Prepared MW-Immunosensitizers Precisely Release NO to Downregulate HIF-1α Expression and Enhance Immunogenic Cell Death.

Microwave thermotherapy (MWTT) has limited its application in the clinic due to its high rate of metastasis and recurrence after treatment. Nitric oxide (NO) is a gaseous molecule that can address the high metastasis and recurrence rates after MWTT by increasing thermal sensitivity, down-regulating the expression of hypoxia-inducible factor-1 (HIF-1), and inducing the immunogenic cell death (ICD). Therefore, GaMOF-Arg is designed, a gallium-based organic skeleton material derivative loaded with L-arginine (L-Arg), and coupled the mitochondria-targeting drug of triphenylphosphine (TPP) on its surface to obtain GaMOF-Arg-TPP (GAT) MW-immunosensitizers. When GAT MW-immunosensitizers are introduced into mice through the tail vein, reactive oxygen species (ROS) are generated and L-Arg is released under MW action. Then, L-Arg reacts with ROS to generate NO, which not only downregulates HIF-1 expression to improve tumor hypoxia exacerbated by MW, but also enhances immune responses by augment calreticulin (CRT) exposure, high mobility group box 1 (HMGB1) release, and T-cell proliferation to achieve prevention of tumor metastasis and recurrence. In addition, NO can induce mitochondria damage to increase their sensitivity to MWTT. This study provides a unique insight into the use of metal-organic framework MW-immunosensitizers to enhance tumor therapy and offers a new way to treat cancer efficiently.

A systems biology-based approach to screen key splicing factors in hepatocellular carcinoma.

A splicing factor is as an important upstream regulator of the alternative splicing process. Hence, it is considered to be a therapeutic target for hepatocellular carcinoma (HCC) tissues. In this study, a systems biology-based methodology was used to screen the essential splicing factors precisely and efficiently. A more comprehensive set of alternative splicing events, which were linked to patient survival, was constructed by performing the bivariate Cox regression and receiver operating characteristic (ROC) analyses. Then, the expression data was obtained from The Cancer Genome Altas (TCGA) data set and the three Gene Expression Omnibus (GEO) datasets. It was used to obtain the survival-related splicing factors, which showed a significantly differential expression in the tumor and normal tissues. Using the topological properties of the bipartite graph association network of the alternative splicing events and the splicing factors, we identified the five key splicing factors. Among them, four factors were found to play a prominent role in the development of HCC. The remaining factor was Survival Motor Neuron Domain Containing 1(SMNDC1), which showed a positive correlation with the immune cell infiltration, the biomarkers of immune cells, and the immune checkpoint genes. By performing quantitative real-time polymerase chain reaction analyses, we proved that SMNDC1 was overexpressed in tumor cells. Following the knockdown of its expression, the proliferation and the migration of HCC cells could be suppressed. These results confirmed that the screening method of this study was reliable and accurate. It provided new insights into the mechanism through which splicing factors elicit tumor development.

PDK1 regulates the progression of esophageal squamous cell carcinoma through metabolic reprogramming.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest human malignancies characterized by late-stage diagnosis, drug resistance, and poor prognosis. Pyruvate dehydrogenase kinase 1 (PDK1) plays an important role in regulating the metabolic reprogramming of cancer cells. However, its expression, function, and regulatory mechanisms of PDK1 in ESCC have not been reported. In this study, we found that PDK1 silence and dichloroacetic acid (DCA) significantly inhibited the growth of ESCC cells and induced cell apoptosis. Interestingly, PDK1 is a direct target of miR-6516-5p, and miR-6516-5p/PDK1 axis suppressed the growth of ESCC cell by inhibiting glycolysis. Moreover, DCA and cisplatin (cis-diammine-dichloroplatinum, DDP) synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress via the inhibition of the Keap1/Nrf2 signaling pathway. And, Tert-butylhydroquinone (TBHQ), a specific activator of the Keap1/Nrf2 signaling, could diminish the synergic antitumor effects of DCA and DDP on ESCC cells. Collectively, our findings indicate that PDK1 may regulate the progression of ESCC by metabolic reprogramming, which provides new strategy for the treatment of ESCC.

Genome-wide methylomic analyses identify prognostic epigenetic signature in lower grade glioma.

