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Kim S, Kim KH, Jung HW, Jeong EO, Lee HJ, Kwon J, Kwon HJ, Choi SW, Koh HS, Kim SH. Elevated Serum IL-6 as a Negative Prognostic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Validation. J Cancer 2025; 16:802-811. [PMID: 39781345 PMCID: PMC11705068 DOI: 10.7150/jca.104759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 01/12/2025] Open
Abstract
Background: Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, necessitating the discovery of reliable serum prognostic biomarkers. This study aimed to investigate the prognostic value of serum Interleukin-6 (IL-6) in GBM patients. Methods: Bioinformatics analysis via gene set enrichment analysis was conducted on The Cancer Genome Atlas RNA-seq data to explore the pathways enriched in samples with high IL-6 expression. The Tumor IMmune Estimation Resource database was used to analyze the association between IL-6 expression and immune cell infiltration. To validate the role of IL-6 in a clinical setting, a retrospective cohort study was conducted on newly diagnosed GBM patients. Serum IL-6 levels were repeatedly measured at key milestone time points, and their correlation with survival data was analyzed. Results: Bioinformatics analysis revealed that high IL-6 expression is associated with the activation of procancer pathways, that there is a positive correlation between IL-6 expression and immune cell infiltration in GBM. Between March 2021 and September 2023, 36 GBM patients and their serum IL-6 measurements at various time points were included in the clinical data analyses. Elevated serum IL-6 levels at baseline, with a cutoff of 7pg/mL, were identified in 11 patients (30.6%). In the multivariate analyses for overall survival (OS), elevated IL-6 was a significant risk factor (p = 0.048), along with unfavorable surgical resection (p = 0.039) and O6-methylguanine-DNA methyltransferase promotor unmethylation (p = 0.027). The median actuarial OS of the high initial IL-6 group was significantly shorter than that of the low initial IL-6 group (6.4 vs. 19.7 months, p < 0.001). However, IL-6 levels at other time points were not related to patient prognosis. Conclusion: Elevated IL-6 mRNA expression is correlated with the activation of procancer pathways, increased immune cell infiltration, and poor prognosis in GBM patients. In addition, elevated serum IL-6 at baseline is a negative prognostic factor confirmed in a clinical study. Serum IL-6 may be a potential prognostic biomarker enhancing the management of GBM.
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Affiliation(s)
- Sup Kim
- Department of Radiation Oncology, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Kyung Hwan Kim
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Hee-won Jung
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Eun-Oh Jeong
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Han-Joo Lee
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Jeanny Kwon
- Department of Radiation Oncology, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Hyon-jo Kwon
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Seung-Won Choi
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Hyeon-Song Koh
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Seon-Hwan Kim
- Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
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Mammadova N, Özler S, Özdemir BG, Avcı F, Koçak N, Çintesun E, Örgül G, Çelik Ç. The role of the Chitinase 3-Like 1 (CHI3L1) genes in the preeclampsia pathophysiology. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2024; 70:e20231574. [PMID: 39045955 PMCID: PMC11288277 DOI: 10.1590/1806-9282.20231574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/10/2024] [Indexed: 07/25/2024]
Abstract
OBJECTIVE The aim of this study was to investigate the relationship between Chitinase 3-Like 1 gene polymorphisms and the occurrence of preeclampsia in a selected cohort of pregnant women. METHODS A total of 75 pregnant women participated in the study, 35 of whom were diagnosed with preeclampsia, while 40 served as healthy controls. The preeclamptic group was subdivided based on severity. Real-time polymerase chain reaction was employed to analyze the serum samples for variations in Chitinase 3-Like 1 gene polymorphisms. RESULTS The rs880633 polymorphism was found to be significantly more frequent in the control group (80%) compared with the overall preeclamptic group (60%) (p<0.05). In the severity-based subgroups, rs880633 appeared in 57.1% of non-severe and 61.9% of severe preeclamptics. Contrarily, the heterozygous form of rs7515776 polymorphism showed a significantly higher prevalence in the preeclamptic cohort (p<0.05), without distinctions in severity subgroups. CONCLUSION The study suggests that the rs880633 polymorphism may serve a protective role against the development of preeclampsia, whereas the rs7515776 polymorphism may be associated with an elevated risk. Further research is warranted to elucidate the clinical implications of these findings.
