Cancer Translational Medicine

Original Research | Open Access

Vol.9 (2023) | Issue-2 | Page No: 54-64

DOI: https://doi-ds.org/doilink/06.2023-39372623/A1

Subtyping of Undifferentiated Pleomorphic Sarcoma and Its Clinical Meaning

Umair Ali Khan Saddozai, Zhendong Lu, Fengling Wang, Muhammad Usman Akbar, Saadullah Khattak, Muhammad Badar, Nazeer Hussain Khan, Longxiang Xie, Yongqiang Li, Xinying Ji, Xiangqian Guo

Affiliations  

1. Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China

2. Gomal Center of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Pakistan

*Corresponding Author


Important Dates  

Date of Submission:   23-Dec-2023

Date of Acceptance:   31-Jan-2023

Date of Publication:   30-Jun-2023

ABSTRACT

Aims: To identify distinct molecular subtypes and define therapeutic targets for Undifferentiated pleomorphic sarcoma (UPS).

Methods: The possibility and an optimal number of UPS molecular subtypes were determined using expression profiling data. Next, clinicopathological characters and molecular pathways in each subtype were analyzed for prospective clinical applications and UPS progression processes. The Chi-square test, Kruskal-Wallis H, and Fisher's exact test were applied to evaluate the statistical significance and P-values lower than 0.05 were considered significant.

Results: Through gene expression profiling data analysis, two distinct molecular subtypes of UPS were consistently identified. Subtype I UPS is associated with Chemokine mediated signaling pathway. Conversely, in subtype II of UPS, a set of genes was observed to be overexpressed and found to be functionally involved in viral protein interaction with cytokine and cytokine receptors. Different therapeutic targets were proposed according to the specificity of subtype molecular patterns, FLT3 and RNF43 are examples of genes associated with subtype I, while ROS1 is a gene associated with subtype II.

Conclusion: These findings may provide a wealth of knowledge for further understanding of the exact pathogenic mechanisms of intrinsic subtypes of UPS and the occurrence and development of different subtypes, and provide recommendations for developing individualized treatment strategies for different subtypes of UPS to improve prognosis.

Keywords: Undifferentiated pleomorphic sarcoma, molecular subtypes, gene expression, subtype specific treatment


INTRODUCTION

Undifferentiated pleomorphic sarcoma (UPS), also known as malignant fibrous histiocytoma (MFH), is a soft tissue malignancy of mesenchymal origin with undefined differentiation. It is also ranked as the second most occurring type of soft tissue sarcoma (STS) usually affecting the aged population with male predominance.[1] Clinically, the morphological features of UPS are extremely variable, and most of them transition from the striae area to the polymorphic area. Most cases occur in people between the ages of 60-70.[2],[3] UPS grows rapidly and generally occurs in the lower extremities with a painless progressive enlargement of the mass. Its progression in the body is mostly sporadic, however, it also tends to develop in the areas of the body exposed to radiation therapy with a median incubation period of 10 years.[4],[5] UPS exhibits aggressive prognostic nature and has a local recurrence rate of 19%-31% and a metastasis rate of 26%-35% with nearly 5% of the patients exhibiting metastases at the time of initial diagnosis.[6],[7] Most UPS have a morphology similar to undifferentiated and polymorphic tumor subtypes, particularly LMS, liposarcoma, and rhabdomyosarcoma[8],[9] reflecting the difficulty of histopathological classification and the reproducibility of a sarcoma diagnosis.[10] Only a few studies have elucidated the genomic alteration of UPS which is still not clear for tumorigenesis mechanism.[11],[12],[13],[14] Therefore, an accurate diagnostic upsurge is essential for these cancer types.[15]

Currently, the primary treatment method for patients with UPS is surgery. However, in instances where the tumor is inoperable or has metastasized, adjunctive chemotherapy and/or radiotherapy may be utilized.[16],[17] Cytotoxic chemotherapy typically results in low to moderate response rates in UPS patients and does not significantly impact overall survival (OS).[17],[18],[19],[20] Initially, sarcomas were the tumor models that underwent immunotherapies, displaying elevated PD-L1 expression levels.[21],[22],[23] Additionally, in immune-compromised patients, molecular therapies are considered viable alternatives to immunotherapy. Researchers have developed tools for identifying molecular event-related subtypes in a variety of tumors, such as pheochromocytoma,[24],[25] mesothelioma,[26],[27] and breast cancer,[28] and have led to prognostic and therapeutic gains with certain success. To date, limited data are available to correlate UPS with various molecular subtypes. However, in the present study, different molecular subtypes of UPS were identified using gene expression profiling data. The identification of distinct therapeutic genes and pathways within UPS molecular subtypes is valuable for accurately diagnosing cancer types in diverse patients and is conducive to the development of new personalized treatment strategies predicated on UPS molecular subtypes.


MATERIAL AND METHODS

UPS subtypes determination

Expression profiling data for cases of UPS were collected from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/) and The Cancer Genome Atlas (TCGA). The GSE49941 dataset containing 22 UPS cases and the second TCGA dataset with the same number of 22 UPS cases were included to determine the molecular subtypes of UPS. To identify UPS molecular subtypes, the included datasets were sequentially filtered by standard deviations, transformed based on gene-based centering, then assessed transformed dataset by the Consensus Clustering Plus from R package[29] using Pearson correlation, gene resampling, maximum evaluated k of 12, and agglomerative hierarchical clustering algorithm. Finally, checked the accuracy of the results of Consensus Clustering Plus by calculation of silhouette width (R package clustering).[linkRef 30-1585]

Gene ontology and gene set enrichment (GSEA) analysis

SAM and SAMseq were performed with a false discovery rate (FDR) of 0.05 to examine the subtype specific genes.[31],[32] David Bioinformatics Resources (https://david.ncifcrf.gov/) (online version 7.6) was used to examine the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for subtype specific genes. Gene expression patterns and pathways for each subtype were discovered by Gene Set Enrichment Analyses (GSEA).[33] While the Target V2 Database (http://www.broadinsitute.org/ccancer/cga/target) was used for studying the potential therapeutic genes for each UPS subtype. 

