Cancer Translational Medicine

Review | Open Access

Vol.8 (2022) | Issue-1 | Page No: 25-36

DOI: https://doi-ds.org/doilink/03.2022-87677796/A4

Updates on Molecular Markers for Gliomas

Jingyao Jie1, Weijuan Zhang2*

Affiliations  

1 Pharmaceutical Department, Henan General Hospital, Zhengzhou, Henan, China

2 Department of Biochemistry and Molecular Biology, School of Medicine, Henan University, Kaifeng, Henan, China

*Corresponding Author: 

Address for Correspondence: Prof. Weijuan Zhang, Department of Biochemistry and Molecular Biology, School of Medicine, Henan University, Jinming Avenue, Kaifeng 475000, Henan, China. E-mail address: zwjuan1965@henu.edu.cn  


Important Dates  

Date of Submission:   20-Jan-2022

Date of Acceptance:   02-Mar-2022

Date of Publication:   30-Mar-2022

ABSTRACT

Glioma is the most common primary brain tumor in the central nervous system. More than half of these gliomas are glioblastoma multiforme (GBM), which is the most malignant form. The median survival time of GBM patients is only 15 months, even with the most active treatment. In recent years, genomic and proteomic analyses of gliomas have greatly expanded our understanding of the physiology, pathology, and pathogenesis of gliomas. Molecular markers such as IDH, MGMT, EGFR, 1P/19q, BRAF, and TP53 have been used to supplement and improve the histological classification of glioma and have important application value in diagnosis, prognosis, and predicting treatment. Circulating tumor markers such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating tumor-derived exosomes and noncoding RNAs (ncRNAs) have potential application value in improving the prognosis and clinical management of glioma patients and are expected to become powerful markers for clinical diagnosis and monitoring. This paper, which is intended to provide a practical resource for both clinical and basic researchers, reviews the most common glioma-associated molecular alterations, biomarkers, and potential therapeutic targets.


INTRODUCTION

Glioma is one of the most common primary central nervous system tumors. In the 2021 WHO Classification of Tumors of the Central Nervous System, gliomas are divided into grade 1 (low malignancy and good prognosis) to grade 4 (high malignancy and poor prognosis) according to biological characteristics such as histopathological characteristics and molecular information.[1] Glioblastoma is the most common and malignant glioma type, belonging to CNS WHO grade 4, accounting for approximately 45%-60% of all gliomas.[2] Glioblastoma is currently considered incurable. Standard GBM treatment includes maximal safe surgical resection and combined chemoradiotherapy.[3] Despite this, the median survival time of patients after this aggressive treatment is only 15 months.[4] Due to the progress in molecular neuro-oncology, the neuropathological evaluation of glioma is no longer limited to providing information about tumor histological type and malignancy grade but may be supplemented by growing number of clinically relevant biomarkers. Especially in the update of the 4th edition of the WHO CNS tumor classification published in 2016, molecular parameters are part of the definition of specific brain tumor entities for the first time.[5] This highlights that tumor markers play an important role in further improving the classification of gliomas, improving the accuracy of diagnosis, judging the prognosis of patients, and developing effective molecular targeted therapeutics in the future. In this paper, the main clinically related molecular markers in gliomas are described, such as IDH, MGMT, EGFR, 1P/19q, BRAF, and TP53.

  At present, the clinical diagnosis of glioma type and malignancy depends on the results of histopathological examination.[6] However, because repeated brain tissue biopsy is difficult to achieve, there is an urgent need for circulating glioma tumor markers to dynamically monitor the condition. In recent years, in clinical research on tumor monitoring, people have shown great interest in liquid biopsy, a noninvasive diagnostic technique. Liquid biopsy provides abundant information for clinical decision-making by allowing the separation and detection of tumor-related cells and tumor derivatives in body fluids (blood, cerebrospinal fluid, etc.).[7] It is a convenient, fast, and noninvasive pathological detection method that can be sampled multiple times, dynamically reflects changes in the tumor gene expression profile, and helps to avoid diagnostic errors caused by tumor heterogeneity.[8] Glioma tumor markers detected by traditional tissue biopsy and liquid biopsy have their own advantages and disadvantages (Table 1). In this review, we also briefly introduce glioma-related circulating tumor markers monitored by liquid biopsy technology and their potential value in improving the management of glioma patients, including CTCs, ctDNA, circulating tumor-derived exosomes, and ncRNAs.

Table 1.
Summary of glioma tumor markers and their advantages and disadvantages

 


GLIOMA BIOMARKERS DETECTED BY TRADITIONAL TISSUE BIOPSY

IDH mutation is a strong favorable prognostic marker

Isocitrate dehydrogenase (IDH) is an important catalytic enzyme in the tricarboxylic acid cycle. In the tricarboxylic acid cycle, the family of IDH enzymes catalyzes the oxidative decarboxylation of isocitrate to produce α-ketoglutarate (α-KG) and simultaneously converts nicotinamide adenine dinucleotide phosphate (NADP+) into NADPH, which provides energy and precursors for cellular metabolism and biosynthesis.

