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Simple Summary: This study investigates the role of circadian clock genes in the progression of astrocytic tumors, a common type of brain tumor. We aimed to understand how these genes, which control the body's daily rhythms, behave differently in low-grade versus high-grade tumors. Our findings reveal that certain circadian clock genes are more active in advanced tumor stages, potentially driving tumor growth. Additionally, we discovered that changes in DNA methylation and microRNAs might regulate these genes. Understanding these molecular changes could help identify new biomarkers for tumor diagnosis and progression, offering new avenues for targeted treatments. This research provides valuable insights into the complex biology of brain tumors and highlights the importance of circadian genes in the development of cancer. This study explores the role of circadian clock genes in the progression of astrocytic tumors, a prevalent type of brain tumor. The aim was to assess the expression patterns of these genes in relation to the tumor grade. Using microarray analysis, qRT-PCR, and methylation-specific PCR, we examined gene expression, DNA methylation patterns, and microRNA interactions in tumor samples from 60 patients. Our results indicate that the expression of key circadian clock genes, such as clock circadian regulator (CLOCK), protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1), protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), protein kinase AMP-activated non-catalytic subunit beta 1 (PRKAB1), protein kinase AMP-activated non-catalytic subunit beta 2 (PRKAB2), period circadian regulator 1 (PER1), period circadian regulator 2 (PER2) and period circadian regulator 3 (PER3), varies significantly with the tumor grade. Notably, increased CLOCK gene expression and protein levels were observed in higher-grade tumors. DNA methylation analysis revealed that the promoter regions of PER1-3 genes were consistently methylated, suggesting a mechanism for their reduced expression. Our findings also underscore the complex regulatory mechanisms involving miRNAs, such as hsa-miR-106-5p, hsa-miR-20b-5p, and hsa-miR-30d-3p, which impact the expression of circadian clock-related genes. This underscores the importance of circadian clock genes in astrocytic tumor progression and highlights their potential as biomarkers and therapeutic targets. Further research is needed to validate these results and explore their clinical implications. [ABSTRACT FROM AUTHOR]

Background: High-grade gliomas in infancy are uncommon and have different clinical and molecular characteristics from those in adults. Recently, advances in molecular diagnostics have made progress in determining treatment strategies; however, the robust treatment has not yet been elucidated. We, herein, present a case of infantile glioma occurring at the cervicomedullary region. Case Description: A 5-month-old infant developed left upper limb weakness and torticollis at 3 months of age. Magnetic resonance imaging revealed T2 hyperintensity from the medulla oblongata to the upper cervical cord. She underwent a biopsy for the lesion and pathological examination findings confirmed the presence of a highgrade astrocytoma with IDH wildtype-, H3K27M wildtype-, BRAF wildtype-, and ETV-NTRK3 fusion-positivity. Postoperatively, she underwent chemoradiotherapy, but she had marked tumor growth during the treatment. According to the new World Health Organization classification, the patient's tumor is an infantile "hemispheric" glioma. Conclusion: The characteristics and prognosis of NTRK-fused glioma are not fully understood, it is noteworthy that these tumors commonly occur in the brainstem. Further studies are needed to determine the prognosis of each tumor type and its sensitivity to treatment. This information will help in the reclassification of the tumors and identification of the precise treatment of this rare type of tumor. [ABSTRACT FROM AUTHOR]

Human astrocytic tumors are primary central nervous system (CNS) tumors that arise either from astrocytes or from precursor cells. A growing number of epidemiological and incidence studies in different countries underlined that, in addition to increasing economic costs for health systems, these cancers are still representing one of the main hurdles in developing a successful therapeutic goal for patients. On the other hand, new-omics technologies are offering customized instruments and more and more advantageous results toward personalized medicine approaches, underlining the concept that each tumor mass undergoes a peculiar transformation process under the control of specific genes’ and proteins’ functional signatures. The main aim of this Special Issue was to collect novel contributions in the wide field of human tumor astrocytic basic and translational research, to suggest further potential therapeutic targets/strategies that might interfere, possibly at the earliest stage of transformation, with the tumor progression, and to increase the molecular-based arsenal to counteract the prognostic poverty of high-grade astrocytic tumors.