Statistical analysis

The Chi-square test, Kruskal-Wallis H, and Fisher's exact test were applied to evaluate the statistical significance of the association between subtypes and clinical factors, and those having P values lower than 0.05 were considered as significant.


RESULTS

Consensus clustering identifies two distinct UPS molecular subtypes

Before performing consensus clustering, UPS expression profiling data were filtered by the standard deviation to retrieve the genes with high expression variations. As shown by the consensus clustering results in GSE49941, two optimal molecular subtypes were determined based on selecting the largest area under the curve of the cumulative distribution function (CDF) [Figure 1 A-C]. Silhouette Width determination was used to confirm the subtype assignment confidence and identified those UPS cases with positive silhouette values for subsequent analysis. Of the 22 UPS cases, all were found to have positive silhouette values; 15 of these 22 cases were defined as subtype I, and 7 cases as subtype II [Figure 1D].

Figure 1
Figure 1. Two UPS molecular subtypes were identified in GSE49941. (A) The ideal number of UPS molecular subtypes is determined through an empirical cumulative distribution plot. (B) A relative increase in the CDF curve's area under the curve as the expected number of molecular subtypes rises. (C) Consensus clustering matrix of two molecular subtypes utilizing UPS samples. (D) UPS sample silhouette analysis using the mandate from consensus clustering.

UPS subtype validation in an independent dataset

To further test the validity of the two UPS molecular subtypes, an additional independent data set from TCGA was collected which contains 22 UPS cases as an independent validation cohort. The consensus clustering analysis showed that the TCGA dataset has two different UPS molecular subtypes as well [Figure 2]. Silhouette analysis revealed that 13 out of 22 samples had positive silhouette values and were subject to the following analysis, including 4 subtype I UPSs and 9 subtype II cases. 

Figure 2.
Figure 2. Two UPS molecular subtypes were defined in TCGA cohort as well. (A) The ideal number of UPS molecular subtypes is determined through an empirical cumulative distribution plot in TCGA dataset. (B) A relative increase in the CDF curve's area under the curve as the expected number of molecular subtypes rises. (C) Consensus clustering matrix of two molecular subtypes of TCGA UPS samples. (D) Silhouette analysis plot for TCGA UPS cases with predefined subtypes from consensus clustering.

Molecular subtypes and their relation with clinical symptoms

The relationship between the two molecular subtypes and clinical features was investigated in the TCGA cohort. UPS molecular subtype II had a higher incidence in metastatic detection (2/9, 22.2%) compared to subtype I UPS (1/6, 16.6%) (P = 1). Between the two molecular subtypes, patients differed significantly in the survival event (Alive and death P = 0.04). In terms of time to survival, the median overall survival (OS) for subtype I UPS was 557 days, which was lower than the 565 days for patients with subtype II UPS, although the difference was not significant (P = 0.6). The mean age of subtype I is 69 years, which is lower than that of subtype II with 71 years [Table 1].

Table 1
Table 1. Clinicopathological characteristics (n = 22) of Undifferentiated pleomorphic sarcoma cases in TCGA cohort

Functional enrichment analysis of UPS subtype-specific genes

SAMseq analysis of TCGA revealed that a total of 787 genes were significantly differentially expressed between two UPS molecular subtypes and 575 of the 787 genes were specifically overexpressed in subtype I UPSs, while the other 212 genes were overexpressed in subtype II UPSs. GO and KEGG analyses were performed to enrich biological functional information for different subtypes. In two different UPS subtypes, the first 200 overexpressed genes were selected for enrichment. The subtype I genes were enriched in 104 biological processes and 20 KEGG pathways, while 39 biological processes and 13 KEGG pathways were enriched in subtype II genes. Notably, 3.9% of the top 200 genes specific for subtype I UPSs were found to be associated with Chemokine mediated signaling pathway, B cell proliferation, and Calcium-mediated signaling [Figure 3A]. On the other hand, genes overexpressed in subtype II UPSs are associated with unique biological pathways such as Viral protein interaction with cytokine and cytokine receptors, and the Amoebiasis pathway [Figure 3B]. Moreover, GSEA analysis showed that the TCGA dataset was enriched with 176 gene sets in which 121 gene sets were shown to be enriched in subtype II and the remaining 55 gene sets overexpressed in subtype I.

Besides this, subtype I was rich in significant biological pathways, including Basal transcription factors and Cell cycle pathways. Subtype II analysis found pathways of Primary immune deficiency and Antigen processing and presentation pathways [Figure 4].

Figure 3.
Figure 3. Specific pathways enriched in two UPS molecular subtypes. (A) Subtype I KEGG pathways. (B) KEGG subtype II pathways.

Figure 4.
Figure 4. Shows that different UPS molecular subtypes have varied gene expression signatures. (A) Illustrating various subtype I and subtype II gene expression patterns. Red are overexpressed while blue down expressed genes. (B, C) GSEA demonstrates the Basal transcription factor and Cell cycle pathways' activity in subtype I. In subtype II, GSEA showed that the signaling pathways for Primary immunodeficiency and the Antigen processing and presentation pathway were active. While FDR stands for false discovery rate and NES for normalized enriched score, respectively.

