scholarly journals A novel signature constructed by ferroptosis-associated genes (FAGs) for the prediction of prognosis in bladder urothelial carcinoma (BLCA) and associated with immune infiltration

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiao-chen Luan ◽  
Teng-yue Zeng ◽  
Qi-jie Zhang ◽  
De-run Xia ◽  
Rong Cong ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Immune Cell ◽  
Risk Groups ◽  
The Cancer Genome Atlas ◽  
Prognostic Analysis ◽  
Regulated Cell Death ◽  
Bladder Urothelial Carcinoma ◽  
Prediction Of Prognosis ◽  
Pathway Analyses

Abstract Background Ferroptosis, a novel form of regulated cell death, has been implicated in the pathogenesis of cancers. Nevertheless, the potential function and prognostic values of ferroptosis in bladder urothelial carcinoma (BLCA) are complex and remain to be clarified. Therefore, we proposed to systematically examine the roles of ferroptosis-associated genes (FAGs) in BLCA. Methods According to The Cancer Genome Atlas (TCGA) database, differently expressed FAGs (DEFAGs) and differently expressed transcription factors (DETFs) were identified in BLCA. Next, the network between DEFAGs and DETFs, GO annotations and KEGG pathway analyses were performed. Then, through univariate, LASSO and multivariate regression analyses, a novel signature based on FAGs was constructed. Moreover, survival analysis, PCA analysis, t-SNE analysis, ROC analysis, independent prognostic analysis, clinicopathological and immune correlation analysis, and experimental validation were utilized to evaluate the signature. Results Twenty-eight DEFAGs were identified, and four FAGs (CRYAB, TFRC, SQLE and G6PD) were finally utilized to establish the FAGs based signature in the TCGA cohort, which was subsequently validated in the GEO database. Moreover, we found that immune cell infiltration, immunotherapy-related biomarkers and immune-related pathways were significantly different between two risk groups. Besides, nine molecule drugs with the potential to treat bladder cancer were identified by the connectivity map database analysis. Finally, the expression levels of crucial FAGs were verified by the experiment, which were consistent with our bioinformatics analysis, and knockdown of TFRC could inhibit cell proliferation and colony formation in BLCA cell lines in vitro. Conclusions Our study identified prognostic ferroptosis-associated genes and established a novel FAGs signature, which could accurately predict prognosis in BLCA patients.

scholarly journals PVT1 is a prognostic marker associated with immune invasion of bladder urothelial carcinoma

2021 ◽  
Vol 19 (1) ◽  
pp. 169-190
Author(s):  
Peiyuan Li ◽  
◽  
Gangjie Qiao ◽  
Jian Lu ◽  
Wenbin Ji ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Immune Cell ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Gene Set Enrichment ◽  
Cox Regression Analysis ◽  
Gene Set ◽  
Bladder Urothelial Carcinoma

<abstract> <p>Plasmacytoma variant translocation 1 (PVT1) is involved in multiple signaling pathways and plays an important regulatory role in a variety of malignant tumors. However, its role in the prognosis and immune invasion of bladder urothelial carcinoma (BLCA) remains unclear. This study investigated the expression of PVT1 in tumor tissue and its relationship with immune invasion, and determined its prognostic role in patients with BLCA. Patients were identified from the cancer genome atlas (TCGA). The enrichment pathway and function of PVT1 were explained by gene ontology (GO) term analysis, gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA), and the degree of immune cell infiltration was quantified. Kaplan–Meier analysis and Cox regression were used to analyze the correlation between PVT1 and survival rate. PVT1-high BLCA patients had a lower 10-year disease-specific survival (DSS P &lt; 0.05) and overall survival (OS P &lt; 0.05). Multivariate Cox regression analysis showed that PVT1 (high vs. low) (P = 0.004) was an independent prognostic factor. A nomogram was used to predict the effect of PVT1 on the prognosis. PVT1 plays an important role in the progression and prognosis of BLCA and can be used as a medium biomarker to predict survival after cystectomy.</p> </abstract>

scholarly journals Integrated Analysis Identifies and Validates a Novel Signature Based on Immune Related Gene Predicting Survival in Bladder Urothelial Carcinoma