Glioma is the most malignant and aggressive type of brain tumour with high heterogeneity and mortality. Although some clinicopathological factors have been identified as prognostic biomarkers, the individual variants and risk stratification in patients with lower grade glioma (LGG) have not been fully elucidated. The primary aim of this study was to identify an efficient DNA methylation combination biomarker for risk stratification and prognosis in LGG. We conducted a retrospective cohort study by analysing whole genome DNA methylation data of 646 patients with LGG from the TCGA and GEO database. Cox proportional hazard analysis was carried out to screen and construct biomarker model that predicted overall survival (OS). The Kaplan-Meier survival curves and time-dependent ROC were constructed to prove the efficiency of the signature. Then, another independent cohort was used to further validate the finding. A two-CpG site DNA methylation signature was identified by multivariate Cox proportional hazard analysis. Further analysis indicated that the signature was an independent survival predictor from other clinical factors and exhibited higher predictive accuracy compared with known biomarkers. This signature was significantly correlated with immune-checkpoint blockade, immunotherapy-related signatures and ferroptosis regulator genes. The expression pattern and functional analysis showed that these two genes corresponding with two methylation sites contained in the model were correlated with immune infiltration level, and involved in MAPK and Rap1 signalling pathway. The signature may contribute to improve the risk stratification of patients and provide a more accurate assessment for precision medicine in the clinic.

Identification and Validation of Ferroptosis-Related DNA Methylation Signature for Predicting the Prognosis and Guiding the Treatment in Cutaneous Melanoma.

Cutaneous melanoma (CM) is one of the most aggressive skin tumors with a poor prognosis. Ferroptosis is a newly discovered form of regulated cell death that is closely associated with cancer development and immunotherapy. The aim of this study was to establish and validate a ferroptosis-related gene (FRG) DNA methylation signature to predict the prognosis of CM patients using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. A reliable four-FRG DNA methylation prognostic signature was constructed via Cox regression analysis based on TCGA database. Kaplan-Meier analysis showed that patients in the high-risk group tended to have a shorter overall survival (OS) than the low-risk group in both training TCGA and validation GEO cohorts. Time-dependent receiver operating characteristic (ROC) analysis showed the areas under the curve (AUC) at 1, 3, and 5 years were 0.738, 0.730, and 0.770 in TCGA cohort and 0.773, 0.775, and 0.905 in the validation cohort, respectively. Univariate and multivariate Cox regression analyses indicated that the signature was an independent prognostic indicator of OS in patients with CM. Immunogenomic profiling showed the low-risk group of patients had a higher immunophenoscore, and most immune checkpoints were negatively associated with the risk signature. Functional enrichment analysis revealed that immune response and immune-related pathways were enriched in the low-risk group. In conclusion, we established and validated a four-FRG DNA methylation signature that independently predicts prognosis in CM patients. This signature was strongly correlated with the immune landscape, and may serve as a biomarker to guide clinicians in making more precise and personalized treatment decisions for CM patients.

Glucose Metabolism, Neural Cell Senescence and Alzheimer's Disease.

Alzheimer's disease (AD), an elderly neurodegenerative disorder with a high incidence and progressive memory decline, is one of the most expensive, lethal, and burdening diseases. To date, the pathogenesis of AD has not been fully illustrated. Emerging studies have revealed that cellular senescence and abnormal glucose metabolism in the brain are the early hallmarks of AD. Moreover, cellular senescence and glucose metabolism disturbance in the brain of AD patients may precede amyloid-ß deposition or Tau protein phosphorylation. Thus, metabolic reprogramming targeting senescent microglia and astrocytes may be a novel strategy for AD intervention and treatment. Here, we recapitulate the relationships between neural cell senescence and abnormal glucose metabolism (e.g., insulin signaling, glucose and lactate metabolism) in AD. We then discuss the potential perspective of metabolic reprogramming towards an AD intervention, providing a theoretical basis for the further exploration of the pathogenesis of and therapeutic approach toward AD.

YAP/TEAD4-induced KIF4A contributes to the progression and worse prognosis of esophageal squamous cell carcinoma.