Potential clinical implication of UPS subtyping

The main purpose of determining the molecular subtypes of UPS is to effectively formulate personalized treatment approaches for different subtypes, which has brought efforts to solve the heterogeneity of tumors in clinical treatment, to better enable UPS patients to obtain a better outcome. To identify therapeutic modules associated with both UPS subtypes, subtype-specificity-based over-expression genes are compared to target databases (http://www.braodinsitute.org/cancer/cga/target) containing gene targets and functional inhibitors[Linkref 34-1589] to obtain potential targets that are beneficial to clinical therapy.[35],[36],[37] A total of 3 genes were specifically expressed in the two UPS molecular subtypes and were potentially beneficial to each UPS subtype [Table 2]. Subtype I highly expressed FLT3 and RNF43, while subtype II expressed ROS1.

Table 2.
Table 2. Target genes enriched in each UPS molecular subtype


DISCUSSION

Malignant fibrous histiocytoma (MFH), commonly referred to as undifferentiated pleomorphic sarcoma (UPS), is a very uncommon soft tissue malignant tumor. According to the WHO classification standard, UPS replaced the MFH concept in 2013.[38] In both men and women, UPS is most common between the ages of 60 and 70. UPS is highly prevalent in the limbs, trunk, head, and neck, as well as other organs and tissues. It is deep-seated, high-grade, highly malignant, and prone to rapid recurrence following surgery.[39] UPS patients frequently exhibit a low 5-year survival rate, ranging from 30% to 50%.[39] For localized disease, surgery accompanied by (neo)adjuvant therapy, in some cases, is the conventional therapeutic approach.[40] In a metastatic situation, chemotherapy is the standard treatment; however, its effectiveness is restricted, and results are often unsatisfactory.[41] Early diagnosis of UPS is instrumental in extending the survival rate of patients. Additionally, the molecular subtyping of cancers based on gene expression profiling data has facilitated the creation of subtype-specific treatments for UPS. The Herceptin clinical trial in breast cancer serves as a prime example of subtype-targeted therapy. Patients with HER2-negative breast cancer did not experience any benefits from Herceptin treatment, while individuals with HER2-positive breast cancer yielded substantial therapy results.[42] The molecular heterogeneity of UPS will be examined in order to get a greater understanding of the genes and pathways connected to UPS. This information will offer novel opportunities to target subtype-specific UPS patients.

In the current study, we have identified two distinct UPS molecular subtypes. Distinctive gene signatures are disclosed in two UPS subtypes by GO and gene set enrichment analysis. Chemokine mediated signaling pathway, B cell proliferation, Calcium mediated signaling, etc., were the pathways over-presented in the subtype I UPSs [Figure 3A] along with the over-expression of WNTB7, PART1, and GREM1 genes in subtype I [Figure 4A].

WNT7B is a widely studied Wnt gene that is frequently up-regulated in various types of cancer, including osteosarcoma.[43],[44],[45] It has been reported that WNT7B significantly promoted osteoblast proliferation and activity through PI3K/Akt/mTORC1.[46] Prostatic androgen regulatory transcription 1 (PART1) is a novel type of lncRNA that can be controlled by androgens. In prostate cancer, it exerts an obvious carcinogenic effect by facilitating proliferation and inhibiting apoptosis of prostate cancer cells.[47] A recent study showed that PART1 may associate with the development and progression of oral squamous cell carcinoma (OSCC), and the expression of PART1 is negatively correlated with the overall and relapse-free survival of patients.[48] Gremlin1 (GREM1) is a bone morphogenetic protein (BMP) signaling modulator that is primarily expressed in stromal cells. It encodes the production of secreted glycosylated proteins that attach with BMP-2, BMP-4, and BMP-7, typically forms homologous and heterodimers, binds to selective BMP to prevent ligand-receptor interactions and subsequent downstream signaling, and regulates a variety of biological processes, including organ morphology, cellular metabolism, and multiple pathological developments.[49],[50] In recent years, studies have reported the clinical significance of GREM1 in human cancers. Guan et al. first examined the expression level and function of GREM1 in glioma. They found that knocking down GREM1 prevented glioma cell viability, migration, invasion, and EMT.[51] Moreover, GREM1 has been studied in human tumors, such as stomach carcinomas,[52] colons,[53] esophagus,[54] kidneys,[55], and the pancreas.[56] In addition, Through GO and gene set enrichment analysis, it was discovered that the pathways overexpressed in subtype II involve viral protein interactions, cytokine activation, Chemokine signaling, as well as Amoebiasis. [Figure 4B]. The ALDH1A superfamily includes ALDH1A1, ALDH1A2, and ALDH1A3. All three isoenzymes are involved in the synthesis of retinol acid, a molecule necessary for tissue differentiation and cell development.[57],[58] ALDH1A1 and ALDH1A3 have been considered as vital biomarkers[59],[60] and targets in many cancers.[61],[62],[63] Some studies have confirmed that ALDH1A3 can be considered as one of the characteristic markers of Mes-GSC, and ALDH1A3 may play an important role in the development of glioma malignancy because of its involvement in stem-cell viability resistance and cell maintenance [Figure 4A].[64],[65] Overexpression of these genes in subtype II UPS and their roles in other cancers may open new doors or opportunities to understand the tumorigenesis or progression mechanisms of subtype II UPSs.