Pleomorphic xanthoastrocytoma has been considered as an astrocytic tumor with relatively favorable prognosis. It corresponds to WHO Grade-II neoplasm. Recently, several patterns with relatively poor prognosis have been recorded and a new concept of "PXA with anaplastic features" has been proposed. The present case is about a 9-year-old girl who presented with symptoms of recurrent headache, seizures and poor academic performance. MRI revealed left fronto-parietal irregular enhancing mass lesion with callosal involvement and right mid-brain arteriovenous malformation. Clinical and radiological examination was suggestive of a high grade glial neoplasm/PNET. A diagnosis of high grade glial neoplasm was rendered on the squash smears submitted for frozen sections based on the presence of spindle cells, admixed with pleomorphic bizarre, giant cells with multilobated nuclei showing few atypical mitosis and abundant eosinophilic cytoplasm. Frontal craniotomy with debulking of the tumor was performed and permanent sections revealed a biphasic glial neoplasm with spindle cells arranged in fascicles admixed with bizarre multinucleated giant cells showing abundant vacuolated and lipidized cytoplasm, nuclear hyperchromasia with intranuclear inclusions. Eosinophilic granular bodies, mitosis of 7/10 HPF, micro vascular proliferation, necrosis and invasion into the underlying brain parenchyma were noted. With these histomorphological findings a diagnosis of pleomorphic xanthoastrocytoma with anaplastic features was rendered.

Astrocytic tumors are the most common neuroepithelial neoplasms with high relapse rate after surgery. Understanding the molecular mechanisms for astrocytic tumorigenesis and progression will lead to early diagnosis and effective treatment of astrocytic tumors. The DEK mRNA and protein expression in normal brain tissues and astrocytic tumors was quantified. To investigate DEK functions in tumor cells, DEK gene was silenced with siRNA in U251 glioblastoma cells. Cell proliferation, cell cycle and apoptosis were then measured. The expression and activity of key genes that regulate cell proliferation and apoptosis were also measured. We identified DEK as a high expressed gene in astrocytic tumor tissues. DEK expression level was positively correlated with the pathological grade of astrocytic tumors. Gene silencing of DEK in U251 glioblastomas inhibited cell proliferation and blocked cells at G0/G1 phase of cell cycle. DEK depletion also induced cell apoptosis, with up-regulated expression of P53 and P21 and down-regulated expression of Bcl-2 and C-myc. The Caspase-3 activity in U251 cells was also significantly increased after knockdown. Our results provided evidences that DEK regulates proliferation and apoptosis of glioblastomas. DEK gene silencing may induce apoptosis through P53-dependent pathway. Our data indicated DEK plays multiple roles to facilitate tumor growth and maintenance. It can be used as a potential target for astrocytic tumor diagnosis and gene therapy. [ABSTRACT FROM AUTHOR]

Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a regulator of gene transcription and has been reported to be associated with biological malignancy in cancers. However, it is unclear whether CPEB4 has any clinical significance in patients with astrocytic tumors, and mechanisms that CPEB4 contribute to progression of astrocytic tumors remain largely unknown. Here, correlation between CPEB4 expression and prognosis of patients with astrocytic tumors were explored by using qPCR, WB and IHC, and X-tile, SPSS software. Cell lines U251 MG and A172 were used to study CPEB4's function and mechanisms. Co-immunoprecipitation, mass spectrometry, immunofluorescent assay, and western blot were performed to observe the interaction between CPEB4 and Vimentin. CPEB4 mRNA and protein levels were markedly elevated in 12/12 astrocytic tumors in comparison to paratumor. High expression of CPEB4 was significantly correlated with clinical progressive futures and work as an independent adverse prognostic factor for overall survival of patients with astrocytic tumors (relative risk 4.5, 95 % CI 2.1-11.2, p = 0.001). Moreover, knockdown of CPEB4 in astrocytic tumor cells inhibited their , clonogenicity, and invasiveness. Five candidate proteins, GRP78, Mortalin, Keratin, Vimentin, and β-actin, were identified, and the interaction between CPEB4 and Vimentin was finally confirmed. Downregulation of CPEB4 could reduce the protein expression of Vimentin. Our studies first validated that CPEB4 interacts with Vimentin and indicated that high CPEB4 expression in astrocytic tumors correlates closely with a clinically aggressive future, and that CPEB4 might represent a valuable prognostic marker for patients with astrocytic tumors. [ABSTRACT FROM AUTHOR]