Aberrant expression of kinesin family member 4A (KIF4A), which is associated with tumor progression, has been reported in several types of cancer. However, its expression and the underlying molecular mechanisms regulating the transcription of KIF4A in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that high KIF4A expression was positively correlated with tumor stage and poor prognosis in ESCC patients. KIF4A silencing significantly inhibited the growth and migration of ESCC cells, arrested cell cycle, and induced apoptosis. Interestingly, KIF4A expression was positively related to the expression of YAP in human ESCC tissues. YAP knockdown or disrupting YAP/TEAD4 interaction by verteporfin repressed KIF4A expression. Also, KIF4A knockdown significantly inhibited the cell growth induced by YAP overexpression. Mechanistically, YAP activated KIF4A transcriptional expression by TEAD4-mediated direct binding to KIF4A promoter. Finally, KIF4A knockdown and verteporfin treatment synergistically inhibited tumor growth in xenograft models. Together, these results indicated that KIF4A, a novel target gene of YAP/TEAD4, may be a progression and prognostic biomarker of ESCC. Targeting drugs for KIF4A combined with YAP inhibitor may be a novel therapeutic strategy for ESCC.

Pan-cancer analysis identifies ESM1 as a novel oncogene for esophageal cancer.

BACKGROUND: Recent studies highlight the crucial role of endothelial cell-specific molecule 1 (ESM1) in the development of multiple cancer types. However, its aberrant expression and prognostic value in human pan-cancer have largely not been described. METHODS AND RESULTS: In this study, we used The Cancer Genome Atlas (TCGA) analysis databases to explore the expression level and prognostic significance of ESM1 in 33 types of human cancer. ESM1 was shown to be over-expressed in 12 cancer types, including BLCA, BRCA, COAD, CHOL, ESCA, HNSC, KIRC, KICH, LIHC, STAD, THCA, and UCEC. The expression of ESM1 was significantly correlated with the overall survival (OS) of patients in CESC, ESCA, KIRC, and KIRP. In addition, high ESM1 level indicated poor disease-free survival (DFS) of patients with ACC, ESCA, PRAD, LIHC, KIRP, and UCS. Through comparative analysis, we discovered that ESM1 was dramatically up-regulated in esophageal cancer (ESCA) and associated with worse patient OS and DFS. The elevation of ESM1 in ESCA was confirmed by the datasets from Cancer RNA-Seq Nexus (CRN) and Gene Expression Omnibus (GEO). Based on Gene Set Enrichment Analysis (GSEA), we analyzed the co-expressed genes of ESM1 in ESCA, and found that ESM1 was closely implicated in cell proliferation and migration and the regulation of Janus kinase (JAK) signaling pathway. Functionally, knockdown of ESM1 significantly suppressed cell proliferation and migration, and decreased the protein level of JAK1. CONCLUSIONS: Taken together, our results suggest for the first time that ESM1 functions as an oncogene and may be a clinical biomarker and/or therapeutic target in ESCA.

LncRNA WDFY3-AS2 suppresses proliferation and invasion in oesophageal squamous cell carcinoma by regulating miR-2355-5p/SOCS2 axis.

Long non-coding RNAs (lncRNAs) widely participate in ESCC development and progression; however, the prognostic factors and therapeutic strategies implicated in ESCC development and progression remain to be under investigation. The purpose of the current study was to explore whether WDFY3-AS2 may be a potential prognostic factor and investigate its biological functions in ESCC. Here, WDFY3-AS2 was frequently down-regulated in ESCC tissues and cells, and its expression was correlated with TNM stage, lymph node metastasis and poor prognosis of ESCC patients. Moreover, WDFY3-AS2 down-regulation significantly promoted cell proliferation and invasion, whereas WDFY3-AS2 up-regulation markedly suppressed cell proliferation and invasion in ESCC EC9706 and TE1 cells, coupled with EMT phenotype alterations. WDFY3-AS2 functioned as a competing endogenous RNA (ceRNA) for sponging miR-2355-5p, further resulted in the up-regulation of its target gene SOCS2, followed by suppression of JAK2/Stat5 signalling pathway, to suppress ESCC cell proliferation and invasion in EC9706 and TE1 cells. These findings suggest that WDFY3-AS2 may participate in ESCC development and progression, and may be a novel prognostic factor for ESCC patients, and thus targeting WDFY3-AS2/miR-2355-5p/SOCS2 signalling axis may be a novel therapeutic strategy for ESCC patients.