We also used the TARGET V2 database to identify the known target genes for subtype I and II UPS and their possible or potential therapeutic agents. These genes include RNF43 and FLT3 for subtype I UPS, and ROS1 for subtype II [Table 2]. Mutations that activate the Wnt/β-catenin signaling pathway have been found in many cancers. And the most common mutations in the signaling pathway are downstream regulators that affect the degradation of β-catenin proteins, such as adenomatous colorectal polyposis (APC) proteins. However, there are also cancers that are driven by genetic mutations, including RNF43, ZNRF3, and RSPO3.[66],[67],[68],[69],[70],[71],[72] These cancers are characterized by hypersensitivity to Wnt ligands, and multiple treatments for Wnt addictive cancers have shown efficacy in preclinical studies, including PORCN inhibitors, anti-FZD antibodies, and anti-R-spondin (RSPO) antibodies.[73],[74],[75],[76],[77] In the current study, we found that more than 60% of patients of both datasets of GSE49941 and TCGA belong to subtype I of UPS [Figure 1D, Figure 2D]. Our results revealed the importance of RNF43 inhibitors in UPS subtype I [Table 2]. Apart from their significant role in many carcinomas, these inhibitors may also play a significant role in the treatment of subtype I UPS. In NSCLC, cholangiocarcinoma, glioblastoma, ovarian, gastric, and colorectal cancers, ROS1 gene rearrangement has been observed.[78] Studies have revealed that the ALK/ROS1/MET TKI crizotinib can target the ROS1 oncogenic fusion protein,[79],[80] and the protein has been approved to treat metastatic ROS1 rearrangement in NSCLC. Crizotinib had an overall response rate of 72% in a phase 1/2 clinical trial (PROFILE 1001), and the median progression-free survival was 19.2 months.[81] These findings suggested that these inhibitors might be helpful for Subtype II UPS patients.


CONCLUSION

By defining distinct molecular subtypes of UPSs, our research has discovered subtype-specific mechanisms that contribute to the tumorigenesis of UPS. These findings may aid in more precise disease targeting and the creation of tailored medications for UPS patients using subtype-specific approaches.

 

FINANCIAL SUPPORT AND SPONSORSHIP

Nil.

 

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

 

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

 

AUTHOR CONTRIBUTIONS

(I) Conceptualization: Xiangqian Guo; (II) Methodology: Xiangqian Guo; (III) Software: Xiangqian Guo, Umair Ali Khan Saddozai; (IV) Validation: Umair Ali Khan Saddozai, Xiangqian Guo; (V) Formal analysis: Umair Ali Khan Saddozai, Xiangqian Guo, Fengling Wang; (VI) Investigation: Umair Ali Khan Saddozai, Xiangqian Guo; (VII) Resources: Xiangqian Guo, Xinying Ji, Yongqiang Li; (Ⅷ) Data Curation: Umair Ali Khan Saddozai, Xiangqian Guo; (Ⅸ) Writing - Original Draft: Umair Ali Khan Saddozai, Zhendong Lu, Muhammad Usman Akbar, Xiangqian Guo; (Ⅹ) Writing - Review & Editing: Umair Ali Khan Saddozai, Muhammad Usman Akbar, Xiangqian Guo, Xinying Ji, Muhammad Badar, Saadullah Khattak, Nazeer Hussain Khan, Longxiang Xie; (Ⅺ) Visualization: Umair Ali Khan Saddozai; (Ⅻ) Supervision: Xiangqian Guo, Xinying Ji, Yongqiang Li; (XIII) Project administration: Xiangqian Guo, Xinying Ji, Yongqiang Li.


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Zhen Wang1, Hongwei Yang2, Xin Wang2, Liang Wang3, Yingduan Cheng4, Yongsheng Zhang5, Yanyang Tu1,2


Nanoparticle Drug Delivery Systems and Three‑dimensional Cell Cultures in Cancer Treatments and Research

Wenjin Shi1, Ding Weng2,3, Wanting Niu2,3


Choline Kinase Inhibitors Synergize with TRAIL in the Treatment of Colorectal Tumors and Overcomes TRAIL Resistance

Juan Carlos Lacal1, Ladislav Andera2


MicroRNA Regulating Metabolic Reprogramming in Tumor Cells: New Tumor Markers

Daniel Otero‑Albiol, Blanca Felipe‑Abrio


Biomarkers of Colorectal Cancer: A Genome‑wide Perspective

José M. Santos‑Pereira1, Sandra Muñoz‑Galván2


Nicotinamide Adenine Dinucleotide+ Metabolism Biomarkers in Malignant Gliomas

Manuel P. Jiménez‑García, Eva M. Verdugo‑Sivianes, Antonio Lucena‑Cacace


Patient-derived Xenografts as Models for Personalized Medicine Research in Cancer

Marco Perez, Lola Navas, Amancio Carnero


Genome‑wide Transcriptome Analysis of Prostate Cancer Tissue Identified Overexpression of Specific Members of the Human Endogenous Retrovirus‑K Family

Behnam Sayanjali1,2


Clinical Utility of Interleukin‑18 in Breast Cancer Patients: A Pilot Study

Reecha A. Parikh, Toral P. Kobawala, Trupti I. Trivedi, Mahnaz M. Kazi, Nandita R. Ghosh


Current and Future Systemic Treatment Options for Advanced Soft‑tissue Sarcoma beyond Anthracyclines and Ifosfamide

Nadia Hindi1,2, Javier Martin‑Broto1,2


The Genomic Organization and Function of IRX1 in Tumorigenesis and Development

Pengxing Zhang1, Hongwei Yang2, Xin Wang2, Liang Wang3, Yingduan Cheng4, Yongsheng Zhang5, Yanyang Tu1,2


Stem Cell‑based Approach in Diabetes and Pancreatic Cancer Management

Yi‑Zhou Jiang1, Demeng Chen2


Mutation Detection with a Liquid Biopsy 96 Mutation Assay in Cancer Patients and Healthy Donors

Aaron Yun Chen, Glenn D. Braunstein, Megan S. Anselmo, Jair A. Jaboni, Fernando Troy Viloria, Julie A. Neidich, Xiang Li, Anja Kammesheidt


The Application of Estrogen Receptor‑1 Mutations’ Detection through Circulating Tumor DNA in Breast Cancer

Binliang Liu, Yalan Yang, Zongbi Yi, Xiuwen Guan, Fei Ma


Circulating MicroRNAs and Long Noncoding RNAs: Liquid Biomarkers in Thoracic Cancers