2020 ◽  
Author(s):  
XuDong Mao ◽  
ShiHan Chen ◽  
GongHui Li
Keyword(s):  
Urothelial Carcinoma ◽  
Cox Regression ◽  
Cox Model ◽  
Risk Groups ◽  
The Cancer Genome Atlas ◽  
Integrated Analysis ◽  
Related Gene ◽  
Prognostic Signature ◽  
Immune Related Gene ◽  
Bladder Urothelial Carcinoma

Abstract BackgroundThis study aimed to develop a prognostic signature based on immune related gene(IRG) predicting survival for patients with bladder urothelial carcinoma(BLCA).Methods1534 IRG’s expression data of 996 BLCA patients form Gene Expression Omnibus database and The Cancer Genome Atlas database were used for development and validation of the prognostic signature. Univariate Cox regression model and Random Survival Forest Variable Hunting algorithm were employed to achieve the variable selection. The independently prognostic ability of the signature was validated by Multivariate Cox model and Kaplan–Meier analysis in independent datasets. A nomogram was established to improve prognosis stratification. The relationship between tumor-infiltrating immune cells and the signature was analyzed using data retrieved from EPIC resource.FindingsA prognostic model consisting of 10 IRGs was developed as our immune signature. Based on this signature, patients were separated into low- and high- risk groups with different survival in both training and validation sets(HR : range from 1.1 [95% CI: 1–1.2; p = 0.038] to 1.3 [95% CI: 1.3–1.5; p <0.001]). Multivariable analyses demonstrated that this signature was an independent prognostic predictor and was strongly associated with important clinicopathological factors. The signature also showed a significantly positive correlation with immune checkpoint molecules, and had a superior prognostic value compared with some important targets. In addition, our signature was found to correlate the enhancement of tumor microenvironment positively.ConclusionsThis signature predicts prognosis for BLCA patients, which may promote individualized treatment and provide potential targets for immunotherapy.

scholarly journals The inhibitory effect of silencing CDCA3 on migration and proliferation in bladder urothelial carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dexin Shen ◽  
Yayun Fang ◽  
Fenfang Zhou ◽  
Zhao Deng ◽  
Kaiyu Qian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Urothelial Carcinoma ◽  
Carcinoma Cells ◽  
Expression Level ◽  
Tumor Cell Growth ◽  
Migration Ability ◽  
Bladder Urothelial Carcinoma ◽  
Related Proteins

Abstract Background CDCA3 is an important component of the E3 ligase complex with SKP1 and CUL1, which could regulate the progress of cell mitosis. CDCA3 has been widely identified as a proto-oncogene in multiple human cancers, however, its role in promoting human bladder urothelial carcinoma has not been fully elucidated. Methods Bioinformatic methods were used to analyze the expression level of CDCA3 in human bladder urothelial carcinoma tissues and the relationship between its expression level and key clinical characteristics. In vitro studies were performed to validate the specific functions of CDCA3 in regulating cell proliferation, cell migration and cell cycle process. Alterations of related proteins was investigated by western blot assays. In vivo studies were constructed to validate whether silencing CDCA3 could inhibit the proliferation rate in mice model. Results Bioinformatic analysis revealed that CDCA3 was significantly up-regulated in bladder urothelial carcinoma samples and was related to key clinical characteristics, such as tumor grade and metastasis. Moreover, patients who had higher expression level of CDCA3 tend to show a shorter life span. In vitro studies revealed that silencing CDCA3 could impair the migration ability of tumor cells via down-regulating EMT-related proteins such as MMP9 and Vimentin and inhibit tumor cell growth via arresting cells in the G1 cell cycle phase through regulating cell cycle related proteins like p21. In vivo study confirmed that silencing CDCA3 could inhibit the proliferation of bladder urothelial carcinoma cells. Conclusions CDCA3 is an important oncogene that could strengthen the migration ability of bladder urothelial carcinoma cells and accelerate tumor cell growth via regulating cell cycle progress and is a potential biomarker of bladder urothelial carcinoma.

scholarly journals Identification of prognostic hypoxia-related genes signature on the tumor microenvironment in esophageal cancer

