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International Journal of Molecular... Jun 2024Photodynamic Therapy (PDT) is recognized for its exceptional effectiveness as a promising cancer treatment method. However, it is noted that overexposure to the dosage...
Photodynamic Therapy (PDT) is recognized for its exceptional effectiveness as a promising cancer treatment method. However, it is noted that overexposure to the dosage and sunlight in traditional PDT can result in damage to healthy tissues, due to the low tumor selectivity of currently available photosensitizers (PSs). To address this challenge, we introduce herein a new strategy where the small molecule-targeted agent, erlotinib, is integrated into a boron dipyrromethene (BODIPY)-based PS to form conjugate to enhance the precision of PDT. This conjugate demonstrates optical absorption, fluorescence emission, and singlet oxygen generation efficiency comparable to the reference compound , which lacks erlotinib. In vitro studies reveal that, after internalization, conjugate predominantly accumulates in the lysosomes of HepG2 cells, exhibiting significant photocytotoxicity with an IC value of 3.01 µM. A distinct preference for HepG2 cells over HELF cells is observed with conjugate but not with compound . In vivo experiments further confirm that conjugate has a specific affinity for tumor tissues, and the combination treatment of conjugate with laser illumination can effectively eradicate H22 tumors in mice with outstanding biosafety. This study presents a novel and potential PS for achieving precise PDT against cancer.
Topics: Humans; Photochemotherapy; Animals; Mice; Porphobilinogen; Photosensitizing Agents; Hep G2 Cells; Liver Neoplasms; Erlotinib Hydrochloride; Boron Compounds
PubMed: 38928126
DOI: 10.3390/ijms25126421 -
Genes Jun 2024Liver cancer manifests as a profoundly heterogeneous malignancy, posing significant challenges in terms of both therapeutic intervention and prognostic evaluation. Given...
Liver cancer manifests as a profoundly heterogeneous malignancy, posing significant challenges in terms of both therapeutic intervention and prognostic evaluation. Given that the liver is the largest metabolic organ, a prognostic risk model grounded in single-cell transcriptome analysis and a metabolic perspective can facilitate precise prevention and treatment strategies for liver cancer. Hence, we identified 11 cell types in a scRNA-seq profile comprising 105,829 cells and found that the metabolic activity of malignant cells increased significantly. Subsequently, a prognostic risk model incorporating tumor heterogeneity, cell interactions, tumor cell metabolism, and differentially expressed genes was established based on eight genes; this model can accurately distinguish the survival outcomes of liver cancer patients and predict the response to immunotherapy. Analyzing the immune status and drug sensitivity of the high- and low-risk groups identified by the model revealed that the high-risk group had more active immune cell status and greater expression of immune checkpoints, indicating potential risks associated with liver cancer-targeted drugs. In summary, this study provides direct evidence for the stratification and precise treatment of liver cancer patients, and is an important step in establishing reliable predictors of treatment efficacy in liver cancer patients.
Topics: Humans; Liver Neoplasms; Prognosis; Single-Cell Analysis; RNA-Seq; Gene Expression Regulation, Neoplastic; Transcriptome; Biomarkers, Tumor; Gene Expression Profiling; Single-Cell Gene Expression Analysis; Metabolic Reprogramming
PubMed: 38927691
DOI: 10.3390/genes15060755 -
Biomolecules Jun 2024Disulfidptosis, a newly identified mode of programmed cell death, is yet to be comprehensively elucidated with respect to its multi-omics characteristics in tumors,...
Disulfidptosis, a newly identified mode of programmed cell death, is yet to be comprehensively elucidated with respect to its multi-omics characteristics in tumors, specific pathogenic mechanisms, and antitumor functions in liver cancer. This study included 10,327 tumor and normal tissue samples from 33 cancer types. In-depth analyses using various bioinformatics tools revealed widespread dysregulation of disulfidptosis-related genes (DRGs) in pan-cancer and significant associations with prognosis, genetic variations, tumor stemness, methylation levels, and drug sensitivity. Univariate and multivariate Cox regression and LASSO regression were used to screen and construct prognosis-related hub DRGs and predictive models in the context of liver cancer. Subsequently, single cell analysis was conducted to investigate the subcellular localization of , a hub DRG, in various solid tumors. Western blotting was performed to validate the expression of at both cellular and tissue levels. Additionally, functional experiments, including CCK8, EdU, clone, and transwell assays, indicated that knockdown promoted the proliferative and invasive capacities of liver cancer cells. Therefore, this study elucidated the multi-omics characteristics of DRGs in pan-cancer and established a prognostic model for liver cancer. Additionally, this study revealed the molecular functions of in liver cancer, suggesting its potential as a therapeutic target for this disease.