Background The human endogenous retrovirus K (HERV-K) has been acquired by the genome of human ancestors million years ago. It is the most complete of the HERVs with transcriptionally active gag, pol and env genes. Splice variants of env, which are rec, 1.5 kb transcript and Np9 have been suggested to be tumorigenic. Transcripts of HERV-K have been detected in a multitude of human cancers. However, no such reports are available concerning glioblastomas (GBM), the most common malignant brain tumor in adults. Patients have a limited prognosis of 14.6 months in median, despite standard treatment. Therefore, we elucidated whether HERV-K transcripts could be detected in these tumors and serve as new molecular target for treatment. Findings We analyzed human GBM cell lines, tissue samples from patients and primary cell cultures of different passages for HERV-K full length mRNA and env, rec and 1.5 kb transcripts. While the GBM cell lines U138, U251, U343 and GaMG displayed weak and U87 strong expression of the full length HERV-K, the splice products could not be detected, despite a weak expression of env mRNA in U87 cells. Very few tissue samples from patients showed weak expression of env mRNA, but none of the rec or 1.5 kb transcripts. Primary cells expressed the 1.5 kb transcript weakly in early passages, but lost HERV-K expression with extended culture time. Conclusions These data suggest that HERV-K splice products do not play a role in human malignant gliomas and therefore, are not suitable as targets for new therapy regimen. [ABSTRACT FROM AUTHOR]

AIM: to compare the AgNOR's mean number with the histological type and grade of cerebral astrocytic tumors. MATERIALS AND METHOD: 16 primary cerebral astrocytic tumors (4 diffuse astrocytomas, 4 anaplastic astrocytomas and 8 glioblastomas) stereotactic biopsied in the Department of Neurosurgery, Clinical Hospital „Prof. Dr. N. Oblu” Iaşi, and histopathologically conventional diagnosed in Department of Neuropathology of the same hospital, were retrospectively identified. Tumor specimens were submitted to a combined staining technique: one – step silver nitrate method for AgNOR protein sites (modified after Ploton et al, 1986) counterstained with periodic acid-Schiff staining for basement membrane of vascular components. The mean AgNOR values (mAgNOR) for tumoral and vascular nuclei were determined. RESULTS: The average values of mean AgNORs/nucleus (mAgNOR/nucleus) presented a linear increase with increasing grade of malignancy from 1.96 for diffuse astrocytoma (GII), 2.34 for anaplastic astrocytoma (GIII), to 3.18 for glioblastoma multiforme (GIV). mAgNOR/tumoral nucleus also showed a linear correlation with the histological tumor grade: 2.27 for diffuse astrocytomas, 2.78 for anaplastic astrocytomas, and 3.35 for glioblastomas multiforme. A distinct difference between the mean values of AgNORs/vascular nucleus was expressed: 1.52 for diffuse astrocytoma (GII), 1.90 for anaplastic astrocytoma (GIII), and 3.18 for glioblastoma multiforme (GIV). There were some overlaps between GIII and GIV astrocytic tumors regarding the mAgNOR/tumoral nucleus: maximum value in anaplastic astrocytomas (GIII) was 2.91 and minimum value in small cells glioblastomas (GIV) was 2.47. Differentiation could be achieved with mAgNORs/vascular nucleus as no extreme value overlapped: maximum value in anaplastic astrocytomas (GIII) was 1.99 and minimum value in small cells glioblastomas (GIV) was 2.54. CONCLUSION: The malignancy grade of an astrocytic tumor can accurately be establish both on histological features of the conventional stained sample and on the average number, the shape and the distribution of AgNORs within tumoral and vascular nuclei, as AgNORs determinations supplement the histological information in small biopsies.