  IDH gene mutations are found in 70%-80% of WHO grade 2 and 3 astrocytomas and oligodendrogliomas and 90% of secondary glioblastomas.[9],[10],[11] In contrast, these mutations are rare in primary GBMs. The vast majority of mutations are caused by the substitution of the 132nd amino acid in IDH1 from arginine to histidine (R132H) and the 172nd amino acid in IDH2 from arginine to lysine (R172K).[12] Among them, IDH1-R132H has the highest mutation frequency, accounting for approximately 90%.[13] Mutated IDH protein consumes α-ketoglutarate to produce the oncometabolite 2-hydroxyglutarate (2-HG), which then accumulates in large quantities and eventually promotes the occurrence and development of glioma. IDH mutation usually occurs in the background of p53 mutation or 1p/19q deletion and rarely occurs simultaneously.[14],[15],[16],[17] IDH mutation is considered to be the initiating event of IDH mutant glioma.[18]

  Regardless of the tumor grade or treatment received, IDH mutation gliomas have longer progression-free survival and overall survival than IDH wild-type gliomas.[19],[20] Many IDH wild-type low-grade gliomas (LGGs) may be as aggressive as GBM and have a very similar prognosis to WHO grade 4 tumors.[21] In contrast, IDH-mutant GBM usually has a significantly better prognosis than either IDH wild-type GBM or IDH wild-type low-grade tumors.[22]

  Mutant IDH protein is a promising therapeutic target. Strategies include direct targeting of IDH through small-molecule IDH inhibitors or IDH-targeted vaccines. For example, Kim et al. developed 3-fluoro-methyl ethanol, which can kill tumor cells by targeted inhibition of IDH1 R132H.[23] Immune targeting of IDH1 R132H in a mouse model also showed antitumor immunity and prolonged the survival time of mice.[24],[25]

MGMT promoter methylation is a prognostic and predictive factor in glioma patients treated with temozolomide

The O6-methylguanine-DNA methyltransferase (MGMT) gene, located on chromosome 10q26, encodes a DNA repair enzyme. Alkylating agents, such as temozolomide (TMZ), induce the production of O6-methylguanine, which leads to the insertion of thymine instead of cytosine in the process of cell replication leading to DNA double-strand breakage, DNA replication failure, and ultimately tumor cell death.[26] This is one of the main therapeutic methods for glioma. As a DNA repair enzyme, MGMT can demethylate O6-methylguanine, effectively repair DNA damage, and irreversibly inactivate itself into alkylated MGMT.[27] The repair capacity of cells depends on the expression level and synthesis rate of MGMT in cells. Therefore, higher expression of MGMT is thought to contribute to temozolomide resistance. In the nucleus, MGMT promoter methylation leads to gene silencing and inhibition of protein synthesis, reducing DNA repair activity, and increasing the sensitivity to temozolomide.[28],[29]

  The promoter methylation of MGMT was observed in approximately 40% of GBMs and approximately 80% of low-grade IDH mutant gliomas. MGMT promoter methylation was identified as a prognostic and predictive biomarker in GBM patients treated with temozolomide and was associated with prolonged progression-free and overall survival in patients treated with alkylating agents.[30] Multiple studies in elderly patients have confirmed that MGMT promoter methylation is a favorable prognostic factor and predictor of temozolomide sensitivity. Due to the increased toxicity of combined radiotherapy and chemotherapy, which are not suitable for elderly patients, recent evidence supports chemotherapy for patients with MGMT promoter methylation and radiotherapy for those without it.[31],[32],[33]

EGFR amplification and EGFRvIII rearrangement strongly suggest the degree of malignancy

The epidermal growth factor receptor (EGFR) gene is located on chromosome 7p12. The gene encodes a transmembrane tyrosine kinase receptor, which contains three domains: an extracellular ligand-binding domain, a transmembrane region, and an intracellular kinase domain. The binding of ligands and EGFR leads to the phosphorylation of tyrosine kinase residues in the intracellular region; further activates intracellular downstream signaling pathways, such as the MAPK, AKT, and JNK pathways; and finally promotes a series of biological behaviors, such as tumor occurrence, development, proliferation, invasion, and metastasis.[34]

  Approximately 40% of primary glioblastomas exhibit overexpression and amplification of the EGFR gene.[35] The degree of tumor malignancy is positively correlated with the amount of EGFR overexpression in gliomas.[36] Tumors with EGFR amplification are usually accompanied by EGFR gene mutations, the most common of which is EGFRvIII rearrangement. This rearrangement is formed by an in-frame deletion of exons 2-7 that encode the extracellular domain of the protein and results in EGFRvIII truncation, with a deletion of 267 amino acid sites of the extracellular ligand-binding region, rendering its activation independent of conventional receptor-ligand binding.[37] EGFRvIII rearrangement is present in approximately 50% of EGFR-amplified glioblastomas. Studies have indicated that the overexpression of EGFRvIII in glioma cells leads to the activation of related downstream signaling pathways (such as the PI3K/Akt pathway), which can induce tumorigenicity and cell proliferation. It can also resist apoptosis by regulating Bcl-XL gene expression.[38],[39],[40] The identification of EGFR amplification and rearrangement (such as EGFRvIII) can be used as an indicator of tumor malignancy and provide clinical diagnosis and prognosis information.[41]

  EGFRvIII is not expressed in normal tissues, therefore, it is an attractive target for immunotherapy.[42] At present, EGFRvIII can be used as a new peptide sequence of tumor-specific targets to develop peptide-based vaccination therapy. Rindopepimut is an EGFRvIII peptide vaccine composed of an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The immune response to this peptide has been proven to specifically eliminate cells expressing EGFRvIII.[43] Phase II clinical trial data showed that this vaccine improved progression-free survival, and EGFRvIII expression disappeared in tumor samples from 67% of patients vaccinated for more than 3 months.[44],[45] However, the results of a phase III trial showed that the combination of rindopepimut and standard temozolomide did not prolong the overall survival of EGFRvIII-positive glioblastoma patients compared with temozolomide alone.[46] Research also showed that injecting antisense RNA to target EGFRvIII in vivo can reduce the volume of the glioma by >40-fold.[47]