Topics: Humans; Liver Neoplasms; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Cell Proliferation; Prognosis; Apoptosis; Computational Biology; Multiomics
PubMed: 38927080
DOI: 10.3390/biom14060677 -
Biomolecules Jun 2024Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers... (Review)
Review
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial-mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages-predominantly with a pro-tumoral role-hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Carcinogenesis; Tumor Microenvironment; Signal Transduction; Animals
PubMed: 38927059
DOI: 10.3390/biom14060656 -
Biomolecules Jun 2024Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been...
Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly co-expressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph-based statistics. Using the Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of or driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-glycan, mevalonate and sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Transcriptome; Gene Expression Regulation, Neoplastic; Gene Expression Profiling; Metabolic Networks and Pathways; Tumor Suppressor Protein p53; Cell Line, Tumor; beta Catenin; Mutation
PubMed: 38927057
DOI: 10.3390/biom14060653 -
Journal of Nanobiotechnology Jun 2024As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of...
As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu, 3,3'-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer.
Topics: Copper; Animals; Carcinoma, Hepatocellular; Photochemotherapy; Liver Neoplasms; Mice; Humans; Photosensitizing Agents; Mice, Inbred BALB C; Cell Line, Tumor; Reactive Oxygen Species; Angiogenesis Inhibitors; Porphyrins; Chlorophyllides; Glutathione; Nanoparticles; Catalysis; Metal Nanoparticles; Drug Liberation; Mice, Nude; Antineoplastic Agents
PubMed: 38926721
DOI: 10.1186/s12951-024-02626-x -
BMC Cancer Jun 2024It is unclear whether hepatectomy, which ranges in invasiveness from partial to major hepatectomy, is safe and feasible for older adult patients. Therefore, we compared... (Observational Study)
Observational Study
BACKGROUND
It is unclear whether hepatectomy, which ranges in invasiveness from partial to major hepatectomy, is safe and feasible for older adult patients. Therefore, we compared its postoperative complications and long-term outcomes between younger and older adult patients.
METHODS
Patients who underwent hepatectomies for hepatocellular carcinoma (N = 883) were evaluated. Patients were divided into two groups: aged < 75 years (N = 593) and ≥ 75 years (N = 290). Short-term outcomes and prognoses were compared between the groups in the entire cohort. The same analyses were performed for the major hepatectomy cohort.
RESULTS
In the entire cohort, no significant differences were found in complications between patients aged < 75 and ≥ 75 years, and the multivariate analysis did not reveal age as a prognostic factor for postoperative complications. However, overall survival was significantly worse in older patients, although no significant differences were noted in time to recurrence or cancer-specific survival. In the multivariate analyses of time to recurrence, overall survival, and cancer-specific survival, although older age was an independent poor prognostic factor for overall survival, it was not a prognostic factor for time to recurrence and cancer-specific survival. In the major hepatectomy subgroup, short- and long-term outcomes, including time to recurrence, overall survival, and cancer-specific survival, did not differ significantly between the age groups. In the multivariate analysis, age was not a significant prognostic factor for complications, time to recurrence, overall survival, or cancer-specific survival.
CONCLUSION
Hepatectomy, including minor and major hepatectomy, may be safe and oncologically feasible options for selected older adult patients with hepatocellular carcinoma.
Topics: Humans; Hepatectomy; Liver Neoplasms; Carcinoma, Hepatocellular; Aged; Male; Female; Retrospective Studies; Middle Aged; Aged, 80 and over; Feasibility Studies; Postoperative Complications; Prognosis; Treatment Outcome; Age Factors; Neoplasm Recurrence, Local; Adult
PubMed: 38926636
DOI: 10.1186/s12885-024-12514-0 -
Scientific Reports Jun 2024Transarterial chemoembolization (TACE) represent the standard of therapy for non-operative hepatocellular carcinoma (HCC), while prediction of long term treatment...