Nicotinamide N-methyltransferase decreases 5-fluorouracil sensitivity in human esophageal squamous cell carcinoma through metabolic reprogramming and promoting the Warburg effect.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with poor prognosis. And different individuals respond to the same drug differently. Increasing evidence has confirmed that metabolism reprogramming was involved in the drug sensitivity of tumor cells. However, the potential molecular mechanism of 5-fluorouracil (5-FU) sensitivity remains to be elucidated in ESCC cells. In this study, we found that the 5-FU sensitivity of TE1 cells was lower than that of EC1 and Eca109 cells. Gas chromatography-mass spectrometry analysis results showed that nicotinate and nicotinamide metabolism and tricarboxylic acid cycle were significantly different in these three cell lines. Nicotinamide N-methyltransferase (NNMT), a key enzyme of nicotinate and nicotinamide metabolism, was significantly higher expressed in TE1 cells than that in EC1 and Eca109 cells. Therefore, the function of NNMT on 5-FU sensitivity was analyzed in vitro and in vivo. NNMT downregulation significantly increased 5-FU sensitivity in TE1 cells. Meanwhile, the glucose consumption and lactate production were decreased, and the expression of glycolysis-related enzymes hexokinase 2, lactate dehydrogenase A, and phosphoglycerate mutase 1 were downregulated in NNMT knockdown TE1 cells. Besides, overexpression of NNMT in EC1 and Eca109 cells caused the opposite effects. Moreover, when glycolysis was inhibited by 2-deoxyglucose, the roles of NNMT on 5-FU sensitivity was weakened. In vivo experiments showed that NNMT knockdown significantly increased the sensitivity of xenografts to 5-FU and suppressed the Warburg effect. Overall, these results demonstrated that NNMT decreases 5-FU sensitivity in human ESCC cells through promoting the Warburg effect, suggesting that NNMT may contribute to predict the treatment effects of the clinical chemotherapy in ESCC.

CASC5 is a potential tumour driving gene in lung adenocarcinoma.

Previous studies have shown that cancer susceptibility candidate 5 (CASC5) plays important roles in several types of cancer. But its expression and clinical significance in human pan-cancer remain largely unclear. In the present study, we comprehensively analysed the expression profile and prognostic values of CASC5 in pan-cancer across 33 cancer types based on the online TCGA analysis databases. CASC5 was found to be abnormally expressed in 16 types of cancer. In addition, dysregulated expression of CASC5 was closely associated with patient overall survival (OS) in kidney renal papillary cell carcinoma (KIRP), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD) and thymoma (THYM). By comparative analysis, we found that CASC5 was significantly up-regulated in LUAD and predicted poor patient OS. High CASC5 expression was closely correlated with tumour advanced stages of patients with LUAD. Through GSEA based on the KEGG database, CASC5 was found to be closely related to DNA replication and microRNA regulation in LUAD. Functionally, knockdown of CASC5 could inhibit cell proliferation of LUAD cells in vitro, rather than affecting cell migration and invasion. Mechanistically, CASC5 promoted proliferation of LUAD cells by targeting miR-139-5p. Collectively, our findings reveal that CASC5 is a novel oncogenic gene in LUAD and may be a potential clinical target and (or) biomarker for this human malignancy. SIGNIFICANCE OF THE STUDY: In this study, we for the first time comprehensively analysed the transcriptional level and prognostic significance of CASC5 in human pan-cancer across 33 cancer types using online TCGA databases. Our study indicates that CASC5 is aberrantly expressed in many tumours and is closely related to the patient overall survival of several tumour types. Our findings reveal that CASC5 is a novel oncogene in LUAD based on bioinformatic analysis and functional experiments. Mechanistically, CASC5 promoted LUAD proliferation by targeting miR-139-5p. Results of this study suggest that CASC5 is a potential clinical target and (or) biomarker for LUAD.

High-throughput sequencing and degradome analysis reveal neutral evolution of Cercis gigantea microRNAs and their targets.

