Nomograms based on ratio indexes to predict severity and prognosis in immune checkpoint inhibitors-related myocarditis: a retrospective analysis.

PURPOSE: Immune checkpoint inhibitors-related myocarditis (ICI-M) is one of the immune-related adverse events (irAEs), which is rare and highly lethal. This study aimed to establish nomograms based on ratio biomarkers to predict the severity and prognosis of ICI-M. METHODS: We retrospectively examined patients with advanced cancers who were also diagnosed with ICI-M at the Fourth Hospital of Hebei Medical University. The patients of ICI-M were divided into mild and severe groups and a 40-day following up was carried out. The major adverse cardiovascular events(MACEs) were regarded as the endpoint. Nomogram-based models were established and validated. RESULTS: Seventy-seven patients were involved, including 31 severe cases(40.3%). Lactate dehydrogenase-to-albumin ratio(LAR) combined with the change rate from baseline to onset of LAR( ▵ LAR) which performed best to diagnose the severe ICI-M was identified to establish the nomogram-based model. The bootstrap-corrected concordance index [0.752 95% confidence interval (CI): 0.635 - 0.866] and calibration plot with good degree of fitting confirmed this diagnostic model. Neutrophil-to-high-density lipoprotein cholesterol ratio(NHR) and LAR were also screened into the nomogram-based model for 40-day MACEs after ICI-M, which performed well by validating for concordance index(0.779 95% CI: 0.677 - 0.865)and calibration plots after being bootstrap-corrected. Moreover, a  ≥ 101% increase in LAR significantly separated patients in MACE-free survival. CONCLUSION: Ratio indexes at onset and their change rates from baseline showed good diagnostic value for the severity of ICI-M and prognostic value for subsequent MACEs, particularly LAR, NHR and their change rates. The nomogram-based models of ratio indexes could provide a potential choice for early detection and monitor of the severe ICI-M and subsequent MACEs.

TLR3 activation enhances abscopal effect of radiotherapy in HCC by promoting tumor ferroptosis.

Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here, we demonstrated that subcutaneous administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) could strengthen the abscopal effect during RT through activating tumor cell ferroptosis signals in bilateral HCC subcutaneous tumor mouse models, which could be significantly abolished by TLR3 knock-out or ferroptosis inhibitor ferrostatin-1. Moreover, poly(I:C) could promote the presentation of tumor neoantigens by dendritic cells to enhance the recruitment of activated CD8+ T cells into distant tumor tissues for inducing tumor cell ferroptosis during RT treatment. Finally, the safety and feasibility of combining poly(I:C) with RT for treating advanced HCC patients were further verified in a prospective clinical trial. Thus, enhancing TLR3 signaling activation during RT could provide a novel strategy for strengthening abscopal effect to improve the clinical benefits of advanced HCC patients.

The impact of middle managers' digital leadership on employee work engagement.

Background: In the rapidly evolving digital landscape, the role of middle managers in organizational structures and processes is increasingly pivotal. Positioned at the nexus of strategic directives and operational execution, they play an important role in driving digital transformation. This study discusses the under examined domain of middle managers' digital leadership and its impact on employee work engagement in the context of digital transformation. Design: Drawing on Social Exchange Theory, this study investigates the influence of middle managers' digital leadership on employee work engagement through the analysis of survey data from 559 respondents across 11 listed companies in Southwest China. It examines the roles of employee empowerment and affective commitment as pivotal mediating variables and investigates the moderating effect of emotional intelligence in these relationships. Research purposes: The study aims to elucidate the mechanisms by which middle managers' digital leadership fosters employee work engagement, highlighting the importance of emotional intelligence, empowerment, and affective commitment in this process. Findings: The study reveals that middle managers' digital leadership has a significant positive impact on employee work engagement. Employee empowerment and affective commitment serve as mediating factors in the relationship between middle managers' digital leadership and employee work engagement. Emotional intelligence moderates the effect of middle managers' digital leadership on employee empowerment. Meanwhile, emotional intelligence further moderates the chain mediating of employee empowerment and affective commitment between middle managers' digital leadership and employees' work engagement. Implications: This research offers valuable insights into the dynamics of leadership and engagement in the digital era, emphasizing the need for organizations to foster digital leadership capabilities in middle management. It provides practical implications for enhancing employee work engagement through strategic digital leadership, emphasizing the role of employee empowerment, affective commitment and emotional intelligence in adapting to digital transformation.