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Affiliation(s)
- Nigar Mammadova
- Afiyet Hospital, Private Clinic of Obstetrics and Gynecology – İstanbul, Turkey
| | - Sibel Özler
- Selcuk University, Faculty of Medicine, Department of Obstetrics and Gynecology – Konya, Turkey
| | - Belma Gözde Özdemir
- Selcuk University, Faculty of Medicine, Department of Obstetrics and Gynecology – Konya, Turkey
| | - Fazıl Avcı
- Selcuk University, Faculty of Medicine, Department of Obstetrics and Gynecology – Konya, Turkey
| | - Nadir Koçak
- Selcuk University, Faculty of Medicine, Department of Medical Genetics – Konya, Turkey
| | - Ersin Çintesun
- Selcuk University, Faculty of Medicine, Department of Obstetrics and Gynecology – Konya, Turkey
| | - Gökçen Örgül
- Selcuk University, Faculty of Medicine, Department of Obstetrics and Gynecology – Konya, Turkey
| | - Çetin Çelik
- Selcuk University, Faculty of Medicine, Department of Obstetrics and Gynecology – Konya, Turkey
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Pathania AS. Immune Microenvironment in Childhood Cancers: Characteristics and Therapeutic Challenges. Cancers (Basel) 2024; 16:2201. [PMID: 38927907 PMCID: PMC11201451 DOI: 10.3390/cancers16122201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 05/23/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
The tumor immune microenvironment is pivotal in cancer initiation, advancement, and regulation. Its molecular and cellular composition is critical throughout the disease, as it can influence the balance between suppressive and cytotoxic immune responses within the tumor's vicinity. Studies on the tumor immune microenvironment have enriched our understanding of the intricate interplay between tumors and their immunological surroundings in various human cancers. These studies illuminate the role of significant components of the immune microenvironment, which have not been extensively explored in pediatric tumors before and may influence the responsiveness or resistance to therapeutic agents. Our deepening understanding of the pediatric tumor immune microenvironment is helping to overcome challenges related to the effectiveness of existing therapeutic strategies, including immunotherapies. Although in the early stages, targeted therapies that modulate the tumor immune microenvironment of pediatric solid tumors hold promise for improved outcomes. Focusing on various aspects of tumor immune biology in pediatric patients presents a therapeutic opportunity that could improve treatment outcomes. This review offers a comprehensive examination of recent literature concerning profiling the immune microenvironment in various pediatric tumors. It seeks to condense research findings on characterizing the immune microenvironment in pediatric tumors and its impact on tumor development, metastasis, and response to therapeutic modalities. It covers the immune microenvironment's role in tumor development, interactions with tumor cells, and its impact on the tumor's response to immunotherapy. The review also discusses challenges targeting the immune microenvironment for pediatric cancer therapies.
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Affiliation(s)
- Anup Singh Pathania
- Department of Biochemistry and Molecular Biology, The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Kośliński P, Pluskota R, Koba M, Siedlecki Z, Śniegocki M. Comparative Analysis of Amino Acid Profiles in Patients with Glioblastoma and Meningioma Using Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS). Molecules 2023; 28:7699. [PMID: 38067430 PMCID: PMC10707850 DOI: 10.3390/molecules28237699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Brain tumors account for 1% of all cancers diagnosed de novo. Due to the specificity of the anatomical area in which they grow, they can cause significant neurological disorders and lead to poor functional status and disability. Regardless of the results of biochemical markers of intracranial neoplasms, they are currently of no diagnostic significance. The aim of the study was to use LC-ESI-MS/MS in conjunction with multivariate statistical analyses to examine changes in amino acid metabolic profiles between patients with glioblastoma, meningioma, and a group of patients treated for osteoarthritis of the spine as a control group. Comparative analysis of amino acids between patients with glioblastoma, meningioma, and the control group allowed for the identification of statistically significant differences in the amino acid profile, including both exogenous and endogenous amino acids. The amino acids that showed statistically significant differences (lysine, histidine, α-aminoadipic acid, phenylalanine) were evaluated for diagnostic usefulness based on the ROC curve. The best results were obtained for phenylalanine. Classification trees were used to build a model allowing for the correct classification of patients into the study group (patients with glioblastoma multiforme) and the control group, in which cysteine turned out to be the most important amino acid in the decision-making algorithm. Our results indicate amino acids that may prove valuable, used alone or in combination, toward improving the diagnosis of patients with glioma and meningioma. To better assess the potential utility of these markers, their performance requires further validation in a larger cohort of samples.