Chromosomal 1p/19q codeletion is a diagnostic marker of oligodendroglioma

The 1p/19q codeletion was first observed in oligodendroglioma samples, which refers to the simultaneous deletion of the short arm of chromosome 1 and the long arm of chromosome 19, which is caused by the unbalanced translocation of the centromeric region.[48] The 1p/19q codeletion has been detected in 80%-90% of oligodendrogliomas, 50%-70% of anaplastic oligodendrogliomas, 15% of diffuse astrocytomas, and only 5.0% of glioblastomas.[49] Therefore, 1p/19q codeletion has been considered a molecular marker for the diagnosis and prognosis of oligodendroglioma.[50] Currently, 1p/19q codeletion is part of the WHO 2021 central nervous system tumor definition, which defines tumors with oligodendrocyte phenotypes.[1] Tumor patients with 1p/19q codeletion are sensitive to chemotherapy drugs, such as PCV (procarbazine, lomustine, vincristine) and temozolomide, and have a good prognosis.[51]

  The diagnosis based on histological features is subjective. Therefore, 1p/19q codeletion is usually detected for suspected oligoastrocytoma or mixed oligoastrocytoma to assist in histological diagnosis. Mixed oligoastrocytoma can be diagnostically classified as either oligodendrocyte or astrocytoma by the status of 1p/19q. The presence of 1p/19q codeletion is an objective diagnostic marker of oligodendrocytes. If there is no 1p/19q deletion, it can be diagnosed as astrocytoma.[52]

 

BRAF gene fusion and mutation are diagnostic markers of pilocytic astrocytoma

The BRAF gene is a proto-oncogene located on human chromosome 7q34 and encodes the BRAF protein which is a member of the MAPK pathway. This pathway plays a key role in cell proliferation, cell survival, differentiation, and apoptosis by regulating the activity of several transcription factors.[53] Alterations in the BRAF gene in central nervous system tumors are mainly gene fusions (KIAA 1549: BRAF) and missense mutations (V600E).[54] The BRAF-KIAA 1549 fusion involves the 5' end of the KIAA 1549 gene and the 3' end of BRAF, leading to the replacement of the N-terminal autoregulation domain of BRAF by the N-terminus of KIAA 1549. As a result, the BRAF protein is continuously activated, and the downstream MAPK pathway is subsequently activated.[55] The BRAF V600E mutation is caused by a single nucleotide exchange (T to A) at codon 600, which causes valine to replace glutamate (V600E).[56] BRAF mutation leads to the activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, which is mainly found in localized low-grade gliomas, such as pilocytic astrocytoma (PA), ganglioglioma (GG), and pleomorphic xanthoastrocytoma (PXA).[57] These tumors usually occur in children or young adults, with a slow course, but may relapse over time. Among central nervous system tumors, PA shows the highest frequency of BRAF gene fusions or mutations. Compared with other CNS tumors, the high specificity of this change in PA has a diagnostic significance.[58]

  These changes in the BRAF gene were detected in 60%-80% of pilocytic astrocytomas but were rare in diffuse invasive astrocytomas. Therefore, the detection of BRAF gene alterations may be helpful for the differential diagnosis between pilocytic astrocytoma and low-grade diffuse astrocytoma.[49]

TP53 gene mutation is a diagnostic marker of glioma and a prognostic indicator of low-grade glioma

TP53 is a tumor suppressor gene located on chromosome 17p13. Its expression product, p53 protein, regulates the cell growth cycle and affects tumor formation by blocking abnormal cell proliferation.[59] TP53 mutation or deletion often leads to tumorigenesis. More than 50% of human tumors involve TP53 gene mutations. TP53 is frequently mutated in astrocytomas (50%-90%) and oligoastrocytomas (40%-50%) but is infrequently mutated in oligodendrogliomas (5%-10%).[60] At present, the expression of p53 protein has been used as a diagnostic biomarker, which is helpful for tumor grading. For low-grade gliomas, TP53 mutation suggests poor prognosis, but it has no predictive value for GBM. The lack of a clear prognostic correlation of p53 in GBM may be due to the complexity of the p53 signaling pathway, such as changes in retinoblastoma (Rb) and mouse double minute-2 (MDM2) in GBM, which are important regulators in the p53 pathway.[61] Therapeutic strategies for p53 mutant genes focus on trying to reactivate this pathway using gene therapy or pharmacological methods, such as inhibiting MDM2. The p53 protein is mainly regulated by MDM2, which inactivates p53 by binding to its transactivation domain or catalyzing its ubiquitination and degradation, thus allowing defective cells to continue reproducing.[62] According to the structure of the p53-MDM2 complex, Chene et al. designed an octapeptide complex that can penetrate cells without further modification and activate wild-type p53 protein in tumor cells.[63] Another nonpeptide small molecule inhibitor, MI-77301, simulates the p53 protein structure responsible for binding to MDM2 and can firmly bind to MDM2, competitively inhibit the binding of p53 to MDM2, inhibit the growth of tumor cells, and have high bioavailability, which is more valuable than polypeptide drugs.[64]


CIRCULATING TUMOR MARKERS OF GLIOMAS DETECTED BY LIQUID BIOPSY

Circulating tumor cells

Circulating tumor cells (CTCs) are the tumor cells that detach from primary or metastatic tumors and enter the peripheral blood.[65] Most CTCs undergo apoptosis or phagocytosis after entering the peripheral blood. Only a few can escape and develop into metastases, which is considered to be the basis of tumor metastasis.[66]