MAIN CONCLUSION: High-throughput sequencing and degradome analysis for Cercis gigantea identified 194 known miRNAs and 23 novel miRNAs with 61 targets. The comparison results of highly conserved miRNAs and non-conserved miRNAs implied that C. gigantea miRNAs were subjected to the neutral evolution. MicroRNAs play a key role in post-transcriptionally regulating gene expression during plant growth, development and other various biological processes. Although numerous miRNAs have been identified and documented, to date, there are no reports on Cercis gigantea (C. gigantea) miRNAs. In this study, C. gigantea miRNAs and their target genes were investigated by extracting RNA from young roots, tender stems, young leaves, and flower buds of C. gigantea to establish a small RNA and a degradome library to further sequence. This study identified 194 known miRNAs belonging to 52 miRNA families and 23 novel miRNAs. Among these, 158 miRNAs from 27 miRNA families were highly conserved and existed in a plurality of plants. In addition, 60 different targets for 30 known families and one target for novel miRNA were identified by high-throughput sequencing and degradome analysis in C. gigantea. The comparison results revealed that highly conserved miRNAs have higher expression levels, more family members and more targets than non-conserved miRNAs, indicating that C. gigantea miRNAs were subjected to the neutral evolution. Meanwhile, these conserved miRNAs were also found to be involved in auxin signal transduction, regulation of transcription, and other developmental processes, which will help further understanding regulatory mechanisms of C. gigantea miRNAs.

Cuproptosis-related gene-located DNA methylation in lower-grade glioma: Prognosis and tumor microenvironment.

Cuproptosis a novel copper-dependent cell death modality, plays a crucial part in the oncogenesis, progression and prognosis of tumors. However, the relationships among DNA-methylation located in cuproptosis-related genes (CRGs), overall survival (OS) and the tumor microenvironment remain undefined. In this study, we systematically assessed the prognostic value of CRG-located DNA-methylation for lower-grade glioma (LGG). Clinical and molecular data were sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We employed Cox hazard regression to examine the associations between CRG-located DNA-methylation and OS, leading to the development of a prognostic signature. Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) analyses were utilized to gauge the accuracy of the signature. Gene Set Enrichment Analysis (GSEA) was applied to uncover potential biological functions of differentially expressed genes between high- and low-risk groups. A three CRG-located DNA-methylation prognostic signature was established based on TCGA database and validated in GEO dataset. The 1-year, 3-year, and 5-year area under the curve (AUC) of ROC curves in the TCGA dataset were 0.884, 0.888, and 0.859 while those in the GEO dataset were 0.943, 0.761 and 0.725, respectively. Cox-regression-analyses revealed the risk signature as an independent risk factor for LGG patients. Immunogenomic profiling suggested that the signature was associated with immune infiltration level and immune checkpoints. Functional enrichment analysis indicated differential enrichment in cell differentiation in the hindbrain, ECM receptor interactions, glycolysis and reactive oxygen species pathway across different groups. We developed and verified a novel CRG-located DNA-methylation signature to predict the prognosis in LGG patients. Our findings emphasize the potential clinical implications of CRG-located DNA-methylation indicating that it may serve as a promising therapeutic target for LGG patients.

Cuproptosis-related DNA methylation signature predict prognosis and immune microenvironment in cutaneous melanoma.

The prognosis for Cutaneous Melanoma (CM), a skin malignant tumor that is extremely aggressive, is not good. A recently identified type of controlled cell death that is intimately related to immunotherapy and the development of cancer is called cuproptosis. Using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, we developed and validated a DNA-methylation located in cuproptosis death-related gene prognostic signature (CRG-located DNA-methylation prognostic signature) to predict CM's prognosis. Kaplan-Meier analysis of our TCGA and GEO cohorts showed that high-risk patients had a shorter overall survival. The area under the curve (AUC) for the TCGA cohort was 0.742, while for the GEO cohort it was 0.733, according to the receiver operating characteristic (ROC) analysis. Furthermore, this signature was discovered as an independent prognostic indicator over CM patients based on Cox-regression analysis. Immunogenomic profiling indicated that majority immune-checkpoints got an opposite relationship with the signature, and patients in the group at low risk got higher immunophenoscore. Several immune pathways were enriched, according to functional enrichment analysis. In conclusion, a prognostic methylation signature for CM patients was established and confirmed. Because of its close relationship to the immune landscape, this signature may help clinicians make more accurate and individualized choices regarding therapy.

Exploring the Role of DNA Methylation Located in Cuproptosis-Related Genes: Implications for Prognosis and Immune Landscape in Hepatocellular Carcinoma.