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Affiliation(s)
- Piotr Kośliński
- Department of Toxicology and Bromatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, dr. A. Jurasza 2, 85-089 Bydgoszcz, Poland; (R.P.); (M.K.)
| | - Robert Pluskota
- Department of Toxicology and Bromatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, dr. A. Jurasza 2, 85-089 Bydgoszcz, Poland; (R.P.); (M.K.)
| | - Marcin Koba
- Department of Toxicology and Bromatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, dr. A. Jurasza 2, 85-089 Bydgoszcz, Poland; (R.P.); (M.K.)
| | - Zygmunt Siedlecki
- Department of Neurosurgery, Neurotraumatology and Pediatric Neurosurgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (Z.S.); (M.Ś.)
| | - Maciej Śniegocki
- Department of Neurosurgery, Neurotraumatology and Pediatric Neurosurgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (Z.S.); (M.Ś.)
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Abu‐Rumeileh S, Barba L, Bache M, Halbgebauer S, Oeckl P, Steinacker P, Güttler A, Keßler J, Illert J, Strauss C, Vordermark D, Otto M. Plasma β-synuclein, GFAP, and neurofilaments in patients with malignant gliomas undergoing surgical and adjuvant therapy. Ann Clin Transl Neurol 2023; 10:1924-1930. [PMID: 37608748 PMCID: PMC10578894 DOI: 10.1002/acn3.51878] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/17/2023] [Accepted: 08/05/2023] [Indexed: 08/24/2023] Open
Abstract
We analyzed the longitudinal concentrations and prognostic roles of plasma β-synuclein (β-syn), glial fibrillary acidic protein (GFAP), and neurofilament proteins (NfL and NfH) in 33 patients with malignant gliomas, who underwent surgical and adjuvant therapy. GFAP and NfL levels were increased in patients with glioblastoma compared to cases with other tumors. β-syn, NfL and NfH increased after surgery, whereas GFAP decreased at long-term follow-up. β-syn and neurofilament concentrations were influenced by surgery and/or radiotherapy regimens. GFAP and neurofilament levels were significantly associated with survival. Plasma neuronal and astrocytic biomarkers are differentially altered in malignant glioma types and displayed distinct trajectories after surgical and adjuvant therapy.