Pablo Reclusa1, Anna Valentino1, Rafael Sirera1,2, Martin Frederik Dietrich3, Luis Estuardo Raez3, Christian Rolfo1


Exosomes Biology: Function and Clinical Implications in Lung Cancer

Martin Frederik Dietrich1, Christian Rolfo2, Pablo Reclusa2, Marco Giallombardo2, Anna Valentino2, Luis E. Raez1


Circulating Tumor DNA: A Potential Biomarker from Solid Tumors’ Monitor to Anticancer Therapies

Ting Chen1,2, Rongzhang He1,3, Xinglin Hu1,3,4, Weihao Luo1, Zheng Hu1,3, Jia Li1, Lili Duan1, Yali Xie1,2, Wenna Luo1,2, Tan Tan1,2, Di‑Xian Luo1,2


Novel Molecular Multilevel Targeted Antitumor Agents

Poonam Sonawane1, Young A. Choi1, Hetal Pandya2, Denise M. Herpai1, Izabela Fokt3,
Waldemar Priebe3, Waldemar Debinski1


Fish Oil and Prostate Cancer: Effects and Clinical Relevance

Pei Liang, Michael Gao Jr.


Stemness‑related Markers in Cancer

Wenxiu Zhao1, Yvonne Li2, Xun Zhang1


Autophagy Regulated by miRNAs in Colorectal Cancer Progression and Resistance

Andrew Fesler1, Hua Liu1, Ning Wu1,2, Fei Liu3, Peixue Ling3, Jingfang Ju1,3


Gastric Metastases Mimicking Primary Gastric Cancer: A Brief Literature Review

Simona Gurzu1,2,3, Marius Alexandru Beleaua1, Laura Banias2, Ioan Jung1


Possibility of Specific Expression of the Protein Toxins at the Tumor Site with Tumor‑specialized Promoter

Liyuan Zhou1,2, Yujun Li1,2, Changchen Hu3, Binquan Wang1,2


SKI‑178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models

Jeremy A. Hengst1,2, Taryn E. Dick1,2, Arati Sharma1, Kenichiro Doi3, Shailaja Hegde4, Su‑Fern Tan5, Laura M. Geffert1,2, Todd E. Fox5, Arun K. Sharma1, Dhimant Desai1, Shantu Amin1, Mark Kester5, Thomas P. Loughran5, Robert F. Paulson4, David F. Claxton6, Hong‑Gang Wang3, Jong K. Yun1,2


A T‑cell Engager‑armed Oncolytic Vaccinia Virus to Target the Tumor Stroma

Feng Yu1, Bangxing Hong1, Xiao‑Tong Song1,2,3


Real‑world Experience with Abiraterone in Metastatic Castration‑resistant Prostate Cancer

Yasar Ahmed1, Nemer Osman1, Rizwan Sheikh2, Sarah Picardo1, Geoffrey Watson1


Combination of Interleukin‑11Rα Chimeric Antigen Receptor T‑cells and Programmed Death‑1 Blockade as an Approach to Targeting Osteosarcoma Cells In vitro

Hatel Rana Moonat, Gangxiong Huang, Pooja Dhupkar, Keri Schadler, Nancy Gordon,
Eugenie Kleinerman


Efficacy and Safety of Paclitaxel‑based Therapy and Nonpaclitaxel‑based Therapy in Advanced Gastric Cancer

Tongwei Wu, Xiao Yang, Min An, Wenqin Luo, Danxian Cai, Xiaolong Qi


Motion Estimation of the Liver Based on Deformable Image Registration: A Comparison Between Four‑Dimensional‑Computed Tomography and Four‑Dimensional-Magnetic Resonance Imaging

Xiao Liang1, Fang‑Fang Yin1,2, Yilin Liu1, Brian Czito2, Manisha Palta2, Mustafa Bashir3, Jing Cai1,2


A Feasibility Study of Applying Thermal Imaging to Assist Quality Assurance of High‑Dose Rate Brachytherapy

Xiaofeng Zhu1, Yu Lei1, Dandan Zheng1, Sicong Li1, Vivek Verma1, Mutian Zhang1, Qinghui Zhang1, Xiaoli Tang2, Jun Lian2, Sha X. Chang2, Haijun Song3, Sumin Zhou1, Charles A. Enke1


Role of Exosome microRNA in Breast Cancer

Wang Qu, Ma Fei, Binghe Xu


Recent Progress in Technological Improvement and Biomedical Applications of the Clustered Regularly Interspaced Short Palindromic Repeats/Cas System

Yanlan Li1,2*, Zheng Hu1*, Yufang Yin3, Rongzhang He1, Jian Hu1, Weihao Luo1, Jia Li1, Gebo Wen2, Li Xiao1, Kai Li1, Duanfang Liao4, Di-Xian Luo1,5


The Significance of Nuclear Factor‑Kappa B Signaling Pathway in Glioma: A Review

Xiaoshan Xu1, Hongwei Yang2, Xin Wang2, Yanyang Tu1


Markerless Four‑Dimensional‑Cone Beam Computed Tomography Projection‑Phase Sorting Using Prior Knowledge and Patient Motion Modeling: A Feasibility Study

Lei Zhang1,2, Yawei Zhang2, You Zhang1,2,3, Wendy B. Harris1,2, Fang‑Fang Yin1,2,4, Jing Cai1,4,5, Lei Ren1,2


The Producing Capabilities of Interferon‑g and Interleukin‑10 of Spleen Cells in Primary and Metastasized Oral Squamous Cell Carcinoma Cells-implanted Mice

Yasuka Azuma1,2, Masako Mizuno‑Kamiya3, Eiji Takayama1, Harumi Kawaki1, Toshihiro Inagaki4, Eiichi Chihara2, Yasunori Muramatsu5, Nobuo Kondoh1