  It is generally believed that brain tumors do not metastasize through blood flow. However, some studies have found that some patients who received organ transplantation from glioma patients had glioma after the operation.[67] This indicates that glioma tumor cells can metastasize to other organs and tissues. CTCs are also found in 20-40% of glioblastoma patients.[7] Data from a glioma mouse model show that CTCs have invasive stem cell-like characteristics; are resistant to radiotherapy, chemotherapy, and apoptosis induced by circulatory stress; and lead to the invasion and recurrence of carcinoma in situ through local micrometastasis.[68] CTCs are detected in metastatic tumors or during tumor recurrence, and thus, they can be used to monitor disease progression and treatment response. Macarthur et al. found a significant reduction in CTCs after radiotherapy and reported an increase in the CTC level in one patient with tumor recurrence, suggesting that CTCs can be used to monitor recurrence of GBM.[69] Sullivan et al. found that the number of CTCs is higher in progressive diseases and that CTCs tend to overexpress genes from mesenchymal subtypes with greater invasiveness.[70] Nayak et al. demonstrated for the first time that cerebrospinal fluid CTC detection has higher sensitivity and specificity than conventional imaging methods and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis (LM).[71]

  The limiting factor for the wide clinical application of CTCs is their limited number in the blood. In the blood of patients with metastatic cancer, there is only one CTC per 109 cells.[72] Such a low content is not sufficient to track therapeutic effects or make CTCs a marker related to therapeutic resistance. Therefore, the sensitivity of CTC detection is a technical challenge. At present, based on the unique biological and physical characteristics of CTCs, different technologies are used to isolate and identify CTCs from the blood and cerebrospinal fluid of glioma patients.[73] For example, cell search systems, CTC chip, ScreenCell, and ParsortixTM have been used. However, thus far, there is still no widely accepted standard method to identify and collect CTCs.[74] In addition, in brain tumor cases, CTCs are easier to collect from cerebrospinal fluid than from blood.

  To date, there are limited data on CTCs related to glioma, and the application of CTCs as a biomarker for glioma patients has just begun. Whether glioma CTCs fully represent heterogeneous tumor cells and the potential of CTCs as clinical biomarkers for glioma in diagnosis, prognosis, prediction, and monitoring remain to be evaluated.

Circulating tumor DNA

Circulating tumor DNA (ctDNA) refers to gene fragments from tumor cells in the circulatory system. ctDNA comes from apoptotic or exfoliated tumor cells.[75] Studies have shown that the mutation spectrum of tumor tissue and its corresponding ctDNA has good consistency, and even cancer-specific mutations not found in tissue biopsy have been identified in blood.[76],[77],[78] Therefore, ctDNA can be used as a tumor biomarker to track tumor mutations and mutation patterns. The amount of ctDNA in serum is related to tumor type, grade, and burden.[79] Therefore, continuous detection of ctDNA levels can enable monitoring of tumor progression, drug effects, and disease recurrence.

  Some experimental results have shown that ctDNA can be detected in the blood of glioma patients, and ctDNA gene mutations can be analyzed to guide treatment and evaluate prognosis. Through imaging and clinical examination, it was found that patients with methylated MGMT ctDNA had a significantly higher response to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) than those with unmethylated MGMT ctDNA.[80] In a prospective study of plasma samples collected from patients with grade 2-4 glioma, it was found that the presence of methylated MGMT ctDNA in blood was associated with increased progression-free survival and overall survival.[81] Salkeni et al. detected ctDNA with EGFRvIII mutation in the peripheral blood of patients with brain tumors.[82] EGFRvIII ctDNA can be used as a monitoring marker during treatment specifically or indirectly targeting EGFRvIII.

  The key factor limiting the clinical application of ctDNA detection is the low concentration of ctDNA in the plasma of glioma patients; thus, highly sensitive detection methods are needed. The common detection methods are PCR and next-generation sequencing technologies. Techniques to further improve the detection ability of ctDNA include isolating mitochondrial ctDNA,[83] analyzing epigenetic changes,[84] or targeting specific fragment size cell-free DNA (cfDNA) to reduce background interference.[85] In addition, the detection of ctDNA in cerebrospinal fluid seems to be more advantageous in nervous system tumors. The information provided by ctDNA in cerebrospinal fluid is more accurate and representative.[86] Compared with ctDNA in plasma, the concentration of ctDNA in cerebrospinal fluid is higher, and the sensitivity of ctDNA mutation detection is higher.[87],[88] Wang et al. found that CSF-derived ctDNA could be detected in all neuroblastoma, ependymoma, and paraventricular high-grade glioma cases, while CSF-derived ctDNA was not detected in the presence of tumors not directly adjacent to cerebrospinal fluid.[89] ctDNA is a promising biomarker of glioma. However, the difficulty of cerebrospinal fluid sampling and the low concentration of glioma ctDNA in plasma are the challenges of the clinical application of this technology.

Circulating tumor-derived exosomes

Exosomes are functional vesicles secreted by cells. They generally exist in biological fluids; contain a large number of nucleic acids, lipids, and proteins of parental cells; and participate in intercellular communication and formation of the tumor microenvironment.[90] The physical structure of exosomes protects their contents from enzymatic degradation.[91]

  The molecular markers and disease effectors carried by cancer cell exosomes, such as mutant oncoproteins, oncogenic transcripts, microRNAs, and DNA sequences, provide opportunities for exosomes to become tumor markers.[92] The concentration of RNA isolated from serum exosomes of patients with glioblastoma is 60 times that of serum-free circulating RNA, which confirms that exosomes have the potential to become an ideal circulating tumor marker.[93]