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Affiliation(s)
- Samir Abu‐Rumeileh
- Department of NeurologyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Lorenzo Barba
- Department of NeurologyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Matthias Bache
- Department of RadiotherapyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Steffen Halbgebauer
- Department of NeurologyUlm University HospitalUlmGermany
- German Center for Neurodegenerative Diseases Ulm (DZNE e. V.)UlmGermany
| | - Patrick Oeckl
- Department of NeurologyUlm University HospitalUlmGermany
- German Center for Neurodegenerative Diseases Ulm (DZNE e. V.)UlmGermany
| | - Petra Steinacker
- Department of NeurologyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Antje Güttler
- Department of RadiotherapyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Jacqueline Keßler
- Department of RadiotherapyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Jörg Illert
- Department of NeurosurgeryMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Christian Strauss
- Department of NeurosurgeryMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Dirk Vordermark
- Department of RadiotherapyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
| | - Markus Otto
- Department of NeurologyMartin‐Luther‐University Halle‐WittenbergHalle (Saale)06120Germany
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Lin P, He L, Tian N, Qi X. The evaluation of six genes combined value in glioma diagnosis and prognosis. J Cancer Res Clin Oncol 2023; 149:12413-12433. [PMID: 37439825 DOI: 10.1007/s00432-023-05082-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 06/29/2023] [Indexed: 07/14/2023]
Abstract
PURPOSE Glioma is the most common and fatal type of brain tumour. Owing to its aggressiveness and lethality, early diagnosis and prediction of patient survival are very important. This study aimed to identify key genes and biomarkers for glioma that can guide clinicians in making rapid diagnosis and prognostication. METHODS Data mining of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Repository of Molecular Brain Neoplasia Data, and Genotype-Tissue Expression Project brain expression data revealed significantly differentially expressed genes (DEGs), and the risk scores of individual patients were calculated. WGCNA was utilized to screen for genes most related to clinical diagnosis. Prognostic genes associated with glioma were selected via combining the LASSO regression with univariate and multivariate Cox regression and protein-protein interaction network analyses. Then, a nomogram was constructed. And CGGA dataset was utilized to validated. The protein expression levels of the signature were detected using the human protein atlas. Drug response prediction was carried out using the package "pRRophetic". RESULTS A six-gene signature (KLF6, CHI3L1, SERPINE1, ANGPT2, TGFBR1, and PTX3) was identified and used to stratify patients into low- and high-risk groups. Survival, ROC curve, and Cox analyses clarified that the six hub genes were a favourable independent prognostic factor for patients with glioma. A nomogram was set up by integrating clinical parameters with risk signatures, showing high precision for predicting 2-, 3-, 4-, 5-years survival. In addition, the expression of most genes was consistent with protein expression. Furthermore, the sensitivity to the top ten drugs in the GDSC database of the high-risk group was significantly higher than the low-risk group. CONCLUSION Based on genetic profiles and clinicopathological features, including age, grade, isocitrate dehydrogenase mutation status, we constructed a comprehensive prognostic model for patients with glioma. These signatures can be regarded as biomarkers to predict the prognosis of gliomas, possibly providing more therapeutic strategies for future clinical research.
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Affiliation(s)
- Ping Lin
- Department of Medical Research Center, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Lingyan He
- Department of Traditional Chinese Medicine, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Nan Tian
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
| | - Xuchen Qi
- Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Department of Neurosurgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China.
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Shi M, Ge Q, Wang X, Diao W, Yang B, Sun S, Wang G, Liu T, Chan AML, Gao Z, Wang Y, Wang Y. Functional analysis of the short splicing variant encoded by CHI3L1/YKL-40 in glioblastoma. Front Oncol 2022; 12:910728. [PMID: 36408158 PMCID: PMC9666495 DOI: 10.3389/fonc.2022.910728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 10/10/2022] [Indexed: 12/04/2023] Open
Abstract
The glycoprotein YKL-40 has been well studied as a serum biomarker of prognosis and disease status in glioblastoma. YKL-40 is a chitinase-like protein with defective chitinase activity that plays an important role in promoting cell proliferation, migration, and metastasis in glioblastoma multiforme (GBM). The short variant (SV) of YKL-40, generated by an alternative splicing event that splices out exon 8, was reported in the early developing human musculoskeletal system, although its role in GBM is still unknown. Our results showed that individual glioblastoma cell lines displayed increased expression of the short variant of YKL-40 after low serum treatment. In addition, unlike the full-length (FL) version, which was localized to all cell compartments, the short isoform could not be secreted and was localized only to the cytoplasm. Functionally, FL YKL-40 promoted cell proliferation and migration, whereas SV YKL-40 suppressed them. Transcriptome analysis revealed that these opposing roles of the two isoforms may be modulated by differentially regulating several oncogenic-related pathways, including p53, the G2/M checkpoint, and MYC-related signaling. This study may provide new ideas for the development of targeted anti-YKL-40 therapy in GBM treatment.