“Eating” Cancer Cells by Blocking CD47 Signaling: Cancer Therapy by Targeting the Innate Immune Checkpoint

Yi‑Rong Xiang, Li Liu


Glycosylation is Involved in Malignant Properties of Cancer Cells

Kazunori Hamamura1, Koichi Furukawa2


Biomarkers in Molecular Epidemiology Study of Oral Squamous Cell Carcinoma in the Era of Precision Medicine

Qing‑Hao Zhu1*, Qing‑Chao Shang1*, Zhi‑Hao Hu1*, Yuan Liu2, Bo Li1, Bo Wang1, An‑Hui Wang1


I‑Kappa‑B Kinase‑epsilon Activates Nuclear Factor‑kappa B and STAT5B and Supports Glioblastoma Growth but Amlexanox Shows Little Therapeutic Potential in These Tumors

Nadège Dubois1, Sharon Berendsen2, Aurélie Henry1,2, Minh Nguyen1, Vincent Bours1,
Pierre Alain Robe1,2


Suppressive Effect of Mesenchymal Stromal Cells on Interferon‑g‑Producing Capability of Spleen Cells was Specifically Enhanced through Humoral Mediator(s) from Mouse Oral Squamous Cell Carcinoma Sq‑1979 Cells In Vitro

Toshihiro Inagaki1,2, Masako Mizuno‑Kamiya3, Eiji Takayama1, Harumi Kawaki1, Eiichi Chihara4, Yasunori Muramatsu5, Shinichiro Sumitomo5, Nobuo Kondoh1


An Interplay Between MicroRNA and SOX4 in the Regulation of Epithelial–Mesenchymal Transition and Cancer Progression

Anjali Geethadevi1, Ansul Sharma2, Manish Kumar Sharma3, Deepak Parashar1


MicroRNAs Differentially Expressed in Prostate Cancer of African‑American and European‑American Men

Ernest K. Amankwah


The Role of Reactive Oxygen Species in Screening Anticancer Agents

Xiaohui Xu1, Zilong Dang2, Taoli Sun3, Shengping Zhang1, Hongyan Zhang1


Panobinostat and Its Combination with 3‑Deazaneplanocin‑A Induce Apoptosis and Inhibit In vitro Tumorigenesis and Metastasis in GOS‑3 Glioblastoma Cell Lines

Javier de la Rosa*, Alejandro Urdiciain*, Juan Jesús Aznar‑Morales, Bárbara Meléndez1,
Juan A. Rey2, Miguel A. Idoate3, Javier S. Castresana


Cancer Stem‑Like Cells Have Cisplatin Resistance and miR‑93 Regulate p21 Expression in Breast Cancer

Akiko Sasaki1, Yuko Tsunoda2, Kanji Furuya3, Hideto Oyamada1, Mayumi Tsuji1, Yuko Udaka1, Masahiro Hosonuma1, Haruna Shirako1, Nana Ichimura1, Yuji Kiuchi1


The Contribution of Hexokinase 2 in Glioma

Hui Liu1, Hongwei Yang2, Xin Wang3, Yanyang Tu1


The Mechanism of BMI1 in Regulating Cancer Stemness Maintenance, Metastasis, Chemo‑ and Radiation Resistance

Xiaoshan Xu, Zhen Wang, Nan Liu, Pengxing Zhang, Hui Liu, Jing Qi, Yanyang Tu


A Multisource Adaptive Magnetic Resonance Image Fusion Technique for Versatile Contrast Magnetic Resonance Imaging

Lei Zhang1,2, Fang‑Fang Yin1,2,3, Brittany Moore1,2, Silu Han1,2, Jing Cai1,2,4


Senescence and Cancer

Sulin Zeng1,2, Wen H. Shen2, Li Liu1


The “Wild”‑type Gastrointestinal Stromal Tumors: Heterogeneity on Molecule Characteristics and Clinical Features

Yanhua Mou1, Quan Wang1, Bin Li1,2


Retreatment with Cabazitaxel in a Long‑Surviving Patient with Castration‑Resistant Prostate Cancer and Visceral Metastasis

Raquel Luque Caro, Carmen Sánchez Toro, Lucia Ochoa Vallejo


Therapy‑Induced Histopathological Changes in Breast Cancers: The Changing Role of Pathology in Breast Cancer Diagnosis and Treatment

Shazima Sheereen1, Flora D. Lobo1, Waseemoddin Patel2, Shamama Sheereen3,
Abhishek Singh Nayyar4, Mubeen Khan5


Glioma Research in the Era of Medical Big Data

Feiyifan Wang1, Christopher J. Pirozzi2, Xuejun Li1


Transarterial Embolization for Hepatocellular Adenomas: Case Report and Literature Review

Jian‑Hong Zhong1,2, Kang Chen1, Bhavesh K. Ahir3, Qi Huang4, Ye Wu4, Cheng‑Cheng Liao1, Rong‑Rong Jia1, Bang‑De Xiang1,2, Le‑Qun Li1,2


Nicotinamide Phosphoribosyltransferase: Biology, Role in Cancer, and Novel Drug Target

Antonio Lucena‑Cacace1,2,3, Amancio Carnero1,2


Enhanced Anticancer Effect by Combination of Proteoglucan and Vitamin K3 on Bladder Cancer Cells

Michael Zhang, Kelvin Zheng, Muhammad Choudhury, John Phillips, Sensuke Konno


Molecular Insights Turning Game for Management of Ependymoma: A Review of Literature

Ajay Sasidharan, Rahul Krishnatry


IDH Gene Mutation in Glioma

Leping Liu1, Xuejun Li1,2


Challenges and Advances in the Management of Pediatric Intracranial Germ Cell Tumors: A Case Report and Literature Review