To date, a variety of tumor-related molecules have been found in the circulating exosomes of glioma patients. These molecular changes can be used for the diagnosis, prognosis, and treatment of glioma. Analysis of clinical samples has shown that tumor grade is positively correlated with the expression of polymerase 1 and transcription release factor (PTRF) in tumor tissues and serum exosomes of patients with glioma. The expression of PTRF in serum exosomes of patients with GBM decreased after surgery. PTRF is a potential biomarker present in tumor samples and serum exosomes.[94] Santangelo et al. found that miR-21, miR-222, and miR-124-3p contained in plasma exosomes were related to the grade and prognosis of glioma.[95] The study found that the level of miR-21 in cerebrospinal fluid exosomes of glioma patients was significantly higher than that in cerebrospinal fluid exosomes from the control group, while there was no difference in the expression of miR-21 in serum exosomes. The level of miR-21 in cerebrospinal fluid exosomes is correlated with spinal and ventricular metastasis and tumor recurrence. After total resection of glioma, the level of exosomal miR-21 decreased significantly. These experimental data indicate that the level of secreted miR-21 can be used as a promising index for glioma diagnosis and prognosis determination.[96]

  Although exosomes are promising targets for biomarker research, their tracking and quantification in clinical samples are still challenging. The relative abundance of nonneoplastic exosomes in the circulation is a challenge when identifying exosome biomarkers in cancer patients. In glioma patients, less than 10% of circulating exosomes are tumor specific.[97] Glioma-derived exosome enrichment strategies are still under study, and there is still no standard method to distinguish tumor and nontumor exosomes.

Circulating tumor Noncoding RNAs

Noncoding RNAs (ncRNAs) are a class of RNA molecules without protein-coding functions. They comprise a large part of the human transcriptome and play an important role in various physiological and pathological processes, especially in cancer. Among the multitude of ncRNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are the most related to the cancer process. Especially in recent years, the discovery of ncRNAs in exosomes has attracted increasing attention.[98]

  MicroRNAs are small ncRNAs composed of approximately 21-25 nucleotides. As a regulator of gene expression, miRNAs complementarily bind to the 3' untranslated region (UTR) of the target mRNA, thereby reducing the stability of the target gene or inhibiting translation.[99] Dysregulation of miRNA expression is closely associated with many human diseases, including cancer. miRNAs may play a role in tumor inhibition or carcinogenesis under certain conditions.[100]

  miRNA dysregulation is associated with glioma diagnosis and prognosis as well as with acquired temozolomide resistance.[101] The expression of miR-21 is upregulated in glioma, and the level of miR-21 is also related to histological grade.[96],[102] In vitro studies have shown that long-term temozolomide treatment of the human GBM cell line D54MG results in acquired TMZ resistance and increased miR-21 expression. Concurrent treatment with a miR-21 inhibitor and temozolomide resulted in a significantly higher apoptosis rate than temozolomide alone. Thus, miR-21 may have the potential as a biomarker for acquired temozolomide resistance.[103] Another study showed that the plasma miRNAs of 50 patients with GBM, especially miR-21, miR-128, and miR-342-3p, were also altered compared with those of normal controls, and miR-128 and miR-342-3p were positively correlated with the histopathological grade of glioma.[104] miRNAs may serve as diagnostic biomarkers and promising therapeutic targets for GBM in the future.

  lncRNAs are RNAs with a length of more than 200 nucleotides and no protein coding function. They regulate gene expression through transcription or posttranscriptional modifications to achieve their biological function.[105] In the past decade, studies have increasingly shown that lncRNAs are involved in many pathophysiological processes, such as cell cycle regulation, cell differentiation, and the innate immune response.[106] In addition, dysregulated expression of lncRNAs has been observed in many human cancers, including glioma, playing the role of tumor suppressors or promoters.[105] In glioma, lncRNAs participate in many malignant biological behaviors. They affect DNA damage, cell cycle regulation, and signal transduction in glioma by acting as miRNA sponges or regulating epigenetic and other biological mechanisms. In glioblastoma, lncRNA MALAT1 has been reported to promote temozolomide resistance in GBM, and MALAT1-targeting nanoparticles can make GBM patients sensitive to temozolomide chemotherapy.[107] The lncRNA HOTAIR is regulated by the bromine domain protein BRD4, which regulates the cell cycle of glioma cells.[108] In recent years, with the increasing popularity of lncRNA research, targeted lncRNA molecules for individualized treatment and diagnosis of glioblastoma patients are still being discovered and explored.


CONCLUSION

Gene and molecular mutations in gliomas provide the basis for the establishment of clinically relevant biomarkers. The practice of neuro-oncology increasingly depends on the molecular diagnosis of tumor tissues. IDH and TP53 gene mutations and 1p/19q codeletion were used in the classification and definition of diffuse gliomas in the WHO classification of CNS tumors in 2016. For example, glioblastoma is divided into IDH wild type, IDH mutant, and not otherwise specified (NOS) according to IDH gene status.[109] This classification is based on the combination of histological and molecular features, breaking the centennial diagnostic principle completely based on microscopy. We must admit that with the introduction of a molecular definition, the traditional microstandard for tumor classification may no longer be applicable. Biomarkers play an increasingly important role in neuro-oncology and have great potential to significantly supplement and improve histological classification to guide clinical management.

  In addition to their diagnostic potential, these biomarkers have proven essential in monitoring disease progression and prognosis and predicting response to treatment. In particular, circulating tumor markers screened and analyzed via liquid biopsy technology can be used to repeatedly monitor tumor status and treatment response because they are easy to obtain. With the development of various studies, an increasing number of circulating tumor markers have been identified. However, due to limited sensitivity or specificity, the clinical application of these markers is very limited. Thus, to apply academic research to clinical applications, there is an urgent need to find a suitable combination of biomarkers and establish standardized detection methods. In the near future, circulating tumor markers are likely to play an important role in the clinical management of glioma.