Although histopathological diagnosis of spinal cord astrocytomas is important for postoperative treatment planning and prognosis, there is a lack of reliable immunohistochemical markers. The purpose of our study was to assess the expression pattern of GFAP-δ in spinal cord astrocytomas in human patients and to evaluate the utility of GFAP-δ as an immunohistochemical diagnostic marker. A total of 22 patients with spinal cord astrocytic tumors were included in this study. Patients were classified according to the WHO designation of human astrocytic tumors; three patients had grade 1 astrocytomas, 14 had grade 2, and five had Grade 3. Normal control spinal cord tissues were obtained at autopsy from the cervical spinal cords of ten patients with no history of cervical trauma or neurological disease. We evaluated BRAF, IDH1, GFAP, and GFAP-δ immunoreactivity in control tissues and astrocytomas. In normal control tissues, GFAP immunoreactivity was detected in astrocytes whereas GFAP-δ immunoreactivity was observed in very few astrocytes adjacent to the subpial layer of the spinal cord. GFAP-δ immunoreactivity was significantly correlated with spinal cord astrocytoma grade in astrocytomas compared to that in normal control tissues. The optical density of GFAP-δ increased significantly with astrocytoma grade (correlation coefficient, R = 0.680). Also, BRAF and IDH1 immunoreactivity were detected in astrocytoma. We suggest that GFAP-δ may be an additional, reliable histopathological diagnostic marker for spinal cord astrocytomas. [ABSTRACT FROM AUTHOR]

Estrogen receptors alpha (ERα) and beta (ERβ) and their co-regulatory proteins are key components of complex signaling networks that specifically regulate the growth and development of various tissues and tumors. Still, their protein expression profiles and possible role in the pathogenesis of astrocytic tumors remain largely unknown. The purpose of the present study is to evaluate the differential protein expression of ΕRα, ERβ, and their co-activators, AIB1, TIF2, and PELP1 in astrocytic tumors of World Health Organization (WHO) grade II-IV, using immunohistochemistry. Potential correlations with clinicopathological parameters and patient prognosis were also explored. ERα protein expression was undetectable while ERβ levels were significantly decreased with progression of tumor grade ( P < 0.001). High expression of ERβ was an independent favorable prognostic factor on multivariate analysis ( P = 0.003). Expression of AIB1, TIF2, and PELP1 was not correlated with ERβ expression and followed an opposite trend, with increasing levels in high-grade relative to low-grade tumors ( P < 0.001). Univariate survival analysis revealed that high AIB1, TIF2, and PELP1 expression was associated with worse prognosis ( P = 0.049, P = 0.033, and P = 0.020, respectively). ERβ and ER co-activators AIB1, TIF2, and PELP1 appear to play an important role in the pathogenesis and progression of astrocytic tumors and might have prognostic significance. The mechanisms underlying their involvement in astrocytic tumorigenesis, as well as their utility for prognostic and therapeutic purposes merit further investigation. [ABSTRACT FROM AUTHOR]

Nogo-A belongs to the reticulon protein family and is expressed in the inner and outer loops of myelin sheaths of oligodendrocytes. We analyzed the patterns of Nogo-A expression in human gliomas in an effort to identify a useful marker for the characterization of oligodendroglial tumors. We determined the expression of Nogo-A in a panel of 58 astrocytic and oligodendroglial tumors using immunohistochemistry and compared the expression of Nogo-A with Olig-2, a recently identified marker for oligodendrogliomas. To localize Nogo-A expression, immunofluorescent staining was performed using other glial markers (MAP-2 and GFAP). We also confirmed the overexpression of the Nogo-A protein in 53 astrocytic and oligodendroglial tumors using Western blot analysis. Based on immunohistochemical analysis, Nogo-A and Olig-2 had specificity in the detection of oligodendroglial tumors from astrocytic tumors ( P = 0.001). The level of Nogo-A staining was highly correlated with Olig-2 ( P = 0.001). The sensitivity and specificity of Nogo-A for oligodendroglial tumors was 86.9% and 57.1%, respectively. Nogo-A expression overlapped that of other oligodendroglial markers, but with different patterns of expression. Western blot analysis revealed that Nogo-A is predominantly expressed in 85.7% of oligodendroglioma cells and 93.7% of anaplastic oligodendroglioma cells. Like other oligodendroglial markers, Nogo-A is highly expressed in oligodendroglial tumors; however, it does not serve as a definite marker specific for oligodendroglial tumors. [ABSTRACT FROM AUTHOR]