BACKGROUND: Copper dysregulation has been linked to liver disease, cardiac dysfunction, neuropathy, and anemia. Previous investigations have been undertaken to demonstrate the impact of cuproptosis-related genes (CRGs) on the poor prognosis of hepatocellular carcinoma (HCC), while the prognostic significance and beneath molecular basis of DNA-methylation sites located in CRGs remain unknown. This study aims to identify CRG-located DNA-methylation sites linked to patient prognosis and establish a novel prognostic biomarkers combination for CRG-located DNA-methylation signature. METHODS: The prognostic biomarkers combination was established through multivariate-Cox-regression after CRG-located DNA-methylation sites tied to the outcome of patients emerged by univariate-Cox-regression. The correlation between signature and immune cell infiltration levels, immune-checkpoint-associated genes was analyzed using spearman correlation and the difference was contrasted between different groups utilizing the Mann-Whitney-U test. Real-time quantitative methylation-specific polymerase chain reaction (RT-qMSP) was used to identify gene methylation. RESULTS: A novel prognostic biomarkers combination for CRG-located DNA-methylation signature was established. Subsequently, the independence of this methylation signature from clinical features and its correlation with immune infiltrative and immune checkpoints in HCC were also investigated. DNA methylation alterations can influence the onset, development, and treatment of various tumors by regulating the transcription of corresponding genes. Our analysis found that cg05706061 contained in prognosis signature was located in the promoter region of the cuproptosis-related gene SLC31A2. The DNA-methylation level of cg05706061 demonstrated significantly different between tumor and normal tissue, and significantly correlated with the expression of SLC31A2. We further investigated the promoter methylation status of SLC31A2 by qMSP, the result showed that the DNA-methylation level of SLC31A2 in HCC cell lines were significantly decreased compared with normal liver cells. CONCLUSIONS: Our findings reveal possible mechanisms of CRG-located DNA-methylation on the advancement of HCC and offers new perspectives for prognostic assessment and treatment options.

Magnetic Bimetallic Heterointerface Nanomissiles with Enhanced Microwave Absorption for Microwave Thermal/Dynamics Therapy of Breast Cancer.

Microwave thermotherapy (MWT) has shown great potential in cancer treatment due to its deep tissue penetration and minimally invasive nature. However, the poor microwave absorption (MA) properties of the microwave thermal sensitizer in the medical frequency band significantly limit the thermal effect of MWT and then weaken the therapeutic efficacy. In this paper, a Ni-based multilayer heterointerface nanomissile of MOFs-Ni-Ru@COFs (MNRC) with improved MA performance in the desired frequency band via introducing magnetic loss and dielectric loss is developed for MWT-based treatment. The loading of the Ni nanoparticle in MNRC mediates the magnetic loss, introducing the MA in the medical frequency band. The heterointerface formed in the MNRC by nanoengineering induces significant interfacial polarization, increasing the dielectric loss and then enhancing the generated MA performance. Moreover, MNRC with the strong MA performance in the desired frequency range not only enhances the MW thermal effect of MWT but also facilitates the electron and energy transfer, generating reactive oxygen species (ROS) at tumor sites to mediate microwave dynamic therapy (MDT). The strategy of strengthening the MA performance of the sensitizer in the medical frequency band to improve MWT-MDT provides a direction for expanding the clinical application of MWT in tumor treatment.

Construction and validation of a novel prognostic signature for cutaneous melanoma based on ferroptosis-related genes.

Ferroptosis, a recently uncovered iron-dependent, non-apoptotic cell death process, has been increasingly linked to cancer development. In this study, our objective was to develop a prognostic model centered on ferroptosis-related genes (FRGs) and assess its efficacy as an overall survival (OS) prediction biomarker. We conducted a systematic analysis of cutaneous melanoma (CM) and devised a novel ferroptosis-related prognostic signature (FRGSig) using the TCGA database. An independent dataset from GSE65904 was employed to corroborate the validity of the FRGSig. Both univariate and multivariate Cox proportional hazard regression analyses were utilized to construct a FRGSig composed of five FRGs. mRNA expression and immunohistochemistry (IHC) analysis demonstrated that the expression of FRGSig genes varied between tumor and normal tissues. According to Kaplan-Meier analysis, patients with elevated FRGsig scores faced a worse prognosis. The predictive accuracy of FRGSig was evaluated using the time-dependent receiver operating characteristic curve (ROC), with the area under the curve (AUC) values for 1, 3, and 5 OS at 0.682, 0.711, 0.735 in the TCGA cohort, and 0.662, 0.695, 0.712 in the validation dataset, respectively. Univariate and multivariate Cox regression analyses demonstrated that FRGSig served as an independent prognostic factor. Further analysis revealed a significant relationship between FRGSig and Tumor Mutational Burden (TMB) as well as immune infiltration levels. Gene set enrichment analysis (GSEA) disclosed functional disparities between high- and low-risk groups, suggesting that immune checkpoint-related pathways could be instrumental in the improved prognosis of the low-risk group. Taken together, the FRGSig has potential guidance for prognosis prediction and clinical treatment of CM.