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Affiliation(s)
- Mengqi Shi
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Qianyun Ge
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Xinrong Wang
- Community Healthcare Center, The Second People’s Hospital of Weifang, Weifang, China
| | - Wenbin Diao
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Ben Yang
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Sipeng Sun
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Guohui Wang
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Tian Liu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Andrew Man-Lok Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Zhiqin Gao
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Yi Wang
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Yubing Wang
- School of Life Science and Technology, Weifang Medical University, Weifang, China
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Ahmadi-Beni R, Shahbazi S, Khoshnevisan A. An integrative bioinformatics investigation and experimental validation of critically involved genes in high-grade gliomas. Diagn Pathol 2022; 17:73. [PMID: 36153549 PMCID: PMC9508723 DOI: 10.1186/s13000-022-01253-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 09/15/2022] [Indexed: 11/10/2022] Open
Abstract
Background Lack of knowledge around underlying mechanisms of gliomas mandates intense research efforts to improve the disease outcomes. Identification of high-grade gliomas pathogenesis which is known for poor prognosis and low survival is of particular importance. Distinguishing the differentially expressed genes is one of the core approaches to clarify the causative factors. Methods Microarray datasets of the treatment-naïve gliomas were provided from the Gene Expression Omnibus considering the similar platform and batch effect removal. Interacting recovery of the top differentially expressed genes was performed on the STRING and Cytoscape platforms. Kaplan–Meier analysis was piloted using RNA sequencing data and the survival rate of glioma patients was checked considering selected genes. To validate the bioinformatics results, the gene expression was elucidated by real-time RT-qPCR in a series of low and high-grade fresh tumor samples. Results We identified 323 up-regulated and 253 down-regulated genes. The top 20 network analysis indicated that PTX3, TIMP1, CHI3L1, LTF and IGFBP3 comprise a crucial role in gliomas progression. The survival was inversely linked to the levels of all selected genes. Further analysis of RNA sequencing data indicated a significant increase in all five genes in high-grade tumors. Among them, PTX3, TIMP1 and LTF did not show any change in low-grade versus controls. Real-time RT-qPCR confirmed the in-silico results and revealed significantly higher expression of selected genes in high-grade samples compared to low-grade. Conclusions Our results highlighted the role of PTX3 and TIMP1 which were previously considered in glioma tumorigenesis as well as LTF as a new potential biomarker.
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Goutnik M, Lucke-Wold B. Commentary: Evaluating potential glioma serum biomarkers, with future applications. World J Clin Oncol 2022; 13:412-416. [PMID: 35662986 PMCID: PMC9153077 DOI: 10.5306/wjco.v13.i5.412] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 03/15/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Systemic inflammation within malignant glioma is a topic of ongoing significance. In this commentary, we highlight recent findings from Gandhi et al and discuss alternative approaches. We present a counter argument with findings that IL-6 markers are controversial. We highlight the potential benefit of looking at microRNAs and other biomarkers. Finally, we present ideas for future application involving differentiation between radiation necrosis and recurrence. The commentary is intended to serve as a catalyst for further scientific discovery.
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Affiliation(s)
- Michael Goutnik
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, United States
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, United States
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10
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Pienkowski T, Kowalczyk T, Garcia-Romero N, Ayuso-Sacido A, Ciborowski M. Proteomics and metabolomics approach in adult and pediatric glioma diagnostics. Biochim Biophys Acta Rev Cancer 2022; 1877:188721. [PMID: 35304294 DOI: 10.1016/j.bbcan.2022.188721] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/26/2022]
Abstract
The diagnosis of glioma is mainly based on imaging methods that do not distinguish between stage and subtype prior to histopathological analysis. Patients with gliomas are generally diagnosed in the symptomatic stage of the disease. Additionally, healing scar tissue may be mistakenly identified based on magnetic resonance imaging (MRI) as a false positive tumor recurrence in postoperative patients. Current knowledge of molecular alterations underlying gliomagenesis and identification of tumoral biomarkers allow for their use as discriminators of the state of the organism. Moreover, a multiomics approach provides the greatest spectrum and the ability to track physiological changes and can serve as a minimally invasive method for diagnosing asymptomatic gliomas, preceding surgery and allowing for the initiation of prophylactic treatment. It is important to create a vast biomarker library for adults and pediatric patients due to their metabolic differences. This review focuses on the most promising proteomic, metabolomic and lipidomic glioma biomarkers, their pathways, the interactions, and correlations that can be considered characteristic of tumor grade or specific subtype.