2021 ◽  
Vol 18 (6) ◽  
pp. 7743-7758
Author(s):  
Linlin Tan ◽  
◽  
Dingzhuo Cheng ◽  
Jianbo Wen ◽  
Kefeng Huang ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
High Risk ◽  
Immune Cells ◽  
Immune Cell ◽  
Risk Group ◽  
Roc Curves ◽  
Risk Groups ◽  
High Risk Group ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas

<abstract> <sec><title>Background</title><p>Hypoxia is a crucial factor in the development of esophageal cancer. The relationship between hypoxia and immune status in the esophageal cancer microenvironment is becoming increasingly important in clinical practice. This study aims to clarify and investigate the possible connection between immunotherapy and hypoxia in esophageal cancer.</p> </sec> <sec><title>Methods</title><p>The Cancer Genome Atlas databases are used to find two types of esophageal cancer cases. Cox regressions analyses are used to screen genes for hypoxia-related traits. After that, the genetic signature is validated by survival analysis and the construction of ROC curves. GSEA is used to compare differences in enrichment in the two groups and is followed by the CIBERSORT tool to investigate a potentially relevant correlation between immune cells and gene signatures.</p> </sec> <sec><title>Results</title><p>We found that the esophageal adenocarcinoma hypoxia model contains 3 genes (PGK1, PGM1, SLC2A3), and the esophageal squamous cell carcinoma hypoxia model contains 2 genes (EGFR, ATF3). The findings demonstrated that the survival rate of patients in the high-risk group is lower than in the lower-risk group. Furthermore, we find that three kinds of immune cells (memory activated CD4+ T cells, activated mast cells, and M2 macrophages) have a marked infiltration in the tissues of patients in the high-risk group. Moreover, we find that PD-L1 and CD244 are highly expressed in high-risk groups.</p> </sec> <sec><title>Conclusions</title><p>Our data demonstrate that oxygen deprivation is correlated with prognosis and the incidence of immune cell infiltration in patients with both types of esophageal cancer, which provides an immunological perspective for the development of personalized therapy.</p> </sec> </abstract>

scholarly journals Effects of Hypoxia in Intestinal Tumors on Immune Cell Behavior in the Tumor Microenvironment

2020 ◽  
Author(s):  
Luping Zhang ◽  
Shaokun Wang ◽  
Yachen Wang ◽  
Weidan Zhao ◽  
Yingli Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Risk Score ◽  
Immune Cell ◽  
Risk Groups ◽  
Low Risk ◽  
Computational Method ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Behavior

Abstract Background: Imbalanced nutritional supply and demand in the tumor microenvironment often leads to hypoxia. The subtle interaction between hypoxia and immune cell behavior plays an important role in tumor occurrence and development. However, the functional relationship between hypoxia and the tumor microenvironment remains unclear. Therefore, we aimed to investigate the effect of hypoxia on the intestinal tumor microenvironment.Method: We extracted the names of hypoxia-related genes from the Gene Set Enrichment Analysis (GSEA) database and screened them for those associated with the prognosis of colorectal cancer, with the final list including ALDOB, GPC1, ALDOC, and SLC2A3. Using the sum of the expression levels of these four genes, provided by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the expression coefficients, we developed a hypoxia risk score model. Using the median risk score value, we divided the patients in the two databases into high- and low-risk groups.GSEA was used to compare the enrichment differences between the two groups.We used the CIBERSORT computational method to analyze immune cell infiltration.Finally,the correlation between these five genes and hypoxia was analyzed. Result: The prognosis of the two groups differed significantly, with a higher survival rate in the low-risk group than in the high-risk group.We found that the different risk groups were enriched by immune-related and inflammatory pathways. We identified activated CD4 memory T cells and M0 macrophages in TCGA and GEO databases and found that CCL2/4/5, CSF1, and CX3CL1 contributed toward the increased infiltration rate of these immune cell types. Finally, we observed a positive correlation between the five candidate genes’ expression and the risk of hypoxia, with significant differences in the level of expression of each of these genes between patient risk groups.Conclusion: Overall, our data suggest that hypoxia is associated with the prognosis and rate of immune system infiltration in patients with colorectal cancer. This finding may improve immunotherapy for colorectal cancer.