Gerard Cathal Millen1, Karen A. Manias1,2, Andrew C. Peet1,2, Jenny K. Adamski1


Assessing the Feasibility of Using Deformable Registration for Onboard Multimodality‑Based Target Localization in Radiation Therapy

Ge Ren1,2,3, Yawei Zhang1,2, Lei Ren1,2


Research Advancement in the Tumor Biomarker of Hepatocellular Carcinoma

Qing Du1, Xiaoying Ji2, Guangjing Yin3, Dengxian Wei3, Pengcheng Lin1, Yongchang Lu1,
Yugui Li3, Qiaohong Yang4, Shizhu Liu5, Jinliang Ku5, Wenbin Guan6, Yuanzhi Lu7


Novel Insights into the Role of Bacterial Gut Microbiota in Hepatocellular Carcinoma

Lei Zhang1, Guoyu Qiu2, Xiaohui Xu2, Yufeng Zhou3, Ruiming Chang4


Central Odontogenic Fibroma with Unusual Presenting Symptoms

Aanchal Tandon, Bharadwaj Bordoloi, Safia Siddiqui, Rohit Jaiswal


The Prognostic Role of Lactate in Patients Who Achieved Return of Spontaneous Circulation after Cardiac Arrest: A Systematic Review and Meta‑analysis

Dongni Ren1, Xin Wang2, Yanyang Tu1,2


Inhibitory Effect of Hyaluronidase‑4 in a Rat Spinal Cord Hemisection Model

Xipeng Wang1,2, Mitsuteru Yokoyama2, Ping Liu3


Research and Development of Anticancer Agents under the Guidance of Biomarkers

Xiaohui Xu1, Guoyu Qiu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Ruling Jia1, Bo Zhao1


Idiopathic Hypereosinophilic Syndrome and Disseminated Intravascular Coagulation

Mansoor C. Abdulla


Phosphorylation of BRCA1‑Associated Protein 1 as an Important Mechanism in the Evasion of Tumorigenesis: A Perspective

Guru Prasad Sharma1, Anjali Geethadevi2, Jyotsna Mishra3, G. Anupa4, Kapilesh Jadhav5,
K. S. Vikramdeo6, Deepak Parashar2


Progress in Diagnosis and Treatment of Mixed Adenoneuroendocrine Carcinoma of Biliary‑Pancreatic System

Ge Zengzheng1, Huang-Sheng Ling2, Ming-Feng Li2, Xu Xiaoyan1, Yao Kai1, Xu Tongzhen3,
Ge Zengyu4, Li Zhou5


Surface-Enhanced Raman Spectroscopy to Study the Biological Activity of Anticancer Agent

Guoyu Qiu1, Xiaohui Xu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Huan Yang5


Alzheimer’s Disease Susceptibility Genes in Malignant Breast Tumors

Steven Lehrer1, Peter H. Rheinstein2


OSMCC: An Online Survival Analysis Tool for Merkel Cell Carcinoma

Umair Ali Khan Saddozai1, Qiang Wang1, Xiaoxiao Sun1, Yifang Dang1, JiaJia Lv1,2, Junfang Xin1, Wan Zhu3, Yongqiang Li1, Xinying Ji1, Xiangqian Guo1


Protective Activity of Selenium against 5‑Fluorouracil‑Induced Nephrotoxicity in Rats

Elias Adikwu, Nelson Clemente Ebinyo, Beauty Tokoni Amgbare


Advances on the Components of Fibrinolytic System in Malignant Tumors

Zengzheng Ge1, Xiaoyan Xu1, Zengyu Ge2, Shaopeng Zhou3, Xiulin Li1, Kai Yao1, Lan Deng4


A Patient with Persistent Foot Swelling after Ankle Sprain: B‑Cell Lymphoblastic Lymphoma Mimicking Soft‑tissue Sarcoma

Crystal R. Montgomery‑Goecker1, Andrew A. Martin2, Charles F. Timmons3, Dinesh Rakheja3, Veena Rajaram3, Hung S. Luu3


Coenzyme Q10 and Resveratrol Abrogate Paclitaxel‑Induced Hepatotoxicity in Rats

Elias Adikwu, Nelson Clemente Ebinyo, Loritta Wasini Harris


Progress in Clinical Follow‑up Study of Dendritic Cells Combined with Cytokine‑Induced Killer for Stomach Cancer

Ling Wang1,2, Run Wan1,2, Cong Chen1,2, Ruiliang Su1,2, Yumin Li1,2


Supraclavicular Lymphadenopathy as the Initial Manifestation in Carcinoma of Cervix

Priyanka Priyaarshini1, Tapan Kumar Sahoo2


ABO Typing Error Resolution and Transfusion Support in a Case of an Acute Leukemia Patient Showing Loss of Antigen Expression

Debasish Mishra1, Gopal Krushna Ray1, Smita Mahapatra2, Pankaj Parida2


Protein Disulfide Isomerase A3: A Potential Regulatory Factor of Colon Epithelial Cells

Yang Li1, Zhenfan Huang2, Haiping Jiang3


Clinicopathological Association of p16 and its Impact on Outcome of Chemoradiation in Head‑and‑Neck Squamous Cell Cancer Patients in North‑East India

Srigopal Mohanty1, Yumkhaibam Sobita Devi2, Nithin Raj Daniel3, Dulasi Raman Ponna4,
Ph. Madhubala Devi5, Laishram Jaichand Singh2


Potential Inhibitor for 2019‑Novel Coronaviruses in Drug Development

Xiaohui Xu1, Zilong Dang2, Lei Zhang3, Lingxue Zhuang4, Wutang Jing5, Lupeng Ji6, Guoyu Qiu1


