Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors-rapamycin, temsirolimus, torin 1, and PP242-suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M-induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol-myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as "stemness-inhibiting drugs" and a promising therapeutic approach to target glioma stem cells.
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PMID:Mammalian target of rapamycin inhibitors, temsirolimus and torin 1, attenuate stemness-associated properties and expression of mesenchymal markers promoted by phorbol-myristate-acetate and oncostatin-M in glioblastoma cells. 2835 21

Glioblastoma-multiforme (GBM), the most aggressive glial tumor, has a worldwide age-adjusted incidence ranging from 0.59-3.69/100000 persons. Despite current multimodal-treatment approach, median-survival time and progression-free survival (PFS) remains short. Glioblastomas display a variety of molecular alterations, which necessitates determining which of these have a prognostic significance. This is a case of a 45-year-old patient who presented with progressive slurring of speech and features of raised intracranial pressure. Computed tomography (CT) scan revealed a large heterogeneously enhancing lesion in the left front-temporal-perisylvian region with solid, cystic areas, suggestive of malignant glioma. Partial tumor-excision was followed by concurrent chemo-radiotherapy. Histopathologically, the tumor was astrocytoma grade-IV. Patient had an extended PFS of 12 mo, with an overall survival of 26 mo. Primary-GBM was confirmed using molecular markers and the immunophenotypic signature was defined by evaluating systemic expression of human telomerase reverse transcriptase, interleukin-6, neutrophil-lymphocyte ratio, tissue inhibitor of metalloproteinases-1, human chitinase-3-like-protein-1 (YKL-40) and high mobility group-A1. Current findings suggest that this signature can identify worst outcomes, independent of clinical criteria.
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PMID:Immunophenotypic signature of primary glioblastoma multiforme: A case of extended progression free survival. 2868 38

In addition to histopathological parameters, evaluation of associated hematological factors is essential for devising a sensitive prognostic scale in glioma. Increased neutrophil-lymphocyte ratio (NLR), a marker of systemic inflammatory response, has recently been associated with worse outcome in various cancers. Given that glioma progression is characterized by inflammation, aggressive angiogenesis, and invasion, increased levels of systemic human-chitinase-3-like-one protein (YKL-40) have also been linked to poor prognosis. The aim of the present study was to assess the plausible association of YKL-40, NLR, and platelet count with increasing tumor grade, and evaluate their status as independent prognostic factors in terms of overall survival (OS) in treatment naive patients with diffuse glioma. Plasma levels of both biochemical markers in 72 diffuse gliomas, median age 42 years, were compared with 36 controls. Comparison of YKL-40, NLR, and PC with respect to tumor grade was found to be significant for each of the markers (P <0.0001) while an inverse significant correlation was seen for YKL-40 and NLR with OS (r = -0.4619, P <0.0001, and r = -0.5561, P < 0.0001, respectively). NLR was the best performing marker with AUC 0.9417 at 97% specificity. In addition, YKL-40 had a positive correlation with NLR (r = 0.4902, P <0.0001), indicating that expression of both markers was linked to inflammation and tumor progression as they were significantly correlated with tumor grade. Expression of YKL-40 and NLR was independently associated with worse survival (HR 1.0062, P = 0.039, and HR 1.1787, P = 0.0003, respectively), thus establishing their clinical utility as prognosticators for diffuse gliomas.
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PMID:Circulatory YKL-40 & NLR: Underestimated Prognostic Indicators in Diffuse Glioma. 3027 66

