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In the last decade, many small molecules, usually characterized by heterocyclic scaffolds, have been designed and synthesized as tyrosine kinase inhibitors (TKIs). Among them, several compounds have been tested at preclinical and clinical levels to treat glioblastoma multiforme (GBM). GBM is the most common and aggressive type of cancer originating in the brain and has an unfavorable prognosis, with a median survival of 15-16 months and a 5-year survival rate of 5%. Despite recent advances in treating GBM, it represents an incurable disease associated with treatment resistance and high recurrence rates. For these reasons, there is an urgent need for the development of new pharmacological agents to fight this malignancy. In this review, we reported the compounds published in the last five years, which showed promising activity in GBM preclinical models acting as TKIs. We grouped the compounds based on the targeted kinase: first, we reported receptor TKIs and then, cytoplasmic and peculiar kinase inhibitors. For each small molecule, we included the chemical structure, and we schematized the interaction with the target for some representative compounds with the aim of elucidating the mechanism of action. Finally, we cited the most relevant clinical trials.

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Glioblastoma (GB) is the most lethal brain cancer in adults, with a 5-year survival rate of 5%. The standard of care for GB includes maximally safe surgical resection, radiation, and temozolomide (TMZ) therapy, but tumor recurrence is inevitable in most GB patients. Here, we describe the development of a blood-brain barrier (BBB)-penetrant tubulin destabilizer, RGN3067, for the treatment of GB. RGN3067 shows good oral bioavailability and achieves high concentrations in rodent brains after oral dosing (Cmax of 7807 ng/mL (20 µM), Tmax at 2 h). RGN3067 binds the colchicine binding site of tubulin and inhibits tubulin polymerization. The compound also suppresses the proliferation of the GB cell lines U87 and LN-18, with IC50s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC50 values for RGN3067 range from 148 to 616 nM. Finally, in a patient-derived xenograft (PDX) mouse model, RGN3067 reduces the rate of tumor growth compared to the control. Collectively, we show that RGN3067 is a BBB-penetrant small molecule that shows in vitro and in vivo efficacy and that its design addresses many of the physicochemical properties that prevent the use of microtubule destabilizers as treatments for GB and other brain cancers.

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Gangliosides are highly abundant in the human brain where they are involved in major biological events. In brain cancers, alterations of ganglioside pattern occur, some of which being correlated with neoplastic transformation, while others with tumor proliferation. Of all techniques, mass spectrometry (MS) has proven to be one of the most effective in gangliosidomics, due to its ability to characterize heterogeneous mixtures and discover species with biomarker value. This review highlights the most significant achievements of MS in the analysis of gangliosides in human brain cancers. The first part presents the latest state of MS development in the discovery of ganglioside markers in primary brain tumors, with a particular emphasis on the ion mobility separation (IMS) MS and its contribution to the elucidation of the gangliosidome associated with aggressive tumors. The second part is focused on MS of gangliosides in brain metastases, highlighting the ability of matrix-assisted laser desorption/ionization (MALDI)-MS, microfluidics-MS and tandem MS to decipher and structurally characterize species involved in the metastatic process. In the end, several conclusions and perspectives are presented, among which the need for development of reliable software and a user-friendly structural database as a search platform in brain tumor diagnostics.

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On average, there are about 300,000 new cases of brain cancer each year. Studies have shown that brain and central nervous system tumors are among the top ten causes of death. Due to the extent of this problem and the percentage of patients suffering from brain tumors, innovative therapeutic treatment methods are constantly being sought. One such innovative therapeutic method is photodynamic therapy (PDT). Photodynamic therapy is an alternative and unique technique widely used in dermatology and other fields of medicine for the treatment of oncological and nononcological lesions. Photodynamic therapy consists of the destruction of cancer cells and inducing inflammatory changes by using laser light of a specific wavelength in combination with the application of a photosensitizer. The most commonly used photosensitizers include 5-aminolevulinic acid for the enzymatic generation of protoporphyrin IX, Temoporfin-THPC, Photofrin, Hypericin and Talaporfin. This paper reviews the photosensitizers commonly used in photodynamic therapy for brain tumors. An overview of all three generations of photosensitizers is presented. Along with an indication of the limitations of the treatment of brain tumors, intraoperative photodynamic therapy and its possibilities are described as an alternative therapeutic method.

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Cellular redox status has a crucial role in brain physiology, as well as in pathologic conditions. Physiologic senescence, by dysregulating cellular redox homeostasis and decreasing antioxidant defenses, enhances the central nervous system's susceptibility to diseases. The reduction of free radical accumulation through lifestyle changes, and the supplementation of antioxidants as a prophylactic and therapeutic approach to increase brain health, are strongly suggested. Bilirubin is a powerful endogenous antioxidant, with more and more recognized roles as a biomarker of disease resistance, a predictor of all-cause mortality, and a molecule that may promote health in adults. The alteration of the expression and activity of the enzymes involved in bilirubin production, as well as an altered blood bilirubin level, are often reported in neurologic conditions and neurodegenerative diseases (together denoted NCDs) in aging. These changes may predict or contribute both positively and negatively to the diseases. Understanding the role of bilirubin in the onset and progression of NCDs will be functional to consider the benefits vs. the drawbacks and to hypothesize the best strategies for its manipulation for therapeutic purposes.