Discovery and Identification of Novel 5-Hydroxy-4H-benzo[1,4]oxazin-3-one Derivatives as Potent ß2-Adrenoceptor Agonists through Structure-Based Design, Synthesis, and Biological Evaluation.

Although ß2-agonists are crucial for treatment of chronic respiratory diseases, optimizing ß2-agonistic activity and selectivity remains essential for achieving favorable therapeutic outcomes. A structure-based molecular design workflow was employed to discover a novel class of ß2 agonists featuring a 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold, which potently stimulated ß2 adrenoceptors (ß2-ARs). Screening for the ß2-agonistic activity and selectivity led to the identification of compound A19 (EC50 = 3.7 pM), which functioned as a partial ß2-agonist in HEK-293 cells containing endogenous ß2-ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot50 = 2.14 min), and long duration of action (>12 h) on isolated guinea pig tracheal strips, as well as advantageous pharmacokinetic characteristics in vivo, rendering A19 suitable for inhalation administration. Moreover, A19 suppressed the upregulation of inflammatory cytokines and leukocytes and improved lung function in a rat model of COPD, thereby indicating that A19 is a potential ß2 agonist candidate for further study.

Human serum albumin as the carrier to fabricate STING-activating peptide nanovaccine for antitumor immunotherapy.

Tumor vaccines are emerging as one of the most promising therapeutic strategies for cancer treatment. With the advantages of low toxicity, convenient production and stable quality control, peptide vaccines have been widely used in preclinical and clinical trials involving various malignancies. However, when used alone, they still suffer from significant challenges including poor stability and immunogenicity as well as the low delivery efficiency, leading to limited therapeutic success. Herein, the STING-activating peptide nanovaccine based on human serum albumin (HSA) and biodegradable MnO2 was constructed, which can improve the stability and immunogenicity of antigenic peptides as well as facilitate their uptake by dendritic cells (DCs). Meanwhile, Mn2+ degraded from the nanovaccine can activate the STING pathway and further promote DCs maturation. In this way, the prepared nanovaccine can efficiently mediate T-cell immune responses, thereby exerting the effects of tumor prevention and therapy. Moreover, the prepared nanovaccine possesses the advantages of low cost, convenient preparation and good biocompatibility, showing great potential for practical applications.

Bulk and single-cell transcriptome reveal the immuno-prognostic subtypes and tumour microenvironment heterogeneity in HCC.

BACKGROUND & AIMS: Accumulating evidences suggest tumour microenvironment (TME) profoundly influence clinical outcome in hepatocellular carcinoma (HCC). Existing immune subtypes are susceptible to batch effects, and integrative analysis of bulk and single-cell transcriptome is helpful to recognize immune subtypes and TME in HCC. METHODS: Based on the relative expression ordering (REO) of 1259 immune-related genes, an immuno-prognostic signature was developed and validated in 907 HCC samples from five bulk transcriptomic cohorts, including 72 in-house samples. The machine learning models based on subtype-specific gene pairs with stable REOs were constructed to jointly predict immuno-prognostic subtypes in single-cell RNA-seq data and validated in another single-cell data. Then, cancer characteristics, immune landscape, underlying mechanism and therapeutic benefits between subtypes were analysed. RESULTS: An immune-related signature with 29 gene pairs stratified HCC samples individually into two risk subgroups (C1 and C2), which was an independent prognostic factor for overall survival. The machine learning models verified the immune subtypes from five bulk cohorts to two single-cell transcriptomic data. Integrative analysis revealed that C1 had poorer outcomes, higher CNV burden and malignant scores, higher sensitivity to sorafenib, and exhibited an immunosuppressive phenotype with more regulators, e.g., myeloid-derived suppressor cells (MDSCs), Mø_SPP1, while C2 was characterized with better outcomes, higher metabolism, more benefit from immunotherapy, and displayed active immune with more effectors, e.g., tumour infiltrating lymphocyte and dendritic cell. Moreover, both two single-cell data revealed the crosstalk of SPP1-related L-R pairs between cancer and immune cells, especially SPP1-CD44, might lead to immunosuppression in C1. CONCLUSIONS: The REO-based immuno-prognostic subtypes were conducive to individualized prognosis prediction and treatment options for HCC. This study paved the way for understanding TME heterogeneity between immuno-prognostic subtypes of HCC.