Pan-cancer analysis on microRNA-mediated gene activation

2018 ◽  
Author(s):  
Hua Tan ◽  
Shan Huang ◽  
Zhigang Zhang ◽  
Xiaohua Qian ◽  
Peiqing Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Immune Cell ◽  
Critical Role ◽  
Mirna Gene ◽  
Regulation Of Gene Expression ◽  
The Cancer Genome Atlas ◽  
Positive Correlation ◽  
Positive Correlations

ABSTRACTWhile microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions. We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA). Results indicated that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate, demonstrating their promising clinical relevance. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs, suggesting a potential epigenetics mechanism underlying the upregulation. Wet-lab experiments revealed that positive correlations partially remain in the in vitro condition. Our study provides the field with new perspectives on the critical role of miRNA in gene regulation and novel insights regarding the complex mechanisms underlying miRNA functions, and reveals the clinical significance of the potential positive regulation of gene expression by miRNA.

scholarly journals ADAM12 as a Clinical Prognostic Indicator Associated with Tumour Immune Infiltration in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Junfan Pan ◽  
Zhidong Huang ◽  
Yiquan Xu
Keyword(s):  
Lung Adenocarcinoma ◽  
Prognostic Model ◽  
Immune Cell ◽  
Genetic Alterations ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Receptor Interaction ◽  
Significant Differential Expression ◽  
Immune Related Genes

Abstract Background: Lung cancer is the most common cause of cancer-related death worldwide. In humans, 22 functional α-disintegrinand metalloproteinases (ADAMs) have been identified, 12 of which have proteolytic activity. The role of ADAMs in cancer has attracted increasing attention. However, the expression and significance of ADAMs in lung adenocarcinoma (LUAD) remain unclear. The current study aimed to explore the expression and prognostic value of ADAM12 in LUAD.Methods: The Cancer Genome Atlas(TCGA) database was used to analyse the expression of ADAMs in LUAD. The cBioPortal database was used to obtain and analyse ADAM12 copy number changes, and the LinkedOmics database was utilised for the analysis of ADAM12-related genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was then performed using TIMER. The relationship between ADAM12 and the tumour immune microenvironment(TIM) was assessed via the TISIDB database. ADAM12 and immune-related genes were used to construct a prognostic model. Knockdown of ADAM12 was performed in vitro in order to verify its biological function. The unpaired t-test was used for comparison between the two groups, ANOVA was used for analysing differences between multiple groups, and the Kaplan-Meier test was used to compare survival between groups.Results: Most ADAMs exhibited significant differential expression in LUAD. ADAM12 expression was significantly higher in LUAD tissues than in healthy tissues, and lower ADAM12 expression was associated with better survival. Genetic alterations of ADAM12 mainly included missense mutations, amplifications, and deep deletions. ADAM12 and positively correlated genes were mainly enriched in protein digestion and absorption, ECM-receptor interaction, and adhesion plaques. ADAM12 had a moderate correlation with immune cell markers EBIP1, CCNB1, EXO1, KNTC1, PRC1 and FAM198B. Prognostic model was established based on ADAM12 and immune-related genes. In vitro experiments revealed that knocking down ADAM12 inhibited cell proliferation, migration and invasion.Conclusion: ADAM12 potentially plays an important role in the occurrence of LUAD and may be utilised as an immunotherapy target and a valuable prognostic biomarker for LUAD.

scholarly journals Pyroptosis-associated molecular classification and prognostic signature in glioma

2021 ◽  
Author(s):  
Yanyan Li ◽  
Lin Shen ◽  
Na Li ◽  
Yajie Zhao ◽  
Qin Zhou ◽  
...  
Keyword(s):  
High Risk ◽  
Clinical Features ◽  
Immune Cell ◽  
Risk Groups ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Prognostic Signature ◽  
Molecular Alterations ◽  
Genome Atlas