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Affiliation(s)
- Tomasz Pienkowski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland.
| | - Tomasz Kowalczyk
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland; Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland
| | - Noemi Garcia-Romero
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
| | - Angel Ayuso-Sacido
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain; Faculty of Medicine, Universidad Francisco de Vitoria, 28223 Madrid, Spain
| | - Michal Ciborowski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
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Gandhi P, Shrivastava R, Garg N, Sorte SK. Novel molecular panel for evaluating systemic inflammation and survival in therapy naïve glioma patients. World J Clin Oncol 2021; 12:947-959. [PMID: 34733616 PMCID: PMC8546655 DOI: 10.5306/wjco.v12.i10.947] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/21/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammation is crucial to tumor progression. A traumatic event at a specific site in the brain activates the signaling molecules, which triggers inflammation as the initial response within the tumor and its surroundings. The educated immune cells and secreted proteins then initiate the inflammatory cascade leading to persistent chronic inflammation. Therefore, estimation of the circulating inflammatory indicators kynurenine (KYN), interleukin-6 (IL-6), tissue-inhibitor of matrix-metalloproteinase-1 and human telomerase reverse transcriptase (hTERT) along with neutrophil-lymphocyte ratio (NLR) has prognostic value. AIM To assess the utility of chosen inflammatory marker panel in estimating systemic inflammation. METHODS The chosen markers were quantitatively evaluated in 90 naive, molecularly sub-typed plasma samples of glioma. A correlation between the markers and confounders was assessed to establish their prognostication power. Follow-up on the levels of the indicators was done 3-mo post-surgery. To establish the validity of circulating KYN, it was also screened qualitatively by dot-immune-assay and by immunofluorescence-immunohistochemistry in tumor tissues. RESULTS Median values of circulating KYN, IL-6, hTERT, tissue-inhibitor of matrix-metalloproteinase-1 and NLR in isocitrate-dehydrogenase-mutant/wildtype and within the astrocytic sub-groups were estimated, which differed from controls, reaching statistical significance (P < 0.0001). All markers negatively correlated with mortality (P < 0.0001). Applying combination-statistics, the panel of KYN, IL-6, hTERT and NLR achieved higher sensitivity and specificity (> 90%) than stand-alone markers, to define survival. The inflammatory panel could discriminate between WHO grades, and isocitrate-dehydrogenase-mutant/wildtype and define differential survival between astrocytic isocitrate-dehydrogenase-mutant/wildtype. Therefore, its assessment for precise disease prognosis is indicated. Association of KYN with NLR, IL-6 and hTERT was significant. Cox-regression described KYN, IL-6, NLR, and hTERT as good prognostic markers, independent of confounders. Multivariate linear-regression analysis confirmed the association of KYN and hTERT with inflammation marker IL-6.There was a concomitant significant decrease in their levels in a 3-mo follow-up. CONCLUSION The first evidence-based study of circulating-KYN in molecularly defined gliomas, wherein the tissue expression was found to be concomitant with plasma levels. A non-invasive model for assessing indicators of chronic systemic inflammation is proposed.
