Arterial thrombotic diseases are leading causes of global morbidity and mortality, primarily driven by platelet hyperactivity. Qiliqiangxin capsules (QLQX), a traditional Chinese medicine approved in China for the treatment of heart failure, have exhibited potential benefits in reducing cardiovascular death. However, its direct effects on platelet activation and thrombosis remain unclear. Ex vivo platelet function assays demonstrated that oral QLQX inhibited agonist‑induced aggregation in platelet‑rich plasma (PRP) from chronic heart failure (CHF) patients and dose-dependently suppressed washed platelet aggregation in wild‑type mice. In parallel, QLQX administration attenuated platelet spreading and clot retraction in washed platelets from both patients with CHF and wild-type mice, and reduced ex vivo thrombus formation area in a microfluidic whole‑blood perfusion under arterial shear stress. Flow cytometry analysis revealed that QLQX did not affect the surface expression levels of the major platelet receptors, but reduced the activation of αIIbβ3 and P-selectin exposure induced by thrombin in mouse platelets. In vivo experiments demonstrated that QLQX treatment inhibited FeCl₃-induced thrombus formation in mesenteric arterioles, reduced collagen/epinephrine-induced pulmonary embolism, and mitigated microvascular thrombosis during myocardial ischemia-reperfusion (I/R) injury, without increasing bleeding in mice. RNA sequencing of platelets from QLQX- versus vehicle-treated mice identified differentially expressed genes enriched in the calcium signaling pathway, and functional assays demonstrated that QLQX inhibited agonist-induced platelet Ca²⁺ influx and PKC phosphorylation. QLQX inhibits platelet activation and thrombosis by targeting Ca²⁺ influx and PKC signaling, supporting its potential therapeutic value in preventing thrombotic complications.

Objective To explore the impact of tertiary lymphoid structure(TLS)on the efficacy of adjuvant transcatheter arterial chemoembolization(TACE)following curative resection in patients with hepatocellular carcinoma(HCC).Methods A retrospective study enrolled 200 patients receiving adjuvant TACE and 145 non-TACE controls who underwent curative resection for HCC at the Department of Hepatobiliary Surgery,Zhongshan Hospital,Fudan University from January 2011 to December 2015.Tumor tissue sections were evaluated for TLS through hematoxylin-eosin(HE)staining.Two hundred patients receiving TACE treatment were divided into the TLS positive group and the TLS negative group.Propensity score matching(PSM)was used to reduce confounding factors.Kaplan-Meier survival curves,log-rank tests and Cox proportional hazards model were employed to assess the impact of TLS on prognosis of patients receiving postoperative adjuvant TACE.Results Before PSM,the TLS positive group(n=101)had significantly longer early recurrence-free survival(RFS)and overall survival(OS)compared to TLS negative group(n=99,P＜0.001).After PSM,there were 69 cases in both the TLS positive and TLS negative groups,with no statistically significant differences in baseline data between the two groups.The TLS positive group still showed significantly longer early RFS(P＜0.001)and OS(P=0.002).The results of the Cox proportional hazards model indicated that the presence of TLS in tumor tissue was an independent protective factor for early RFS(HR=0.240,P＜0.001)and OS(HR=0.282,P＜0.001)in patients undergoing postoperative adjuvant TACE treatment.Subgroup analysis of 345 patients showed that among patients with TLS present in tumor tissue,those receiving adjuvant TACE had longer early RFS(P=0.034)and OS(P=0.018)compared to those who did not receive adjuvant TACE,while the efficacy of adjuvant TACE was not significant in patients without TLS.Conclusions TLS is an important indicator affecting the efficacy of postoperative adjuvant TACE and patient prognosis.