  The poor prognosis of patients with GBM is not only due to a combination of factors, including the rapid proliferation, extensive invasion, tumor genetic heterogeneity of tumors, and therapeutic drug resistance of GBM, but also due to a poor understanding of the molecular pathogenesis and a lack of timely diagnosis and sensitive therapeutic monitoring tools. Therefore, it is very important to elucidate the molecular mechanism of the occurrence and development of glioma and further explore reliable biomarkers. With more research on the molecular characteristics of glioma, we will further understand the predictive, prognostic, and therapeutic value of different genetic alterations and develop targeted drugs based on these biomarkers. Future treatment may be based on the comprehensive analysis of the genome, proteome, and transcriptome to identify specific tumor types, therapeutic targets, drug sensitivity, and other factors to achieve personalized treatment.

 

FINANCIAL SUPPORT AND SPONSORSHIP
Nil.

CONFLICTS OF INTEREST
There are no conflicts of interest.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable
 


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Lili Zhou1,2, Hai Yi1*, Dan Chen1, Qian Zhang1, Fangyi Fan1, Ling Qiu1, Nan Zhang1, Yi Su1


Peroxisome Proliferator-Activated Receptor-γ Agonists as New Targets of Lung Cancer Therapy

Shixiong Wei1*


Microcirculation Specialist Consensus on Diagnosis and Treatment of Superficial Varicose Veins of Lower Limbs

Wang Lei1, Zheng Yuehong1*


Anticoagulation might not be necessary for asymptomatic central venous catheter-related thrombosis in adults

Wei Zhang1, Zhi Xiang1, Qin Ma2, Chuanlin Zhang3, Yu Zhao1, Qining Fu1*


The Roles of microRNA in the Diagnosis and Prognosis of Papillary Thyroid Cancer

Jingya Gao1*, Li Liu2*


Lung Cancer Tumor Microenvironment: An Update on Recent Advances in Research

Guangda Yuan1, Bowen Hu1, Yong Yang1*


Quantified ADC Values and Attenuation Trends for Diagnosing Prostate Cancer with Multiple b Values MRI

Jing Hu1#, Jingying Bu1#,Zhe Wang2#, Zhengdan Su2, Xiaoxian Wang2, Haiyao Pi3, Diliang Li2, Zhaoyang Pu4, Xin Tian1*


Differential Expression of T-box Transcription Factor TBX19 Regulates the Progression of Hepatocellular Carcinoma

Guifang He1, Yanjiao Hu2, Fuguo Dong3, Changchang Liu1, Duo Cai1, Shihai Liu1*


Advances in Pathogenesis and Non-surgical Therapy of Cutaneous Basal Cell Carcinoma

Yichen Wu1, Jia Chen2*


Quercetin Inhibits the Proliferation and Migration of Pancreatic Adenocarcinoma by Targeting the Prognostic-related Gene MMP1 via Bioinformatics and Network Pharmacology

Zhenhua Zu1,2#, Zhongguo Zhu3#, Zhiyu Xia2, Hongrang Chen1*, Yongsheng Li1*


Huge Lung Fibroleiomyomatous Hamartoma in the Pleural Cavity – A Case report

Minghui Liu1#, Xin Li1#, Hongbing Zhang1, Fan Ren1, Ming Dong1, Chunqiu Xia1, Jun Chen1,2*


Increased Expression of IL-17A, IL-6, STAT3, TGF-β, and VEGF: Potential Biomarkers in Bladder Cancer?

Zishen Xiao1, Chengxia Bai1, Teng Zhao1, Jiayu Lin1, Lijuan Yang1, Jian Liu2, Zhenjiang Wang1, Ying Sun3,4, Yanbo Liu1*


Identification of NSD2 as a Potential Diagnostic and Prognostic Biomarker for Hepatocellular Carcinoma

Wei Zhao1#, Xinyu Xiao1#, Yu Gao1,2, Shanshan Liu3, Xiuzhen Zhang1, Changhong Yang1, Qiling Peng1, Ning Jiang2*, Jianwei Wang1*


Quercetin Inhibits Glioma Proliferation by Targeting CDK1 and CCNB1 - Bioinformatics and Network Pharmacology

Huaixu Li1#, Peng Gao1#, Haotian Tian1, Zhenyu Han2, Xingliang Dai1*, Hongwei Cheng1*


Selective Internal Radiation Therapy with Yttrium-90 Microspheres in Hepatocellular Carcinoma – Applications and recent advances

Wei Wang1, Dawei Xie1, Bing Li1, Minghao Chen1*


Irreversible Electroporation in Pancreatic Cancer – Applications and recent advances

Yuanyuan Sun1, Qian Li2, Jia Hu2, Yanfang Liu2*, Xiaosong Li2*


Prognostic Value of Bismuth Typing and Modified T‑stage in Hilar Cholangiocarcinoma

Shengen Yi, Xiongjian Cui, Li Xiong, Xiaofeng Deng, Dongni Pei, Yu Wen, Xiongying Miao


MicroRNAs are Related to Rituximab in Combination with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Resistance in Patients with Diffuse Large B-cell Lymphoma

Haibo Huang1, Junjiao Gu1, Shuna Yao1, Zhihua Yao1, Yan Zhao1, Qingxin Xia2, Jie Ma2, Ling Mai3, Shujun Yang1, Yanyan Liu1


Comparison of Intra-voxel Incoherent Motion Diffusion Magnetic Resonance Imaging and Apparent Diffusion Coefficient in the Evaluation of Focal Malignant Liver Masses