Best‑Match Blood Transfusion in Pediatric Patients with Mixed Autoantibodies

Debasish Mishra1, Dibyajyoti Sahoo1, Smita Mahapatra2, Ashutosh Panigrahi3


Characteristics and Outcome of Patients with Pheochromocytoma

Nadeema Rafiq1, Tauseef Nabi2, Sajad Ahmad Dar3, Shahnawaz Rasool4


Comparison of Histopathological Grading and Staging of Breast Cancer with p53‑Positive and Transforming Growth Factor‑Beta Receptor 2‑Negative Immunohistochemical Marker Expression Cases

Palash Kumar Mandal1, Anindya Adhikari2, Subir Biswas3, Amita Giri4, Arnab Gupta5,
Arindam Bhattacharya6


Chemical Compositions and Antiproliferative Effect of Essential Oil of Asafoetida on MCF7 Human Breast Cancer Cell Line and Female Wistar Rats

Seyyed Majid Bagheri1,2, Davood Javidmehr3, Mohammad Ghaffari1, Ehsan Ghoderti‑Shatori4


Cyclooxygenase‑2 Contributes to Mutant Epidermal Growth Factor Receptor Lung Tumorigenesis by Promoting an Immunosuppressive Environment

Mun Kyoung Kim1, Aidin Iravani2, Matthew K. Topham2,3


Potential role of CircMET as A Novel Diagnostic Biomarker of Papillary Thyroid Cancer

Yan Liu1,2,3,4#, Chen Cui1,2,3,4#, Jidong Liu1,2,3,4, Peng Lin1,2,3,4,Kai Liang1,2,3,4, Peng Su5, Xinguo Hou1,2,3,4, Chuan Wang1,2,3,4, Jinbo Liu1,2,3,4, Bo Chen6, Hong Lai1,2,3,4, Yujing Sun1,2,3,4* and Li Chen 1,2,3,4*


Cuproptosis-related Genes in Glioblastoma as Potential Therapeutic Targets

Zhiyu Xia1,2, Haotian Tian1, Lei Shu1,2, Guozhang Tang3, Zhenyu Han4, Yangchun Hu1*, Xingliang Dai1*


Cancer Diagnosis and Treatments by Porous Inorganic Nanocarriers

Jianfeng Xu1,2, Hanwen Zhang1,2, Xiaohui Song1,2, Yangong Zheng3, Qingning Li1,2,4*


Delayed (20 Years) post-surgical Esophageal Metastasis of Breast Cancer - A Case Report

Bowen Hu1#, Lingyu Du2#, Hongya Xie1, Jun Ma1, Yong Yang1*, Jie Tan2*


Construction of Glioma Prognosis Model and Exploration of Related Regulatory Mechanism of Model Gene

Suxia Hu, Abdusemer Reyimu, Wubi Zhou, Xiang Wang, Ying Zheng, Xia Chen, Weiqiang Li, Jingjing Dai


ESRP2 as a Non-independent Potential Biomarker-Current Progress in Tumors

Yuting Chen, Yuzhen Rao, Zhiyu Zeng, Jiajie Luo, Chengkuan Zhao, Shuyao Zhang


Resection of Bladder Tumors at the Ureteral Orifice Using a Hook Plasma Electrode: A Case Report

Jun Li, Ziyong Wang, Qilin Wang


Structural Characterization and Bioactivity for Lycium Barbarum Polysaccharides

Jinghua Qi1,2,  Hangping Chen3,Huaqing Lin2,4,Hongyuan Chen1,2,5* and Wen Rui2,3,5,6*


The Role of IL-22 in the Prevention of Inflammatory Bowel Disease and Liver Injury

Xingli Qi1,2, Huaqing Lin2,3, Wen Rui2,3,4,5 and Hongyuan Chen1,2,3


RBM15 and YTHDF3 as Positive Prognostic Predictors in ESCC: A Bioinformatic Analysis Based on The Cancer Genome Atlas (TCGA)

Yulou Luo1, Lan Chen2, Ximing Qu3, Na Yi3, Jihua Ran4, Yan Chen3,5*


Mining and Analysis of Adverse Drug Reaction Signals Induced by Anaplastic Lymphoma Kinase-Tyrosine Kinase Inhibitors Based on the FAERS Database

Xiumin Zhang1,2#, Xinyue Lin1,3#, Siman Su1,3#, Wei He3, Yuying Huang4, Chengkuan Zhao3, Xiaoshan Chen3, Jialin Zhong3, Chong Liu3, Wang Chen3, Chengcheng Xu3, Ping Yang5, Man Zhang5, Yanli Lei5*, Shuyao Zhang1,3*


Advancements in Immunotherapy for Advanced Gastric Cancer

Min Jiang1#, Rui Zheng1#, Ling Shao1, Ning Yao2, Zhengmao Lu1*


Tumor Regression after COVID-19 Infection in Metastatic Adrenocortical Carcinoma Treated with Immune Checkpoint Blockade: A Case Report

Qiaoxin Lin1, Bin Liang1, Yangyang Li2, Ling Tian3*, Dianna Gu1*


Mining and Analysis of Adverse Events of BRAF Inhibitors Based on FDA Reporting System

Silan Peng1,2#, Danling Zheng1,3#, Yanli Lei4#, Wang Chen3, Chengkuan Zhao3, Xinyue Lin1, Xiaoshan Chen3, Wei He3, Li Li3, Qiuzhen Zhang5*, Shuyao Zhang1,3*


Malignant Phyllodes Tumor with Fever, Anemia, Hypoproteinemia: A Rare and Strange Case Report and Literature Review

Zhenghang Li1, Yuxian Wei1*


Construction of Cuproptosis-Related LncRNA Signature as a Prognostic Model Associated with Immune Microenvironment for Clear-Cell Renal Cell Carcinoma

Jiyao Yu1#, Shukai Zhang2#, Qingwen Ran3, Xuemei Li4,5,6*


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