Potential oral VEGFR2 inhibitors: Treatment of wet age-related macular degeneration.

Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD.

Personalized neoantigen vaccine enhances the therapeutic efficacy of bevacizumab and anti-PD-1 antibody in advanced non-small cell lung cancer.

Clinically, a considerable number of non-small cell lung cancer (NSCLC) patients are unable to receive or resist chemotherapy, and the efficacy of non-chemotherapy treatment strategies based on anti-angiogenic agents combined with immune checkpoint blockade is still unsatisfactory. Neoantigen vaccine, based on personalized tumor DNA mutations, could elicit tumor specific T cell infiltration into the tumor site, exerting potent anti-tumor efficacy. Here, we evaluated the feasibility and safety of a new antitumor strategy by adding neoantigen vaccine to the regimen of bevacizumab and anti-PD-1 antibody. Firstly, 7 novel immunogenic neoantigen peptides were identified and developed for neoantigen vaccine (LLCvac), which can elicit strong antitumor immune response in vivo. Then, in orthotopic lung cancer model, LLCvac further combining with bevacizumab and anti-PD-1 antibody exerted a stronger antitumor effect, exhibiting significant decrease of tumor volume without obvious toxicity. Furthermore, tumor immune microenvironment assessment also showed that the proportion of neoantigen-specific T cells in blood could be induced dramatically by the combined therapy. And a large amount of neoantigen-specific Ki67-positive CD8+ T cells were found in tumor tissues, which infiltrated tumor tissues effectively to kill tumor cells expressing identified neoantigens. Overall, these results suggested that this combined therapy could safely induce robust antitumor efficacy, serving as an effective chemotherapy-free strategy for NSCLC treatment.

Hydrogel Crosslinked with Nanoparticles for Prevention of Surgical Hemorrhage and Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is acknowledged as an immunosuppressive neoplasm, whereby the inactive microenvironment facilitates immune tolerance and evasion of HCC. Post-surgical resected liver cancer exhibits a proclivity for relapse, rendering prevention of recurrence challenging as it may transpire at any point subsequent to surgery. Among the various anti-recurrence interventions, the primary clinical approach involving the administration of regimens atezolizumab and bevacizumab (A+T) is deemed the most efficacious in reversing the tumor microenvironment, albeit still lacking in complete satisfaction. Therefore, the objective is to utilize a recently developed block copolymer as a protective carrier for two specific monoclonal antibody drugs. Subsequently, a modified hemostatic hydrogel will be synthesized for application during hepatic surgery. The immunotherapy impact of this approach is significantly prolonged and intensified due to the combined hemostasis properties and controlled release of the constituents within the synthesized nanocomposite hydrogel. Furthermore, these nanocomposite hydrogels exhibit remarkable efficacy in preventing postoperative wound bleeding and substantially enhancing the safety of liver cancer resection. This research on the anti-recurrence hydrogel system presents a novel therapeutic approach for addressing local recurrence of liver cancer, potentially offering a substantial contribution to the field of surgical treatment for liver cancer in the future.

Design, synthesis and biological evaluation of carbamate derivatives incorporating multifunctional carrier scaffolds as pseudo-irreversible cholinesterase inhibitors for the treatment of Alzheimer's disease.

In this study, a series of carbamate derivatives incorporating multifunctional carrier scaffolds were designed, synthesized, and evaluated as potential therapeutic agents for Alzheimer's disease (AD). We used tacrine to modify the aliphatic substituent, and employed rivastigmine, indole and sibiriline fragments as carrier scaffolds. The majority of compounds exhibited good inhibitory activity for cholinesterase. Notably, compound C7 with sibiriline fragment exhibited potent inhibitory activities against human acetylcholinesterase (hAChE, IC50 = 30.35 ± 2.07 nM) and human butyrylcholinesterase (hBuChE, IC50 = 48.03 ± 6.41 nM) with minimal neurotoxicity. Further investigations have demonstrated that C7 exhibited a remarkable capacity to safeguard PC12 cells against H2O2-induced apoptosis and effectively suppressed the production of reactive oxygen species (ROS). Moreover, in an inflammation model of BV2 cells induced by lipopolysaccharide (LPS), C7 effectively attenuated the levels of pro-inflammatory cytokines. After 12 h of dialysis, C7 continued to exhibit an inhibitory effect on cholinesterase activity. An acute toxicity test in vivo demonstrated that C7 exhibited a superior safety profile and no hepatotoxicity compared to the parent nucleus tacrine. In the scopolamine-induced AD mouse model, C7 (20 mg/kg) significantly reduced cholinesterase activity in the brain of the mice. C7 was tested in a pharmacological AD mouse model induced by Aß1-42 and attenuated memory deficits at doses as low as 5 mg/kg. The pseudo-irreversible cholinesterase inhibitory properties and multifunctional therapeutic attributes of C7 render it a promising candidate for further investigation in the treatment of AD.

Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy.

Patients with hepatocellular carcinoma (HCC) at the same clinical stage can have extremely different prognoses, and molecular subtyping provides an opportunity for individualized precision treatment. In this study, genomic, transcriptomic, proteomic, and phosphoproteomic profiling of primary tumor tissues and paired para-tumor tissues from HCC patients (N = 160) are integrated. Proteomic profiling identifies three HCC subtypes with different clinical prognosis, which are validated in three publicly available external validation sets. A simplified panel of nine proteins associated with metabolic reprogramming is further identified as a potential subtype-specific biomarker for clinical application. Multi-omics analysis further reveals that three proteomic subtypes have significant differences in genetic alterations, microenvironment dysregulation, kinase-substrate regulatory networks, and therapeutic responses. Patient-derived cell-based drug tests (N = 26) show personalized responses for sorafenib in three proteomic subtypes, which can be predicted by a machine-learning response prediction model. Overall, this study provides a valuable resource for better understanding of HCC subtypes for precision clinical therapy.

Spleen-targeted neoantigen DNA vaccine for personalized immunotherapy of hepatocellular carcinoma.

Neoantigens are emerging as attractive targets to develop personalized cancer vaccines, but their immunization efficacy is severely hampered by their restricted accessibility to lymphoid tissues where immune responses are initiated. Leveraging the capability of red blood cells (RBCs) to capture and present pathogens in peripheral blood to the antigen-presenting cells (APCs) in spleen, we developed a RBC-driven spleen targeting strategy to deliver DNA vaccine encoding hepatocellular carcinoma (HCC) neoantigen. The DNA vaccine-encapsulating polymeric nanoparticles that were intentionally hitchhiked on the preisolated RBCs could preferentially accumulate in the spleen to promote the neoantigen expression by APCs, resulting in the burst of neoantigen-specific T-cell immunity to prevent tumorigenesis in a personalized manner, and slow down tumor growth in the established aggressively growing HCC. Remarkably, when combined with anti-PD-1, the vaccine achieved complete tumor regression and generated a robust systemic immune response with long-term tumor-specific immunological memory, which thoroughly prevented tumor recurrence and spontaneous lung metastasis. This study offers a prospective strategy to develop personalized neoantigen vaccines for augmenting cancer immunotherapy efficiency in immune "cold" HCC.

Identification of tumor mutations in plasma based on mutation variant frequency change (MVFC).

To overcome the dependency of strategies utilizing cell-free DNA (cfDNA) on tissue sampling, the emergence of sequencing panels for non-invasive mutation screening was promoted. However, cfDNA sequencing with panels still suffers from either inaccuracy or omission, and novel approaches for accurately screening tumor mutations solely based on plasma without gene panel restriction are urgently needed. We performed unique molecular identifier (UMI) target sequencing on plasma samples and peripheral blood mononuclear cells (PBMCs) from 85 hepatocellular carcinoma (HCC) patients receiving surgical resection, which were divided into an exploration dataset (20 patients) or an evaluation dataset (65 patients). Plasma mutations were identified in pre-operative plasma, and the mutation variant frequency change (MVFC) between post- and pre-operative plasma was then calculated. In the exploration dataset, we observed that plasma mutations with MVFC < 0.2 were enriched for tumor mutations identified in tumor tissues and had frequency changes that correlated with tumor burden; these plasma mutations were therefore defined as MVFC-identified tumor mutations. The presence of MVFC-identified tumor mutations after surgery was related to shorter relapse-free survival (RFS) in both datasets and thus indicated minimum residual disease (MRD). The combination of MVFC-identified tumor mutations and Alpha Fetoprotein (AFP) could further improve MRD detection (P < 0.0001). Identification of tumor mutations based on MVFC was also confirmed to be applicable with a different gene panel. Overall, we proposed a novel strategy for non-invasive tumor mutation screening using solely plasma that could be utilized in HCC tumor-burden monitoring and MRD detection.