Transarterial chemoembolization (TACE) represent the standard of therapy for non-operative hepatocellular carcinoma (HCC), while prediction of long term treatment outcomes is a complex and multifactorial task. In this study, we present a novel machine learning approach utilizing radiomics features from multiple organ volumes of interest (VOIs) to predict TACE outcomes for 252 HCC patients. Unlike conventional radiomics models requiring laborious manual segmentation limited to tumoral regions, our approach captures information comprehensively across various VOIs using a fully automated, pretrained deep learning model applied to pre-TACE CT images. Evaluation of radiomics random survival forest models against clinical ones using Cox proportional hazard demonstrated comparable performance in predicting overall survival. However, radiomics outperformed clinical models in predicting progression-free survival. Explainable analysis highlighted the significance of non-tumoral VOI features, with their cumulative importance superior to features from the largest liver tumor. The proposed approach overcomes the limitations of manual VOI segmentation, requires no radiologist input and highlight the clinical relevance of features beyond tumor regions. Our findings suggest the potential of this radiomics models in predicting TACE outcomes, with possible implications for other clinical scenarios.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic; Deep Learning; Male; Female; Middle Aged; Aged; Tomography, X-Ray Computed; Treatment Outcome; Radiomics
PubMed: 38926517
DOI: 10.1038/s41598-024-65630-z -
Discovery Medicine Jun 2024As the most common type of primary liver cancer, hepatocellular carcinoma (HCC) is reportedly the third leading cause of cancer-related death globally. Advanced... (Review)
Review
As the most common type of primary liver cancer, hepatocellular carcinoma (HCC) is reportedly the third leading cause of cancer-related death globally. Advanced steatotic liver disease (SLD) emerges as the most prominent contributor to HCC worldwide. In this paper, we review the extrahepatic features of metabolic dysfunction-associated SLD that exacerbate the risk for HCC, including insulin resistance, obesity-related factors such as physical inactivity and dietary patterns, as well as influences of genetics, ethnicity, gender-specific hormonal differences, alcohol-associated liver disease (ALD), smoking habits, and alterations in gut microbiota. Additionally, the mechanisms underlying how these extrahepatic features contribute to the development, as well as the detection and surveillance of HCC, are elaborated. With a better understanding of these factors, targeted interventions can be designed to prevent HCC development or ameliorate its clinical outcomes.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Fatty Liver; Obesity; Insulin Resistance; Risk Factors; Gastrointestinal Microbiome
PubMed: 38926099
DOI: 10.24976/Discov.Med.202436185.103 -
International Journal of Radiation... Jul 2024Significant improvements within radioembolization imaging and dosimetry permit the development of an accurate and personalized pretreatment plan using technetium...
PURPOSE
Significant improvements within radioembolization imaging and dosimetry permit the development of an accurate and personalized pretreatment plan using technetium 99m-labeled macroaggregated albumin (Tc-MAA) and single-photon emission computed tomography (SPECT) combined with anatomical CT (SPECT/CT). Despite these potential advantages, the clinical transition to pretreatment protocols with SPECT/CT is hindered by their unknown safety constraints. This study aimed to address this issue by establishing novel dose limits for Tc-MAA SPECT/CT to enable quantitative pretreatment planning.
METHODS AND MATERIALS
Stratification criteria to determine images most viable for dosimetry analysis were created from a cohort of 85 patients. SPECT/CT, cone beam CT, and activity calculations derived from the local deposition method were used to create an accurate pretreatment protocol. Planar and SPECT/CT images were compared using linear regression and modified Bland-Altman analyses to convert accepted planar dose limits to SPECT/CT. To validate these new dose limits, activity calculations based on SPECT/CT were compared with those calculated with the body surface area and planar methods for three treatment plans.
RESULTS
A total of 38 of 85 patients were deemed viable for dosimetry analysis. SPECT yielded greater lung shunt fractions (LSFs) than planar imaging when LSFs were <4.89%, whereas SPECT yielded lower LSFs than planar imaging when LSFs were >4.89%. Planar to SPECT/CT dose conversions were 0.76×, 0.70×, and 0.55× for the whole liver, normal liver, and lungs, respectively. Patients with SPECT LSFs ≤4.89% were safely treated with the direct application of planar lung dose limits. Activity calculations with the newly established SPECT/CT dose limits were greater than those of the body surface area method by a median range of 33.1% to 61.9% and were lower than planar-based activity calculations by a median range of 12.5% to 13.7% for the whole liver and by 29.4% to 32.2% for the normal liver.
CONCLUSIONS
This study demonstrated a safe method for translating dose limits from Tc-MAA planar imaging to SPECT/CT. A robust pretreatment protocol was further developed guided by the current knowledge in the field. Established SPECT/CT dose limits safely treated 97.5% of patients and permitted the application of independent pretreatment planning with Tc-MAA SPECT/CT.
Topics: Humans; Technetium Tc 99m Aggregated Albumin; Single Photon Emission Computed Tomography Computed Tomography; Embolization, Therapeutic; Liver Neoplasms; Male; Female; Aged; Middle Aged; Radiotherapy Planning, Computer-Assisted; Radiopharmaceuticals; Aged, 80 and over; Body Surface Area; Cone-Beam Computed Tomography
PubMed: 38925768
DOI: 10.1016/j.ijrobp.2023.12.049