Jinrong Qu1, Xiang Li1, Lei Qin2, Lifeng Wang1, Junpeng Luo1, Jianwei Zhang1, Hongkai Zhang1, Jing Li1, Fei Sun3, Shouning Zhang1, Yanle Li1, Cuicui Liu1, Hailiang Li1


Extracting Breathing Signal Using Fourier Transform from Cine Magnetic Resonance Imaging

Jing Cai1,2, Yilin Liu2, Fangfang Yin1,2


Split End Family RNA Binding Proteins: Novel Tumor Suppressors Coupling Transcriptional Regulation with RNA Processing

Hairui Su1, Yanyan Liu2, Xinyang Zhao1


Thioredoxin-interacting Protein as a Common Regulation Target for Multiple Drugs in Clinical Therapy/Application

Pengxing  Zhang1, Xiaoling Pang2,3, Yanyang Tu1,4


Associations of Age and Chemotherapy with Late Skin and Subcutaneous Tissue Toxicity in a Hypofractionated Adjuvant Radiation Therapy Schedule in Post‑mastectomy Breast Cancer Patients

Mohammad Akram1, Ghufran Nahid1, Shahid Ali Siddiqui1, Ruquiya Afrose2


Monitoring of Disease Activity in Chronic Myeloid Leukemia‑chronic Phase Patients Treated with Indian Generic Veenat (NATCO) Imatinib Mesylate: A Tertiary Care Experience

Khushboo Dewan, Tathagat Chatterjee


Review of Cancer Immunotherapy: Application of Chimeric Antigen Receptor T Cells and Programmed Death 1/Programmed Death‑ligand 1 Antibodies

Tengfei Zhang1,2, Ling Cao1, Zhen Zhang1, Dongli Yue1, Yu Ping1, Hong Li1, Lan Huang1, Yi Zhang1,3,4,5


Systematic Review of MicroRNAs and its Therapeutic Potential in Glioma

Nan Liu1, Yanyang Tu2


The Involvement of p53‑miR‑34a‑CDK4 Signaling During the Development of Cervical Cancer

Huijun Zuo, Jieqi Xiong, Hongwei Chen, Sisun Liu, Qiaoying Gong, Fei Guo


Unusual Clinical Presentation of a Rare Type of Breast Malignancy: A Case Report and a Short Review of Literature

Nadeesha J. Nawarathna1, Navam R. Kumarasinghe1, Palitha Rathnayake2,
Ranjith J. K. Seneviratne1


Sweet’s Syndrome in Acute Lymphoblastic Leukemia with t (9:22)

Khushboo Dewan, Shailaja Shukla


Analysis of the Correlationship between Prostate Specific Antigen Related Variables and Risk Factor in Patients with Prostate Carcinoma

Daoyuan Wang1, Tiejun Yang2, Yongqiang Zou1, Xinqiang Yang1


Recent Progress in Genetic and Epigenetic Profile of Diffuse Gastric Cancer

Zhengxi He1, Bin Li1,2


Strategies for Management of Spinal Metastases: A Comprehensive Review

Zhantao Deng, Bin Xu, Jiewen Jin, Jianning Zhao, Haidong Xu


Application and Perspectives of Traditional Chinese Medicine in the Treatment of Liver Cancer

Xia Mao, Yanqiong Zhang, Na Lin


Primary Hepatic Carcinoid Tumor: A Case Report and Literature Review

Yupeng Lei1, Hongxia Chen2, Pi Liu1, Xiaodong Zhou1


Expression Characteristics of miR‑10b in Nasopharyngeal Carcinoma

Gang Li, Yunteng Zhao, Jianqi Wang, Haoran Huang, Mengwen Zhang


An Update on Immunohistochemistry in Translational Cancer Research

Zonggao Shi, M. Sharon Stack


Promoter Methylated Tumor Suppressor Genes in Glioma

Yingduan Cheng1, Yanyang Tu2, Pei Liang3


Palliative Treatment of Malignant Pleural Effusion

Chenyang Liu1*, Qian Qian2*, Shen Geng1, Wenkui Sun1, Yi Shi1


Functional Perspective and Implications of Gene Expression by Noncoding RNAs

Xiaoshuang Yan1, Huanyu Xu2, Zhonghai Yan3


Expression of E3 Ubiquitin Ligases in Multiple Myeloma Patients after Treatment with the Proteasome Inhibitor Bortezomib

James Joseph Driscoll


miR‑505 Downregulates 6‑Phosphofructo‑2‑Kinase/ Fructose‑2,6‑Biphosphatase 4 to Promote Cell Death in Glioblastoma

Esther H. Chung, Hongwei Yang, Hongyan Xing, Rona S. Carroll, Mark D. Johnson


Utility of Fine Needle Aspiration Cytology in Diagnosing Bone Tumors

Sonal Mahajan1, Akash Arvind Saoji2, Anil Agrawal1


Histone H2A and H2B Deubiquitinase in Developmental Disease and Cancer

Demeng Chen1, Caifeng Dai2, Yizhou Jiang3


Genetic Characteristics of Glioblastoma: Clinical Implications of Heterogeneity

Qian Li1, Yanyang Tu1,2


Acute Lymphoblastic Leukemia with Normal Platelet Count

Khushboo Dewan, Kiran Agarwal


Galanin is a Novel Epigenetic Silenced Functional Tumor Suppressor in Renal Cell Carcinoma

Shengkun Sun1*, Axiang Xu1*, Guoqiang Yang1, Yingduan Cheng2

 


Selenium Dioxide Induced Apoptosis in Cervical Cancer Cells via Regulating Apoptosis-related Let-7a MicroRNA and Proteins