Transarterial chemoembolization (TACE) is commonly used to treat patients with unresectable hepatocellular carcinoma (HCC); however, TACE alone has demonstrated unsatisfactory survival benefits. Our previous studies suggested that TACE plus oral medication of thalidomide, carmofur and compound mylabris capsule (TCC cocktail) may be a better therapeutic option. In this randomized, open-label, multicenter clinical trial, 72 treatment-naive HCC patients were randomly assigned to receive cTACE alone or cTACE plus oral TCC cocktail between July 2018 and October 2019. The primary endpoint of this trial was the 1-, 2- and 3-year overall survival (OS) rates. The second endpoints of this trial included 1-, 2- and 3-year progression-free survival (PFS) rates, objective response rates (ORR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety with adverse events (AEs). The 1-, 2- and 3-year OS rates were significantly higher in the cTACE plus TCC group than in the cTACE group (83.2 https://www.chictr.org.cn/showproj.html?proj=27493 as ChiCTR1800016335 on 25th May 2018 named an open-label, multicenter, randomized, prospective clinical trial of thalidomide based triple oral regimen for low-dose maintenance therapy after TACE in advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is characterized by an immunosuppressive tumor microenvironment (TME) that critically propels malignant evolution. Sphingomyelin synthase 2 (SGMS2), the pivotal sphingolipid metabolizing enzyme, catalyzes the conversion of ceramide to sphingomyelin. Emerging evidence highlights sphingolipid metabolism as a key regulator of tumor immunity, particularly in shaping macrophage phenotypes within the TME. However, the macrophage-specific contributions of SGMS2 to HCC progression remain unexplored. This study elucidates the critical role of SGMS2 in shaping TME and influencing patient prognosis. Bulk RNA-seq analysis was performed using TCGA-LIHC datasets (n = 371). Single-cell RNA sequencing and spatial transcriptomics were used to identify SGMS2-expressing cell types and evaluate spatial immune interactions. Clinical validation was performed on a cohort of 188 HCC patients (2017–2022) using multiplex immunofluorescence to quantify SGMS2+ macrophages and NR4A3hi NK cells. THP-1 monocytes were transfected with lentiviral SGMS2 overexpression vectors and differentiated into macrophages via PMA induction. Co-culture assays with liver tumor cells were performed in transwell plates for 48 h, followed by tumor cell apoptosis assessment using Annexin V-FITC/PI staining and flow cytometry. High SGMS2 expression in HCC tissues was associated with improved patient prognosis. SGMS2 was mainly expressed in macrophages within the HCC immune microenvironment, promoting their polarization toward the M1-like phenotype. High infiltration of SGMS2+ macrophages significantly prolonged overall survival (OS), recurrence-free survival (RFS), and early RFS. Notably, patients with high infiltration of SGMS2+ macrophages accompanied by low infiltration of SGMS2- macrophages had the most favorable prognosis. Mechanistically, SGMS2+ macrophages secreted CXCL2, recruiting CD56dimCD16highNR4A3high cytotoxic NK cells, enhancing tumor cell apoptosis and improving prognosis. In patients receiving PD-1 therapy, those with high infiltration of SGMS2+ macrophages and CD56dimCD16highNR4A3high NK cells demonstrated superior treatment responsiveness and prolonged survival. SGMS2 could polarize macrophages toward the M1 phenotype. SGMS2+ macrophages secrete CXCL2 to recruit CD56dimCD16highNR4A3high NK cells, thereby enhancing tumor apoptosis. High infiltration of SGMS2+ macrophages and CD56dimCD16highNR4A3high NK cells correlates with superior PD-1 therapy responsiveness and extended survival.

Background:Bevacizumab, immune checkpoint inhibitors (ICIs), interventional therapy, either alone or in combination, have demonstrated promising anti-tumor activities in unresectable hepatocellular carcinoma (HCC). However, the optimal dosing strategy for bevacizumab within combination regimens remains undetermined. This study aimed to compare the efficacy and safety of different bevacizumab doses in triple therapy combining bevacizumab, ICIs, and interventional therapy for unresectable HCC. Methods:A retrospective study included patients with unresectable HCC treated with interventional therapy combined with bevacizumab (full dose or half dose) and ICIs between December 2020 and July 2023 was conducted. Propensity score matching (PSM, 1:1) was applied to minimize confounding effects. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were compared and evaluated. Treatment-related adverse events (AEs) were analyzed to assess safety. Results:Among 66 enrolled patients, 36 received full-dose bevacizumab, and 30 received half-dose bevacizumab. The full-dose group exhibited significantly longer PFS compared to the half-dose group (median PFS: not attained vs. 8.0 months, P<0.001). Median OS was not reached in either group, with 1-year OS rate of 86% in the full-dose group and 83% in the half-dose group. Although full-dose group showed numerically higher ORR (55.6% vs. 36.7%, P=0.13) and DCR (88.9% vs. 83.3%, P=0.51), these differences did not reach statistical significance. Half-dose group experienced comparable AEs with full-dose group. Post-PSM analyses corroborated these findings. Conclusions:Although full-dose bevacizumab in triple therapy showed prolonged PFS compared to half-dose group, no statistically significant differences were observed in long-term survival outcomes or treatment-related AEs between the two groups. For unresectable HCC patients with severe liver cirrhosis, half-dose bevacizumab may serve as a safer alternative without compromising survival benefits.

Advanced hepatocellular carcinoma (HCC) patients have poor prognosis. As an endogenous antioxidant enzyme involved in a variety of bioprocesses, sulfiredoxin-1 (SRXN1) plays an irreplaceable role in promoting the development of tumors. However, the role and working mechanism of SRXN1 in HCC remain unclear. In this study, we confirmed that SRXN1 promoted the cell proliferation of HCC at genetic and pharmacological level, respectively. Transcriptome sequencing analysis revealed SRXN1 knockdown had a significant effect on the expression of lysosome biogenesis related genes. Further experiments validated that lysosome biogenesis and autophagic flux were enhanced after SRXN1 inhibition and reduced as SRXN1 overexpression. Mechanism study revealed that ROS accumulation induced TFEB nuclear translocation, followed by increased autophagy. Following this rationale, the combination of SRXN1 inhibitor and sorafenib demonstrated noticeable synergistic antitumor effect through the boost of ROS both in vivo and in vitro. Taken together, SRXN1 could be a potential therapeutic target for HCC therapy.