Phosphoprotein enriched in astrocytes 15 kDa (PEA-15) is a multifunctional protein that was first identified in brain astrocytes and that has subsequently been shown to be expressed in different tissues. Despite its many important roles, the clinical significance of PEA-15 expression levels in astrocytic tumors has yet to be properly defined. We studied the PEA-15 expression pattern of 65 patients [diagnosed according to World Health Organization (WHO) criteria] with diffuse astrocytoma (WHO grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). PEA-15 expression levels were immunohistochemically measured and categorized as no, low, or high expression. All tumors expressed PEA-15 in our study. Twenty-three (35.4%) and 42 (64.6%) tumors expressed low and high PEA-15 levels, respectively. In grade II astrocytoma (diffuse astrocytoma) and grade III astrocytoma (anaplastic astrocytoma), 100% and 88.9% of patients expressed high PEA-15 levels, respectively, while a smaller number (50%) of patients with grade IV astrocytoma (glioblastoma) expressed high PEA-15 levels. PEA-15 expression level was inversely associated with WHO grade ( P = 0.0006). Next, we evaluated prognosis and PEA-15 expression levels in 43 patients with high-grade astrocytomas based on the following parameters: age, gender, WHO grade, surgical resection extent, MIB-1 labeling index (LI), and PEA-15 expression level. Multivariable analyses revealed that high PEA-15 expression level displayed a significant correlation with longer overall survival (OS) in high-grade astrocytomas ( P = 0.0024). Patients with total resection survived significantly longer ( P = 0.0044) than those with lower resection extent, while patients with MIB-1 labeling index ≤25% indicated significant ( P = 0.0434) correlation with OS as well. In conclusion, PEA-15 expression level was inversely associated with WHO grade and may serve as an important prognostic factor for high-grade astrocytomas. [ABSTRACT FROM AUTHOR]

Abstract: Astrocytic tumor is one of the most common primary tumors of the adult brain. Although there are several biochemical markers for the categorization of astrocytic tumor, few markers are used for histopathological diagnosis. Therefore, we evaluated glial fibrillary acidic protein (GFAP)-δ, a product of alternative splicing variants of GFAP-α, as a diagnostic marker. GFAP-δ immunoreactive (GFAP-δ+) astrocyte was rarely detected in tissue samples from autopsy controls. In tissue samples from patients with low-grade astrocytic tumor (grades I and II), GFAP-δ+ cells appeared stellate, polygonal or round shape. In tissue samples from patients with high-grade astrocytic tumor (grades III and IV), GFAP-δ+ cells showed round or spindle shape. GFAP-δ immunoreactivities in grades III and IV astrocytic tumor cells were increased by 1.4- and 1.7-fold in comparison to grade I astrocytic tumor cells. GFAP-δ immunoreactivity was also observed in cell bodies along the margins of astrocytic tumor showing normal histological findings, even though astroglia had normal morphology (showing strong GFAP and glutamine synthase immunoreactivities and a stellate shape with well-developed processes). Furthermore, the malignancy of astrocytic tumor was directly correlated with the degree of GFAP-δ immunoreactivity. These findings suggest that GFAP-δ may be a useful diagnostic marker for the evaluation of functional cataplasia or proliferation of astrocytic tumor. [Copyright &y& Elsevier]

We report an extremely rare tumor presenting with rhabdoid features in the left temporoparietal lobe near the trigone in an 18-year-old Japanese man. This tumor mainly consisted of medium to large round cells that proliferated diffusely and incoherently with a scant extracellular matrix. These tumor cells had an eccentric nucleus and an eosinophilic cytoplasm containing inclusion bodies and bundles of intermediate filaments. The nuclei of these cells were vesicular with prominent nucleoli. This tumor had an area appearing to be diffuse astrocytoma peripherally and lacked a primitive neuroectodermal tumor component, a mesenchymal component, and epithelial differentiation. INI expression, which is not observed in atypical teratoid/ rhabdoid tumor (AT/RT), was found in this tumor. From these findings, we concluded that this tumor was not AT/RT but an astrocytic tumor with rhabdoid features. We also concluded that the tumor cells exhibiting rhabdoid features had secondarily arisen from the peripheral area presenting an appearance of diffuse astrocytoma. [ABSTRACT FROM AUTHOR]