Sisun Liu1, Jieqi Xiong2, Ling Guo3, Min Xiu1,4, Feng He1,4, Yuanlei Lou5, Fei Guo6,7


Low Expression of Polo‑like Kinase 1 is Associated with Poor Prognosis in Liver Cancer

Weixia Li1, Kunpeng Liu1, Dechen Lin2, Xin Xu2, Haizhen Lu3, Xinyu Bi4, Mingrong Wang2


Extracorporeal Photopheresis for Steroid‑refractory Chronic Graft‑versus‑host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta‑Analysis

Runzhe Chen1, Baoan Chen1, Peter Dreger2, Michael Schmitt2, Anita Schmitt2


Glucans and Cancer: Historical Perspective

Petr Sima1, Luca Vannucci1, Vaclav Vetvicka2


Implications of Circadian Rhythm Regulation by microRNAs in Colorectal Cancer

Song Wu1, Andrew Fesler2, Jingfang Ju2


BCL2 Family, Mitochondrial Apoptosis, and Beyond

Haiming Dai1, X. Wei Meng2, Scott H. Kaufmann2


Quantum Dot‑based Immunohistochemistry for Pathological Applications

Li Zhou1, Jingzhe Yan2, Lingxia Tong3, Xuezhe Han4, Xuefeng Wu5, Peng Guo6


CD24 as a Molecular Marker in Ovarian Cancer: A Literature Review

Lu Huang1, Weiguo Lv2, Xiaofeng Zhao1


Etiological Trends in Oral Squamous Cell Carcinoma: A Retrospective Institutional Study

Varsha Salian, Chethana Dinakar, Pushparaja Shetty, Vidya Ajila


Effect of Irinotecan Combined with Cetuximab on Liver Function in Patients with Advanced Colorectal Cancer with Liver Metastases

Yan Liang1, Yang Li2, Xin Li3, Jianfu Zhao4


The Role of Precision Medicine in Pancreatic Cancer: Challenges for Targeted Therapy, Immune Modulating Treatment, Early Detection, and Less Invasive Operations

Khaled Kyle Wong1, Zhirong Qian2, Yi Le3


Targeting Signal Transducer and Activator of Transcription 3 for Colorectal Cancer Prevention and Treatment with Natural Products

Weidong Li1,2*, Cihui Chen3*, Zheng Liu2, Baojin Hua1


The Potential of Wnt Signaling Pathway in Cancer: A Focus on Breast Cancer

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


Imaging‑driven Digital Biomarkers

Enrico Capobianco


Target‑Matching Accuracy in Stereotactic Body Radiation Therapy of Lung Cancer: An Investigation Based on Four‑Dimensional Digital Human Phantom

Jing Cai1,2, Kate Turner2, Xiao Liang2, W. Paul Segars2,3, Chris R. Kelsey1, David Yoo1, Lei Ren1,2, Fang‑Fang Yin1,2


Downregulation of Death‑associated Protein Kinase 3 and Caspase‑3 Correlate to the Progression and Poor Prognosis of Gliomas

Ye Song, Tianshi Que, Hao Long, Xi’an Zhang, Luxiong Fang, Zhiyong Li, Songtao Qi


Hyaluronic Acid in Normal and Neoplastic Colorectal Tissue: Electrospray Ionization Mass Spectrometric and Fluor Metric Analysis

Ana Paula Cleto Marolla1, Jaques Waisberg2, Gabriela Tognini Saba2, Demétrius Eduardo Germini2, Maria Aparecida da Silva Pinhal1


Melanoma Antigen Gene Family in the Cancer Immunotherapy

Fengyu Zhu1, Yu Liang1, Demeng Chen2, Yang Li1


Combined Chronic Lymphocytic Leukemia and Pancreatic Neuroendocrine Carcinoma: A Collision Tumor Variation

Kaijun Huang1, Panagiotis J. Vlachostergios1, Wanhua Yang2, Rajeev L. Balmiki3


Antiproliferative and Apoptotic Effect of Pleurotus ostreatus on Human Mammary Carcinoma Cell Line (Michigan Cancer Foundation‑7)

Krishnamoorthy Deepalakshmi, Sankaran Mirunalini


Impact of Age on the Biochemical Failure and Androgen Suppression after Radical Prostatectomy for Prostate Cancer in Chilean Men

Nigel P. Murray1,2, Eduardo Reyes1,3, Nelson Orellana1, Cynthia Fuentealba1, Omar Jacob1


Carcinoma of Unknown Primary: 35 Years of a Single Institution’s Experience

Rana I. Mahmood1,2, Mohammed Aldehaim1,3, Fazal Hussain4, Tusneem A. Elhassan4,
Zubeir A. Khan5, Muhammad A. Memon6


Metformin in Ovarian Cancer Therapy: A Discussion

Yeling Ouyang1, Xi Chen2, Chunyun Zhang1, Vichitra Bunyamanop1, Jianfeng Guo3


The Progress in Molecular Biomarkers of Gliomas

Jing Qi1, Hongwei Yang2, Xin Wang2, Yanyang Tu1


Correlation between Paclitaxel Tc > 0.05 and its Therapeutic Efficacy and Severe Toxicities in Ovarian Cancer Patients

Shuyao Zhang1*, Muyin Sun2*, Yun Yuan3*, Miaojun Wang4*, Yuqi She1*, Li Zhou5, Congzhu Li5, Chen Chen1, Shengqi Zhang4


Identifying Gaps and Relative Opportunities for Discovering Membrane Proteomic Biomarkers of Triple‑negative Breast Cancer as a Translational Priority

Bhooma Venkatraman


The Molecular Mechanism and Regulatory Pathways of Cancer Stem Cells

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*


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


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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