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Affiliation(s)
- Puneet Gandhi
- Department of Research, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Richa Shrivastava
- Department of Research, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Nitin Garg
- Department of Neurosurgery, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Sandeep K Sorte
- Department of Neurosurgery, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
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Song Y, Hao D, Jiang H, Huang M, Du Q, Lin Y, Liu F, Chen B. Nrf2 Regulates CHI3L1 to Suppress Inflammation and Improve Post-Traumatic Osteoarthritis. J Inflamm Res 2021; 14:4079-4088. [PMID: 34466014 PMCID: PMC8403022 DOI: 10.2147/jir.s310831] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 08/18/2021] [Indexed: 01/16/2023] Open
Abstract
Introduction Post-traumatic osteoarthritis (PTOA) is an inflammatory condition that occurs following mechanical joint trauma and that results in joint degeneration. This study sought to evaluate the regulatory function of nuclear factor erythroid 2-related factor 2 (Nrf2) in a murine model of anterior cruciate ligament transection (ACLT)-induced PTOA and in an in vitro model of synoviocyte inflammation induced by LPS treatment with the goal of exploring the role of chitinase 3-like-1 (CHI3L1) in this pathogenic context. Methods PTOA model mice were intra-articularly injected with Nrf2 overexpression lentiviral vector, and safranin O-fast green staining as well as the Osteoarthritis Research Society International (OARSI) Scoring System were used to evaluate the severity of cartilage damage. Protein expression in the synovial tissue was evaluated by Western blotting, immunohistochemical staining, and ELISA. Additionally, murine synoviocytes were infected with Nrf2 overexpression lentivirus and stimulated with LPS. The levels of inflammatory cytokines were detected by ELISA. ROS levels were measured using dihydroethidium (DHE) dye. Results We determined that the overexpression of Nrf2 was sufficient to reduce cartilage degradation in the context of PTOA in vivo, and we observed a significant decrease in the expression of matrix metalloproteinase 13 (MMP13) in the articular cartilage of samples from mice overexpressing Nrf2 relative to control mice. Synovial CHI3L1 expression and serum TNF-α, IL-1β, and IL-6 levels were reduced in animals overexpressing this transcription factor relative to PTOA model controls. Consistent with these findings, murine synoviocytes treated with LPS exhibited dose-dependent increases in ROS, TNF-α, IL-1β, IL-6, Nrf2, and CHI3L1 levels, whereas Nrf2 overexpression was sufficient to suppress these increases. Conclusion Our data indicated that Nrf2 negatively regulates CHI3L1, suggesting that this signaling axis may regulate PTOA progression and may thus be a viable therapeutic target in individuals affected by this condition.
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Affiliation(s)
- Yang Song
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.,Division of Traumatology and Joint, Department of Orthopaedics, Shunde Hospital, Southern Medical University, Foshan, 528308, People's Republic of China
| | - Dake Hao
- Department of Surgery, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA
| | - Huan Jiang
- Department of Anesthesiology, Shunde Hospital, Southern Medical University, Foshan, 528308, People's Republic of China
| | - Mingguang Huang
- Division of Traumatology and Joint, Department of Orthopaedics, Shunde Hospital, Southern Medical University, Foshan, 528308, People's Republic of China
| | - Qingjun Du
- Division of Traumatology and Joint, Department of Orthopaedics, Shunde Hospital, Southern Medical University, Foshan, 528308, People's Republic of China
| | - Yi Lin
- Division of Traumatology and Joint, Department of Orthopaedics, Shunde Hospital, Southern Medical University, Foshan, 528308, People's Republic of China
| | - Fei Liu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Bin Chen
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
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Ali H, Harting R, de Vries R, Ali M, Wurdinger T, Best MG. Blood-Based Biomarkers for Glioma in the Context of Gliomagenesis: A Systematic Review. Front Oncol 2021; 11:665235. [PMID: 34150629 PMCID: PMC8211985 DOI: 10.3389/fonc.2021.665235] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/18/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Gliomas are the most common and aggressive tumors of the central nervous system. A robust and widely used blood-based biomarker for glioma has not yet been identified. In recent years, a plethora of new research on blood-based biomarkers for glial tumors has been published. In this review, we question which molecules, including proteins, nucleic acids, circulating cells, and metabolomics, are most promising blood-based biomarkers for glioma diagnosis, prognosis, monitoring and other purposes, and align them to the seminal processes of cancer. METHODS The Pubmed and Embase databases were systematically searched. Biomarkers were categorized in the