Purpose: Integrative analysis was performed in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas to describe the pyroptosis-associated molecular classification and prognostic signature in glioma. Experimental Design: Pyroptosis-related genes were used for consensus clustering and to develop a prognostic signature. The immune statuses, molecular alterations and clinical features of differentially expressed genes were analyzed among different subclasses and risk groups. A lncRNA-miRNA-mRNA network was built, and drug sensitivity analysis was used to identify small molecular drugs for the identified genes. Results: Glioma can be divided into two subclasses using 30 pyroptosis-related genes. Cluster 1 displayed high immune signatures and poor prognosis as well as high immune-related function scores. A prognostic signature based on 15 pyroptosis-related genes of the CGGA cohort can predict the overall survival of glioma and was well validated in the TCGA cohort. Cluster 1 had higher risk scores. The high-risk group had high immune cell and function scores and low DNA methylation of pyroptosis-related genes. The differences in pyroptosis-related gene mutations and somatic copy numbers were significant between the high-risk and low-risk groups. The ceRNA regulatory network uncovered the regulatory patterns of different risk groups in glioma. Nine pairs of target genes and drugs were identified. Conclusions: Pyroptosis-related genes can reflect the molecular biological and clinical features of glioma subclasses. The established prognostic signature can predict prognosis and distinguish molecular alterations in glioma patients. Our comprehensive analyses provide valuable guidelines for improving glioma patient management and individualized therapy.

scholarly journals RNA-seq Explores the Mechanism of Oxygen-Boosted Sonodynamic Therapy Based on All-in-One Nanobubbles to Enhance Ferroptosis for the Treatment of HCC

2021 ◽  
Author(s):  
Yichi Chen ◽  
Haitao Shang ◽  
Chunyue Wang ◽  
Jiaqi Zeng ◽  
Shentao Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Target Genes ◽  
Immune Cell ◽  
Low Frequency ◽  
Rna Seq ◽  
Sonodynamic Therapy ◽  
Kegg Pathways ◽  
Prognostic Analysis ◽  
Before And After

Abstract Background The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by Hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) have failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention. Methods In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety. Results MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. Then we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes "SLC37A2" and "ITGB7" may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma. Conclusions The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.

scholarly journals Immune Landscape of Thyroid Cancers: New Insights

2021 ◽  
Vol 11 ◽  
Author(s):  
Elisa Menicali ◽  
Martina Guzzetti ◽  
Silvia Morelli ◽  
Sonia Moretti ◽  
Efisio Puxeddu
Keyword(s):  
Thyroid Cancer ◽  
Immune System ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Thyroid Tumors ◽  
Thyroid Cancers ◽  
Immune Destruction

Immune system plays a key role in cancer prevention as well as in its initiation and progression. During multistep development of tumors, cells must acquire the capability to evade immune destruction. Both in vitro and in vivo studies showed that thyroid tumor cells can avoid immune response by promoting an immunosuppressive microenvironment. The recruitment of immunosuppressive cells such as TAMs (tumor-associated macrophages), TAMCs (tumor-associated mast cells), MDSC (myeloid-derived suppressor cells), TANs (tumor-associated neutrophils) and Tregs (regulatory T cells) and/or the expression of negative immune checkpoints, like PD-L1 (programmed death-ligand 1), CTLA-4 (cytotoxic T-lymphocyte associated protein 4), and/or immunosuppressive enzymes, as IDO1 (indoleamine 2,3-dioxygenase 1), are just some of the mechanisms that thyroid cancer cells exploit to escape immune destruction. Some authors systematically characterized immune cell populations and soluble mediators (chemokines, cytokines, and angiogenic factors) that constitute thyroid cancer microenvironment. Their purpose was to verify immune system involvement in cancer growth and progression, highlighting the differences in immune infiltrate among tumor histotypes. More recently, some authors have provided a more comprehensive view of the relationships between tumor and immune system involved in thyroid carcinogenesis. The Cancer Genome Atlas (TCGA) delivered a large amount of data that allowed to combine information on the inflammatory microenvironment with gene expression data, genetic and clinical-pathological characteristics, and differentiation degree of papillary thyroid carcinoma (PTC). Moreover, using a new sensitive and highly multiplex analysis, the NanoString Technology, it was possible to divide thyroid tumors in two main clusters based on expression of immune-related genes. Starting from these results, the authors performed an immune phenotype analysis that allowed to classify thyroid cancers in hot, cold, or intermediate depending on immune infiltration patterns of the tumor microenvironment. The aim of this review is to provide a comprehensive and updated view of the knowledge on immune landscape of thyroid tumors. Understanding interactions between tumor and microenvironment is crucial to effectively direct immunotherapeutic approaches in the treatment of thyroid cancer, particularly for those not responsive to conventional therapies.

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