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Sensors (Basel, Switzerland) Jun 2024This study describes a novel method for grading pathological sections of gliomas. Our own integrated hyperspectral imaging system was employed to characterize 270 bands...
Study on an Automatic Classification Method for Determining the Malignancy Grade of Glioma Pathological Sections Based on Hyperspectral Multi-Scale Spatial-Spectral Fusion Features.
This study describes a novel method for grading pathological sections of gliomas. Our own integrated hyperspectral imaging system was employed to characterize 270 bands of cancerous tissue samples from microarray slides of gliomas. These samples were then classified according to the guidelines developed by the World Health Organization, which define the subtypes and grades of diffuse gliomas. We explored a hyperspectral feature extraction model called SMLMER-ResNet using microscopic hyperspectral images of brain gliomas of different malignancy grades. The model combines the channel attention mechanism and multi-scale image features to automatically learn the pathological organization of gliomas and obtain hierarchical feature representations, effectively removing the interference of redundant information. It also completes multi-modal, multi-scale spatial-spectral feature extraction to improve the automatic classification of glioma subtypes. The proposed classification method demonstrated high average classification accuracy (>97.3%) and a Kappa coefficient (0.954), indicating its effectiveness in improving the automatic classification of hyperspectral gliomas. The method is readily applicable in a wide range of clinical settings, offering valuable assistance in alleviating the workload of clinical pathologists. Furthermore, the study contributes to the development of more personalized and refined treatment plans, as well as subsequent follow-up and treatment adjustment, by providing physicians with insights into the underlying pathological organization of gliomas.
Topics: Glioma; Humans; Brain Neoplasms; Neoplasm Grading; Hyperspectral Imaging; Algorithms; Image Processing, Computer-Assisted
PubMed: 38931588
DOI: 10.3390/s24123803 -
International Journal of Molecular... Jun 2024Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence...
Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of , , and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant and glioblastomas, wild-type glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67.
Topics: Humans; Glioblastoma; Tumor Suppressor Protein p53; Ki-67 Antigen; Female; Middle Aged; Male; Aged; Adult; Isocitrate Dehydrogenase; Brain Neoplasms; X-linked Nuclear Protein; Neovascularization, Pathologic; Microvascular Density; Retrospective Studies; Endoglin; Antigens, CD34; Biomarkers, Tumor; Immunohistochemistry
PubMed: 38928515
DOI: 10.3390/ijms25126810 -
International Journal of Molecular... Jun 2024Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms... (Review)
Review
Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.
Topics: Glioblastoma; Humans; Neoplasm Recurrence, Local; Brain Neoplasms; Tumor Microenvironment; Oncolytic Virotherapy; Animals
PubMed: 38928445
DOI: 10.3390/ijms25126733 -
International Journal of Molecular... Jun 2024SARS-CoV-2 is the causative agent of the COVID-19 pandemic, the acute respiratory disease which, so far, has led to over 7 million deaths. There are several symptoms...
SARS-CoV-2 is the causative agent of the COVID-19 pandemic, the acute respiratory disease which, so far, has led to over 7 million deaths. There are several symptoms associated with SARS-CoV-2 infections which include neurological and psychiatric disorders, at least in the case of pre-Omicron variants. SARS-CoV-2 infection can also promote the onset of glioblastoma in patients without prior malignancies. In this study, we focused on the Envelope protein codified by the virus genome, which acts as viroporin and that is reported to be central for virus propagation. In particular, we characterized the electrophysiological profile of E-protein transfected U251 and HEK293 cells through the patch-clamp technique and FURA-2 measurements. Specifically, we observed an increase in the voltage-dependent (Kv) and calcium-dependent (KCa) potassium currents in HEK293 and U251 cell lines, respectively. Interestingly, in both cellular models, we observed a depolarization of the mitochondrial membrane potential in accordance with an alteration of U251 cell growth. We, therefore, investigated the transcriptional effect of E protein on the signaling pathways and found several gene alterations associated with apoptosis, cytokines and WNT pathways. The electrophysiological and transcriptional changes observed after E protein expression could explain the impact of SARS-CoV-2 infection on gliomagenesis.