BACKGROUND:Current embolic agents in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter instability and easy leakage, discounting TACE efficacy with residual HCC. Moreover, clinical TACE aggravates hypoxia and pro-metastatic microenvironments, rendering patients with HCC poor prognosis. METHODS:Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO2 (HMnO2). The conditions and capacity of HMnO2 to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO2@DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO2@DOX on HCC. The subcutaneous HCC mouse model and rabbit VX2 HCC model were established to investigate its anti-tumor and anti-metastasis efficacy and explore its potential anti-tumor mechanism. FINDINGS:The high adhesion and crosslinking of Zein with HMnO2@DOX impart Zein-HMnO2@DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO2 decomposition in response to water and acidic tumor microenvironment, respectively, enable continuous DOX release and Fenton-like reaction for reactive oxygen species (ROS) production and O2 release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O2 release down-regulates hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and glucose transporter protein 1 (GLUT1), which thereby re-programmes TACE-aggravated hypoxic and pro-metastatic microenvironments to repress HCC metastasis towards lung. Mechanistic explorations uncover that such Zein-based TACE agents disrupt oxidative stress, angiogenesis and glycometabolism pathways to inhibit HCC progression. INTERPRETATION:This innovative work not only provides a new TACE agent for HCC, but also establishes a new strategy to ameliorate TACE-aggravated hypoxia and metastasis motivation against clinically-common HCC metastasis after TACE operation. FUNDING:Excellent Young Science Fund for National Natural Science Foundation of China (82022033); National Natural Science Foundation of China (Grant No. 82373086, 82102761); Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (Grant No. ZY2021009); Shanghai Young Top-Notch Talent.

BACKGROUND:Tumor lysis syndrome is a life-threatening complication in the treatment of cancer. However, it rarely occurs in solid tumors, especially in hepatocellular carcinoma. CASE PRESENTATION:We present a 52-year-old male Asian patient with advanced hepatocellular carcinoma treated with hepatic artery infusion chemotherapy that resulted in tumor lysis syndrome. The patient developed symptoms of oliguria, seizure, hyperkalemia, hyperuricemia, hypocalcemia, hyperphosphatemia, and increased creatinine. He recovered from it after adequate hydration, correction of metabolic abnormalities, and renal replacement therapy. CONCLUSIONS:This case highlights the importance of maintaining a high index of suspicion of TLS even in solid tumors such as hepatocellular carcinoma, especially with a large tumor burden. It also underscores the need for early intervention in suspected TLS for a successful outcome.

As an important first-line drug for advanced hepatocellular carcinoma（HCC）, lenvatinib shows non-inferior therapeutic effects to sorafenib as well as better performance in certain aspects. However, lenvatinib resistance emerged eventually as most other anticancer drugs. Epidermal growth factor receptor（EGFR） bypass activation, the overexpression of fibroblast growth factor receptor 1（FGFR1） and the appearance of cancer stem cells in HCC are the causes of lenvatinib resistance. Lenvatinib combined with immune checkpoint inhibitors（ICIs） has been proven to have good efficacy in clinical trials. This review summarizes the new research findings on the mechanism of lenvatinib resistance and new strategies for improving the efficacy of lenvatinib in recent years, which could be helpful for treatment of HCC patients with lenvatinib.

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.

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Several studies have demonstrated the potency of Chinese herbs in protecting the liver from inflammation, hypoxia, fibrosis, and cancer. The roots of Actinidia chinensis Planch. exhibit strong anti-tumour effects; however, their mechanisms of action in HCC are not clearly understood. 'Methods: To investigate the molecular mechanisms underlying the anti-cancer effect of A chinensis Planch. root extract (acRoot) in HCC and hepatic stellate cells (HSCs). The HSC line LX2 and HCC cell line MHCC97H were cultured under oxygen-rich or oxygen-deprived conditions and then exposed to various acRoot concentrations for different periods. Subsequently, cell viability, cytotoxicity, and enzyme-linked immunosorbent assays and western blotting were conducted to assess the effects of acRoot treatment. Results: acRoot decreased the number of viable LX2 and MHCC97H cells in a concentration- and time-dependent manner. Under hypoxic and/or co-culture conditions, pro-inflammatory cytokine expression was up-regulated in both cell lines; however, the expression levels were significantly decreased following treatment with acRoot. Additionally, acRoot inhibited hypoxia-induced activation of LX2 cells and inflammation and epithelial-mesenchymal transition (EMT) in MHCC97H cells. Moreover, acRoot inhibited cross-talk between LX2 and MHCC97H cells, further inhibiting cellular activation, inflammation, and EMT.Conclusion: These results show the therapeutic potential of acRoot as an anti-cancer, anti-inflammatory, and anti-fibrotic agent, shedding new light on the medicinal properties of Chinese herbs.

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.

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.

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.

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.

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-β, 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.

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.

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 (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.