Mechanisms of portal vein tumour thrombus formation and development in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Portal vein tumour thrombus (PVTT) is considered one of most fearful complications of HCC and is strongly associated with a poor prognosis. Clarification of the mechanisms underlying the formation and development of PVTT is crucial for developing novel therapeutic strategies for HCC patients. Several studies have been made to uncover that tumour microenvironment, stem cells, abnormal gene expression and non-coding RNAs deregulation are associated with PVTT in patients with HCC in the last decade. However, the exact molecular mechanisms of PVTT in patients with HCC are still largely unknown. In the present review, we briefly summarized the molecular mechanisms underlying the formation and development of PVTT in HCC.

Design, synthesis, and evaluation of N-methyl-propargylamine derivates as isoform-selective monoamine oxidases inhibitors for the treatment of nervous system diseases.

A novel series of N-methyl-propargylamine derivates were designed, synthesized, and evaluated as isoform-selective monoamine oxidases (MAO) inhibitors for the treatment of nervous system diseases. The in vitro studies showed some of the compounds exhibited considerable MAO-A selective inhibitory activity (IC50 of 14.86-17.16 nM), while some of the others exhibited great MAO-B selective inhibitory activity (IC50 of 4.37-17.00 nM). Further studies revealed that compounds A2 （IC50 against MAO-A: 17.16 ± 1.17 nM） and A5 (IC50 against MAO-B: 17.00 ± 1.10 nM) had significant abilities to protect PC12 cells from H2O2-induced apoptosis and reactive oxygen species (ROS) production. The parallel artificial membrane permeability assay showed A2 and A5 would be potent to cross the blood-brain barrier. The results indicated that A2 showed potential use in the therapy of MAO-A related diseases, such as depression and anxiety; while A5 exhibited promising ability in the treatment of MAO-B related diseases, such as Alzheimer's disease and Parkinson's disease.

Dysregulation of global circular RNA abundance regulated by spliceosomes predicts prognosis in hepatocellular carcinoma.

CircRNAs have been reported to play crucial roles in tumor progression and recurrence, showing potential as biomarkers in cancer. However, the global abundance of circRNA and their involvement in hepatocellular carcinoma (HCC) development have not been fully explored. Whole transcriptome sequencing was performed on tumor and peritumor from 60 patients with HCC to quantify the expression of circRNAs, and the global circRNA abundance was calculated by circRNA index (CRI). Gene-set enrichment analysis and weighted gene co-expression network analysis were used to reveal the biological signaling pathways associated with the global circRNA abundance. The correlation between the global circRNA abundance and the infiltration level of CD8+ T cells was explored by immunohistochemical assays. Small interfering RNA was used to knock down the pre-messenger RNA spliceosome in HCC cell lines to verify the regulation of spliceosome in global circRNA abundance. We found that dysregulation of global circRNA abundance in both tumor and peritumor could lead to worse prognosis. The immunohistochemical assay further revealed that the dysregulation of global circRNA abundance in both tumor and peritumor would obstruct the CD8+ T cells from invading into the tumor, which might explain its correlation with HCC prognosis. We also demonstrated that the spliceosome genes were the main factors to regulate the global circRNA abundance in HCC, and these results were also confirmed by knockdown experiments. Conclusion: This study revealed the association between the global circRNA abundance and patients' prognosis and its underlying mechanism.

Personalized neoantigen vaccine combined with PD-1 blockade increases CD8+ tissue-resident memory T-cell infiltration in preclinical hepatocellular carcinoma models.