Topics: Humans; Glioblastoma; HEK293 Cells; SARS-CoV-2; COVID-19; Cell Line, Tumor; Membrane Potential, Mitochondrial; Coronavirus Envelope Proteins; Apoptosis; Brain Neoplasms
PubMed: 38928376
DOI: 10.3390/ijms25126669 -
International Journal of Molecular... Jun 2024Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the...
Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In , T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn) or MIOS (mios). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the mios cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.
Topics: Glioblastoma; Abietanes; Humans; Mechanistic Target of Rapamycin Complex 1; Autophagy; Cell Line, Tumor; Dictyostelium; Cell Proliferation; Nuclear Proteins; Sestrins
PubMed: 38928292
DOI: 10.3390/ijms25126586 -
Genes Jun 2024Glioblastoma multiforme (GBM)is the most common and aggressive primary brain tumor. Although temozolomide (TMZ)-based radiochemotherapy improves overall GBM patients'...
Glioblastoma multiforme (GBM)is the most common and aggressive primary brain tumor. Although temozolomide (TMZ)-based radiochemotherapy improves overall GBM patients' survival, it also increases the frequency of false positive post-treatment magnetic resonance imaging (MRI) assessments for tumor progression. Pseudo-progression (PsP) is a treatment-related reaction with an increased contrast-enhancing lesion size at the tumor site or resection margins miming tumor recurrence on MRI. The accurate and reliable prognostication of GBM progression is urgently needed in the clinical management of GBM patients. Clinical data analysis indicates that the patients with PsP had superior overall and progression-free survival rates. In this study, we aimed to develop a prognostic model to evaluate the tumor progression potential of GBM patients following standard therapies. We applied a dictionary learning scheme to obtain imaging features of GBM patients with PsP or true tumor progression (TTP) from the Wake dataset. Based on these radiographic features, we conducted a radiogenomics analysis to identify the significantly associated genes. These significantly associated genes were used as features to construct a 2YS (2-year survival rate) logistic regression model. GBM patients were classified into low- and high-survival risk groups based on the individual 2YS scores derived from this model. We tested our model using an independent The Cancer Genome Atlas Program (TCGA) dataset and found that 2YS scores were significantly associated with the patient's overall survival. We used two cohorts of the TCGA data to train and test our model. Our results show that the 2YS scores-based classification results from the training and testing TCGA datasets were significantly associated with the overall survival of patients. We also analyzed the survival prediction ability of other clinical factors (gender, age, KPS (Karnofsky performance status), normal cell ratio) and found that these factors were unrelated or weakly correlated with patients' survival. Overall, our studies have demonstrated the effectiveness and robustness of the 2YS model in predicting the clinical outcomes of GBM patients after standard therapies.
Topics: Humans; Glioblastoma; Brain Neoplasms; Male; Female; Magnetic Resonance Imaging; Middle Aged; Prognosis; Adult; Aged; Disease Progression; Temozolomide; Genomics; Survival Rate; Clinical Relevance
PubMed: 38927654
DOI: 10.3390/genes15060718 -
Genes May 2024Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of...
Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development.
Topics: Humans; Male; Astrocytoma; Sertoli Cell-Only Syndrome; Mutation, Missense; Adult; Exome Sequencing; DNA Helicases; Azoospermia
PubMed: 38927643
DOI: 10.3390/genes15060707 -
Biomolecules May 2024Manganese (Mn) is an essential heavy metal in the human body, while excess leads to neurotoxicity, as observed in this study, where 100 µM of was administered to the...
Manganese (Mn) is an essential heavy metal in the human body, while excess leads to neurotoxicity, as observed in this study, where 100 µM of was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We quantitated pathway and gene changes in homeostatic cell-based adaptations to exposure. Utilizing the Gene Expression Omnibus, we accessed the GSE70845 dataset as a microarray of SH-SY5Y cells published by Gandhi et al. (2018) and applied statistical significance cutoffs at < 0.05. We report 74 pathway and 10 gene changes with statistical significance. ReactomeGSA analyses demonstrated upregulation of histones (5 out of 10 induced genes) and histone deacetylases as a neuroprotective response to remodel/mitigate -induced DNA/chromatin damage. Neurodegenerative-associated pathway changes occurred. NF-κB signaled protective responses via Sirtuin-1 to reduce neuroinflammation. Critically, activated three pathways implicating deficits in purine metabolism. Therefore, we validated that urate, a purine and antioxidant, mitigated -losses of viability in SH-SY5Y cells. We discuss as a hypoxia mimetic and trans-activator of HIF-1α, the central trans-activator of vascular hypoxic mitochondrial dysfunction. induced a 3-fold increase in mRNA levels for antioxidant metallothionein-III, which was induced 100-fold by hypoxia mimetics deferoxamine and zinc.