Logic gate controlled theranostic nanoagents for in situ microwave thermal therapeutic efficacy evaluation.

In vivo monitoring of treatment response is of great significance for tumor therapy in clinical trials, but it remains a formidable challenge. Herein, we demonstrate a logic AND gate theranostic nanoagent that responds to the coexistence of endogenous and exogenous stimuli, namely HAuCl4@1-Tetradecanol@Gd-based metal-organic framework@SiO2 nanocomposites (APGS NCs). Upon microwave (MW) irradiation, HAuCl4 in the inner part of APGS NCs reacts with the tumor-associated glutathione (GSH). Subsequently, it transforms into an active luminescent form of Au@1-Tetradecanol@Gd-MOF@SiO2 nanocomposites (AuPGS NCs). The intensity of generated fluorescence is correlated with the tumor thermal-injury status. Thus, the generation of AuPGS NCs with high intensity fluorescence under the co-activation of MW and GSH can visualize the treatment effects during MW thermal therapy and instantly modulate the irradiation time and range for optimal outcomes. Hence, this logic gate controlled APGS NCs makes MW thermal therapy eliminate tumor cells completely. This research offers an effective strategy for the design and preparation of activatable theranostic nanoagents for precise tumor imaging and therapy.

Programmed Upregulation of HSP70 by Metal-Organic Frameworks Nanoamplifier for Enhanced Microwave Thermal-Immunotherapy.

Thermotherapy can directly kill tumor cells whilst being accompanied by immune-enhancing effects. However, this immune-enhancing effect suffers from insufficient expression of immune response factors (e.g., heat shock protein 70, HSP70), resulting in no patient benefiting due to the recurrence of tumor cells after thermotherapy. Herein, a nanoengineered strategy of programmed upregulating of the immune response factors for amplifying synergistic therapy is explored. Metal-organic frameworks nanoamplifiers (teprenone/nitrocysteine@ZrMOF-NH2 @L-menthol@triphenylphosphine, GGA/CSNO@ZrMOF-NH2 -LM-TPP nanoamplifier, and GCZMT nanoamplifier) achieve excellent microwave (MW) thermal-immunotherapy by programmed induction of HSP70 expression. After intravenous administration, GCZMT nanoamplifiers target the mitochondria, and then release nitric oxide (NO) under MW irradiation. NO inhibits the growth of tumor cells by interfering with the energy supply of cells. Subsequently, under the combination of MW, NO, and GGA, HSP70 expression can be programmed upregulated, which can induce the response of cytotoxic CD4+ T cells and CD8+ T cells, and effectively activate antitumor immunotherapy. Hence, GCZMT nanoamplifier-mediated MW therapy can achieve a satisfactory therapeutic effect with the tumor inhibition of 97%. This research offers a distinctive insight into the exploitation of metal-organic frameworks nanoamplifiers for enhanced tumor therapy, which provides a new approach for highly effective cancer treatment.

Nanocarrier-based Drug Delivery System for Cancer Therapeutics: A Review of the Last Decade.

In recent years, due to the shortcomings of conventional chemotherapy, such as poor bioavailability, low treatment index, and unclear side effects, the focus of cancer research has shifted to new nanocarriers of chemotherapeutic drugs. By using biodegradable materials, nanocarriers generally have the advantages of good biocompatibility, low side effects, targeting, controlled release profile, and improved efficacy. More to the point, nanocarrier based anti-cancer drug delivery systems clearly show the potential to overcome the problems associated with conventional chemotherapy. In order to promote the in-depth research and development in this field, we herein summarized and analyzed various nanocarrier based drug delivery systems for cancer therapy, including the concepts, types, characteristics, and preparation methods. The active and passive targeting mechanisms of cancer therapy were also included, along with a brief introduction of the research progress of nanocarriers used for anti-cancer drug delivery in the past decade.