identified biomolecules and biosources. Biomarker characteristics were assessed using the area under the curve (AUC), accuracy, sensitivity and/or specificity values and the degree of statistical significance among the assessed clinical groups was reported. RESULTS 7,919 references were identified: 3,596 in PubMed and 4,323 in Embase. Following screening of titles, abstracts and availability of full-text, 262 articles were included in the final systematic review. Panels of multiple biomarkers together consistently reached AUCs >0.8 and accuracies >80% for various purposes but especially for diagnostics. The accuracy of single biomarkers, consisting of only one measurement, was far more variable, but single microRNAs and proteins are generally more promising as compared to other biomarker types. CONCLUSION Panels of microRNAs and proteins are most promising biomarkers, while single biomarkers such as GFAP, IL-10 and individual miRNAs also hold promise. It is possible that panels are more accurate once these are involved in different, complementary cancer-related molecular pathways, because not all pathways may be dysregulated in cancer patients. As biomarkers seem to be increasingly dysregulated in patients with short survival, higher tumor grades and more pathological tumor types, it can be hypothesized that more pathways are dysregulated as the degree of malignancy of the glial tumor increases. Despite, none of the biomarkers found in the literature search seem to be currently ready for clinical implementation, and most of the studies report only preliminary application of the identified biomarkers. Hence, large-scale validation of currently identified and potential novel biomarkers to show clinical utility is warranted.
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Affiliation(s)
- Hamza Ali
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - Romée Harting
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - Ralph de Vries
- Medical Library, Vrije Universiteit, Amsterdam, Netherlands
| | - Meedie Ali
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - Thomas Wurdinger
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - Myron G. Best
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
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Holst CB, Christensen IJ, Vitting-Seerup K, Skjøth-Rasmussen J, Hamerlik P, Poulsen HS, Johansen JS. Plasma IL-8 and ICOSLG as prognostic biomarkers in glioblastoma. Neurooncol Adv 2021; 3:vdab072. [PMID: 34286278 PMCID: PMC8284624 DOI: 10.1093/noajnl/vdab072] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background CNS immune privilege has been challenged in recent years. Glioblastoma (GBM) immune dysfunction includes complex interactions with the immune system outside the CNS. The aim of this study was to determine diagnostic and prognostic potential of immune-related proteins in plasma in GBM and interrogate biomarker presence in the brain tumor microenvironment (TME). Methods One hundred and fifty-eight patients with glioma WHO grade II–IV were included. Plasma collected at surgery was screened for 92 proteins using proximity extension assay technology and related to clinical outcome. Secretion and expression of candidate prognostic biomarkers were subsequently analyzed in 8 GBM cell lines and public RNAseq data. Results Plasma levels of 20 out of 92 screened proteins were significantly different in patients with GBM compared to patients with astrocytoma WHO grade II–III. High plasma interleukin-8 (IL-8) (hazard ratio [HR] = 1.52; P = .0077) and low CD244 (HR = 0.36; P = .0004) were associated with short progression-free survival and high plasma IL-8 (HR = 1.40; P = .044) and low ICOS ligand (ICOSLG) (HR = 0.17; P = .0003) were associated with short overall survival (OS) in newly diagnosed patients with GBM. A similar trend was found for ICOSLG (HR = 0.34; P = .053) in recurrent GBM. IL-8 was mostly secreted and expressed by mesenchymal GBM cell lines and expressed by vascular cells and immune cells in the TME. This was also the case for ICOSLG, although less consistent, and with additional expression in tumor-associated oligodendrocytes. Conclusions High plasma IL-8 and low ICOSLG at surgery are associated with short OS in newly diagnosed GBM. Source of plasma ICOSLG may be found outside the TME.
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Affiliation(s)
- Camilla Bjørnbak Holst
- Department of Radiation Biology, Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.,Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Kristoffer Vitting-Seerup
- Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.,Bioinformatics Centre, Department of Biology, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Jane Skjøth-Rasmussen
- Department of Neurosurgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Petra Hamerlik
- Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
| | - Hans Skovgaard Poulsen
- Department of Radiation Biology, Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Julia Sidenius Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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