BACKGROUND: Personalized neoantigen vaccine could induce a robust antitumor immune response in multiple cancers, whose efficacy could be further enhanced by combining with programmed cell death 1 blockade (α-PD-1). However, the corresponding immune response and synergistic mechanisms remain largely unclear. Here, we aimed to develop clinically available combinational therapeutic strategy and further explore its potential antitumor mechanisms in hepatocellular carcinoma (HCC). METHODS: Neoantigen peptide vaccine (NeoVAC) for murine HCC cell line Hepa1-6 was developed and optimized by neoantigen screening and adjuvant optimization. Then the synergistic efficacy and related molecular mechanisms of NeoVAC combined with α-PD-1 in HCC were evaluated by orthotopic HCC mouse model, single-cell RNA sequencing, tetramer flow cytometry, immunofluorescence, etc. The tumor-killing capacity of CD8+ tissue-resident memory T cells (CD8+ TRMs) was assessed by orthotopic HCC mouse model, and autologous patient-derived cells. RESULTS: NeoVAC, which consisted of seven high immunogenic neoantigen peptides and clinical-grade Poly(I:C), could generate a strong antitumor immune response in HCC mouse models. Significantly, its efficacy could be further improved by combining with α-PD-1, with 80% of durable tumor regression and long-term immune memory in orthotopic HCC models. Moreover, in-depth analysis of the tumor immune microenvironment showed that the percentage of CD8+ TRMs was remarkedly increased in NeoVAC plus α-PD-1 treatment group, and positively associated with the antitumor efficacy. In vitro and in vivo T-cell cytotoxicity assay further confirmed the strong tumor-killing capacity of CD8+ TRMs sorting from orthotopic mouse HCC or patient's HCC tissue. CONCLUSIONS: This study showed that NeoVAC plus α-PD-1 could induce a strong antitumor response and long-term tumor-specific immune memory in HCC by increasing CD8+ TRMs infiltration, which might serve as a potential immune-therapeutic target for HCC.

Mesoporous Nanoparticles for Diagnosis and Treatment of Liver Cancer in the Era of Precise Medicine.

Primary liver cancer is the seventh-most-common cancer worldwide and the fourth-leading cause of cancer mortality. In the current era of precision medicine, the diagnosis and management of liver cancer are full of challenges and prospects. Mesoporous nanoparticles are often designed as specific carriers of drugs and imaging agents because of their special morphology and physical and chemical properties. In recent years, the design of the elemental composition and morphology of mesoporous nanoparticles have greatly improved their drug-loading efficiency, biocompatibility and biodegradability. Especially in the field of primary liver cancer, mesoporous nanoparticles have been modified as highly tumor-specific imaging contrast agents and targeting therapeutic medicine. Various generations of complexes and structures have been determined for the complicated clinical management requirements. In this review, we summarize these advanced mesoporous designs in the different diagnostic and therapeutic fields of liver cancer and discuss the relevant advantages and disadvantages of transforming applications. By comparing the material properties, drug-delivery characteristics and application methods of different kinds of mesoporous materials in liver cancer, we try to help determine the most suitable drug carriers and information media for future clinical trials. We hope to improve the fabrication of biomedical mesoporous nanoparticles and provide direct evidence for specific cancer management.

Metabolism-Related Gene Pairs to Predict the Clinical Outcome and Molecular Characteristics of Early Hepatocellular Carcinoma.

Recurrence is the main factor affecting the prognosis of early hepatocellular carcinoma (HCC), which is not accurately evaluated by clinical indicators. The metabolic heterogeneity of HCC hints at the possibility of constructing a stratification model to predict the clinical outcome. On the basis of the relative expression orderings of 2939 metabolism-related genes, an individualized signature with 10 metabolism-related gene pairs (10-GPS) was developed from 250 early HCC samples in the discovery datasets, which stratified HCC patients into the high- and low-risk subgroups with significantly different survival rates. The 10-GPS was validated in 311 public transcriptomic samples from two independent validation datasets. A nomogram that included the 10-GPS, age, gender, and stage was constructed for eventual clinical evaluation. The low-risk group was characterized by lower proliferation, higher metabolism, increased activated immune microenvironment, and lower TIDE scores, suggesting a better response to immunotherapy. The high-risk group displayed hypomethylation, higher copy number alterations, mutations, and more overexpression of immune-checkpoint genes, which might jointly lead to poor outcomes. The prognostic accuracy of the 10-GPS was further validated in 47 institutional transcriptomic samples and 101 public proteomic samples. In conclusion, the 10-GPS is a robust predictor of the clinical outcome for early HCC patients and could help evaluate prognosis and characterize molecular heterogeneity.