Background: Complex local and systemic immune dysfunction in glioblastoma (GBM) may affect survival. Interleukin (IL)-6 and YKL-40 are pleiotropic biomarkers present in the tumor microenvironment and involved in immune regulation. We therefore analyzed plasma IL-6, YKL-40, and genetic variation in YKL-40 and explored their ability to distinguish between glioma subtypes and predict survival in GBM. Methods: One hundred fifty-eight patients with glioma WHO grade II-IV were included in the study. Plasma collected at surgery was analyzed for IL-6 and YKL-40 (CHI3L1) by ELISA. CHI3L1 rs4950928 genotyping was analyzed on whole-blood DNA. Results: Neither plasma IL-6 nor YKL-40 corrected for age or rs4950928 genotype could differentiate GBM from lower grade gliomas. GC and GG rs4950928 genotype were associated with lower plasma YKL-40 levels (CC vs. GC, p = 0.0019; CC vs. GG, p = 0.01). Only 10 and 14 out of 94 patients with newly diagnosed GBM had elevated IL-6 or YKL-40, respectively. Most patients received corticosteroid treatment at time of blood-sampling. Higher pretreatment plasma IL-6 was associated with short overall survival (OS) [HR = 1.19 (per 2-fold change), p = 0.042] in univariate analysis. The effect disappeared in multivariate analysis. rs4950928 genotype did not associate with OS [HR = 1.30, p = 0.30]. In recurrent GBM, higher YKL-40 [HR = 2.12 (per 2-fold change), p = 0.0005] but not IL-6 [HR = 0.99 (per 2-fold change), p = 0.92] were associated with short OS in univariate analysis. Conclusion: In recurrent GBM high plasma YKL-40 may hold promise as a prognostic marker. In newly diagnosed GBM perioperative plasma IL-6, YKL-40, and genetic variation in YKL-40 did not associate with survival. Corticosteroid use may complicate interpretation of results.
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PMID:Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40. 3236 59

Glioma is a type of malignant tumor arising from glial cells of the brain or the spine. Circulation-derived macrophage infiltration is a characteristic of the glioma microenvironment. The polarization status of circulation-derived macrophages in patients with glioma remains unclear. Therefore, the present study aimed to evaluate the polarization status of circulation-derived macrophages in patients with glioma. A total of 40 patients with glioma and 38 healthy volunteers were recruited. The polarization status of macrophage-like cells in the peripheral blood of patients with glioma was evaluated. In addition, the associations between the polarization status of macrophage-like cells and glioma stage or the expression levels of the glioma tumor marker chitinase-3-like protein 1 (also termed YKL-40) were evaluated. The number of macrophage-like cells (CD115+CD1c-CD2-CD15-CD19-CD14+CD16+CD11b+) was higher in the peripheral blood of patients with glioma compared with that of healthy volunteers. There were fewer M1 macrophage-like cells, and more M2 macrophage-like cells were induced in the peripheral blood of patients with glioma compared with healthy controls. Specifically, the number of M2a/M2b macrophage-like cells increased, whereas that of M2c macrophage-like cells decreased in the peripheral blood of patients with glioma compared with healthy controls. The polarization status of macrophage-like cells in patients with glioma was not significantly associated with glioma stage or with the glioma marker YKL-40. Overall, the results of the present study revealed that the polarization status of macrophage-like cells in the peripheral blood of patients with glioma was abnormal, offering potential novel diagnostic and therapeutic targets, such as different macrophage subsets, for glioma.
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PMID:Abnormal polarization of macrophage-like cells in the peripheral blood of patients with glioma. 3256 24

Gliomas account for approximately 70% of primary brain tumors in adults. Of all gliomas, grade IV astrocytoma, also called glioblastoma, has the poorest overall survival, with <5% of patients surviving five years after diagnosis. Due to the aggressiveness, lethal nature, and impaired surgical accessibility of the tumor, early diagnosis of the tumor and, in addition, prediction of the patient's survival time are important. We hypothesize that combining the protein level values of highly recognizable glioblastoma serum biomarkers could help to achieve higher specificity and sensitivity in predicting glioma patient outcome as compared to single markers. The aim of this study was to select the most promising astrocytoma patient overall survival prediction variables from five secretory proteins-glial fibrillary acidic protein (GFAP), matrix metalloproteinase-2 (MMP-2), chitinase 3-like 1 (CHI3L1), osteopontin (OPN), and amphiregulin (AREG)-combining them with routinely used tumor markers to create a Patient Survival Score calculation tool. The study group consisted of 70 astrocytoma patients and 31 healthy controls. We demonstrated that integrating serum CHI3L1 and OPN protein level values and tumor isocitrate dehydrogenase 1 IDH1 mutational status into one parameter could predict low-grade astrocytoma patients' two-year survival with 93.8% accuracy.
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PMID:The Evaluation of AREG, MMP-2, CHI3L1, GFAP, and OPN Serum Combined Value in Astrocytic Glioma Patients' Diagnosis and Prognosis. 3322 3


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