Topics: Humans; Manganese; Neuroblastoma; Cell Line, Tumor; Cell Survival; Neuroprotective Agents; Biomarkers
PubMed: 38927051
DOI: 10.3390/biom14060647 -
Biomolecules May 2024Lysophosphatidic acid (LPA) is a well-documented pro-oncogenic factor in different cancers, but relatively little is known on its biological activity in neuroblastoma....
Lysophosphatidic acid (LPA) is a well-documented pro-oncogenic factor in different cancers, but relatively little is known on its biological activity in neuroblastoma. The LPA effects and the participation of the tyrosine kinase receptor anaplastic lymphoma kinase (ALK) in LPA mitogenic signaling were studied in human neuroblastoma cell lines. We used light microscopy and [H]-thymidine incorporation to determine cell proliferation, Western blot to study intracellular signaling, and pharmacological and molecular tools to examine the role of ALK. We found that LPA stimulated the growth of human neuroblastoma cells, as indicated by the enhanced cell number, clonogenic activity, and DNA synthesis. These effects were curtailed by the selective ALK inhibitors NPV-TAE684 and alectinib. In a panel of human neuroblastoma cell lines harboring different ALK genomic status, the ALK inhibitors suppressed LPA-induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), which are major regulators of cell proliferation. ALK depletion by siRNA treatment attenuated LPA-induced ERK1/2 activation. LPA enhanced ALK phosphorylation and potentiated ALK activation by the ALK ligand FAM150B. LPA enhanced the inhibitory phosphorylation of the tumor suppressor FoxO3a, and this response was impaired by the ALK inhibitors. These results indicate that LPA stimulates mitogenesis of human neuroblastoma cells through a crosstalk with ALK.
Topics: Humans; Lysophospholipids; Anaplastic Lymphoma Kinase; Neuroblastoma; Cell Proliferation; Cell Line, Tumor; Signal Transduction; Phosphorylation; Piperidines; Carbazoles; Forkhead Box Protein O3; Mitogen-Activated Protein Kinase 3; MAP Kinase Signaling System
PubMed: 38927035
DOI: 10.3390/biom14060631 -
Acta Neuropathologica Communications Jun 2024A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has...
Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), new name and new problems: an illustration of one case with atypical morphology and biology.
A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has recently been identified, based on a distinct DNA methylation profile and has been added to the 2021 World Health Organization Classification of CNS Tumors. This glioneuronal tumor mainly affects the supratentorial area in children and recurrently presents with a monosomy of chromosome 14. Herein, we report the case of a DNA-methylation based diagnosis of DGONC having atypical features, such as pseudo-rosettes and the absence of a chromosome 14 monosomy, thus rendering its diagnosis very challenging. Because of the wide variety of morphologies harbored by DGONC, a large range of differential diagnoses may be hypothesized from benign to malignant. Interestingly, the current case, like one previously reported, exhibited a co-expression of OLIG2, synaptophysin and SOX10, without GFAP immunopositivity. This particular immunophenotype seems to be a good indicator for a DGONC diagnosis. The classification of DGONC amongst glioneuronal or embryonal tumors is still debated. The clinical (a pediatric supratentorial tumor), morphological (from a benign oligodendroglioma-like tumor with microcalcifications and possible neuropil-like islands to a malignant embryonal tumor with a possible spongioblastic pattern), and immunohistochemical (co-expression of OLIG2 and synaptophsyin) profiles resemble CNS, neuroblastoma, FOXR2-activated and may potentially bring them together in a future classification. Further comprehensive studies are needed to conclude the cellular origin of DGONC and its prognosis.
Topics: Child; Humans; Brain Neoplasms; DNA Methylation; Oligodendroglioma
PubMed: 38926880
DOI: 10.1186/s40478-024-01822-y