed that SRXN1 was upregulated in HCC samples compared with the normal liver tissues. Patients with SRXN1 upregulation had shorter survival time. SRXN1 overexpression was significantly correlated with advanced clinicopathological parameters. The prognostic nomogram based on SRXN1 expression was proved to be more accurate than routine staging systems for the prediction of overall survival. Protein-protein interaction network analysis demonstrated the first neighbor genes of SRXN1 mainly participated in response to oxidative stress. In brief, SRXN1 could be a prognostic biomarker for the management of HCC.

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis.

BACKGROUND: Fibrinogen-like protein 1 (FGL1)-Lymphocyte activating gene 3 (LAG-3) pathway is a promising immunotherapeutic target and has synergistic effect with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1). However, the prognostic significance of FGL1-LAG-3 pathway and the correlation with PD-L1 in hepatocellular carcinoma (HCC) remain unknown. METHODS: The levels of LAG-3, FGL1, PD-L1 and cytotoxic T (CD8+T) cells in 143 HCC patients were assessed by multiplex immunofluorescence. Associations between the marker's expression and clinical significances were studied. RESULTS: We found FGL1 and LAG-3 densities were elevated while PD-L1 and CD8 were decreased in HCC tissues compared to adjacent normal liver tissues. High levels of FGL1 were strongly associated with high densities of LAG-3+cells but not PD-L1. CD8+ T cells densities had positive correlation with PD-L1 levels and negative association with FGL1 expression. Elevated densities of LAG-3+cells and low levels of CD8+ T cells were correlated with poor disease outcome. Moreover, LAG-3+cells deteriorated patient stratification based on the abundance of CD8+ T cells. Patients with positive PD-L1 expression on tumor cells (PD-L1 TC+) tended to have an improved survival than that with negative PD-L1 expression on tumor cells (PD-L1 TC-). Furthermore, PD-L1 TC- in combination with high densities of LAG-3+cells showed the worst prognosis, and PD-L1 TC+ patients with low densities of LAG-3+cells had the best prognosis. CONCLUSIONS: LAG-3, FGL1, PD-L1 and CD8 have distinct tissue distribution and relationships with each other. High levels of LAG-3+cells and CD8+ T cells represent unfavorable and favorable prognostic biomarkers for HCC respectively.