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Brain cancers are among the most aggressive malignancies with high mortality and morbidity worldwide. The pathogenesis of brain cancers is a very complicated process involving various genetic mutations affecting several oncogenic signaling pathways like Wnt/ß-catenin axis. Uncontrolled activation of this oncogenic signaling is associated with decreased survival rate and poor prognosis in cancer patients. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) were shown to play important roles in regulating cell proliferation, differentiation, and apoptosis by regulating the expression of their target genes. Aberrant expression of these non-coding RNAs (ncRNAs) was reported in many human cancers, including glioblastoma, medulloblastoma, meningioma, and pituitary adenoma. Multiple lncRNAs were shown to participate in brain tumor pathogenesis by targeting Wnt signaling regulatory miRNAs. SNHG7/miR-5095, PCAT6/miR-139-3p, SNHG6/miR-944, SNHG1/ miR-556-5p, SNHG17/ miR-506-3p, LINC00702/miR-4652-3p, DLGAP1-AS1/miR-515-5p, HOTAIR/miR-1, HOTAIR/miR-206, CRNDE/miR-29c-3p, AGAP2-AS1/ miR-15a/b-5p, CLRN1-AS1/miR-217, MEG3/miR-23b-3p, and GAS5/miR-27a-5p are identified lncRNA/miRNA pairs that are involved in this process. Therefore, recognition of the expression profile and regulatory role of ncRNAs on the Wnt signaling may offer a novel approach to the diagnosis, prognosis, and treatment of human cancers. This review summarizes previous data on the modulatory role of lncRNAs/miRNAs on the Wnt/ß-catenin pathway implicated in tumor growth, EMT, metastasis, and chemoresistance in brain cancers.

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Aberrant glycosylation has been associated with several processes of tumorigenesis from cell signaling, migration and invasion, to immune regulation and metastasis formation. The biosynthesis of glycoconjugates is regulated through concerted and finely tuned enzymatic reactions. This includes the levels and activity of glycosyltransferases and glycosidases, nucleotide sugar metabolism, substrate availability, epigenetic condition, and cellular functional state. Glioblastoma (GBM) is the most aggressive brain tumor, frequently occurring in adults with overall survival not surpassing 17 months after diagnosis. GBM has been classified by the World Health Organization (WHO) as a grade 4 astrocytoma and stratified into G-CIMP, proneural, classical, and mesenchymal subtypes. Several biomolecular features associated with GBM aggressiveness have been elucidated; however, more studies are needed to elucidate the role of glycosylation in GBM pathology, looking at their potential as cancer targets. Here, we focus on the alteration of genes involved in protein N- and O-linked glycosylation in GBM. Specifically, the mRNA levels of glycogenes were analyzed using astrocytoma-TCGA-RNAseq datasets from public repositories. A total of 68 genes were differentially regulated in the most aggressive, mesenchymal subtype of GBM compared to the proneural and classical subtypes, and the expression of these genes was compared to normal brain tissues. Among them, we focused on 38 genes coding for proteins that belong to: 1) asparagine glycosylation (ALG); 2) glycosyltransferases (B3T, B4T); 3) fucosyltransferase (FUT); 4) acetylgalactosaminyltransferases (GALNT); 5) hexosaminidase (HEX); 6) mannosidase (MAN); 7) acetylglucosaminyltransferase (MGAT); 8) sialidase or neuraminidase (NEU); 9) solute carrier 35 family (SLC); and 10) sialyltransferase (ST). The differential expression of some genes was already reported in several solid tumors; however, several of them were found to be dysregulated in GBM for the first time. These data represent an important starting point to perform further orthogonal and functional validations to pinpoint the role of these glycogenes in GBM as diagnostic and therapeutic targets.

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Glioblastoma (GBM) is the most common primary brain tumor. Due to high resistance to treatment, local invasion, and a high risk of recurrence, GBM patient prognoses are often dismal, with median survival around 15 months. The current standard of care is threefold: surgery, radiation therapy, and chemotherapy with temozolomide (TMZ). However, patient survival has only marginally improved. Radioimmunotherapy (RIT) is a fourth modality under clinical trials and aims at combining immunotherapeutic agents with radiotherapy. Here, we develop in vitro assays for the rapid evaluation of RIT strategies. Using a standard cell irradiator and an Electric Cell Impedance Sensor, we quantify cell migration following the combination of radiotherapy and chemotherapy with TMZ and RIT with durvalumab, a PD-L1 immune checkpoint inhibitor. We measure cell survival using a cloud-based clonogenic assay. Irradiated T98G and U87 GBM cells migrate significantly (p < 0.05) more than untreated cells in the first 20−40 h post-treatment. Addition of TMZ increases migration rates for T98G at 20 Gy (p < 0.01). Neither TMZ nor durvalumab significantly change cell survival in 21 days post-treatment. Interestingly, durvalumab abolishes the enhanced migration effect, indicating possible potency against local invasion. These results provide parameters for the rapid supplementary evaluation of RIT against brain tumors.

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Despite the multiple ongoing and novel initiatives for developing brain-targeted drug delivery systems, insurmountable obstacles remain. A perfect drug delivery device that can bypass the brain-blood barrier and boost therapeutic efficacy is urgently needed for clinical applications. Exosomes hold unrivaled benefits as a drug delivery vehicle for treating brain diseases due to their endogenous and innate attributes. Unique properties, such as the ability to penetrate physical barriers, biocompatibility, innate targeting features, ability to leverage natural intracellular trafficking pathways, favored tumor homing, and stability, make exosomes suitable for brain-targeted drug delivery. Herein, we provide an overview of recent exosome-based drug delivery nanoplatforms and discuss how these inherent vesicles can be used to deliver therapeutic agents to the brain to cure neurodegenerative diseases, brain tumors, and other brain disorders. Moreover, we review the current roadblocks associated with exosomes and other brain-targeted drug delivery systems and discuss future directions for achieving successful therapy outcomes.

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This study was conducted to examine, at the county level, the relationship between pediatric cancer incidence rate and atrazine and nitrate mean concentrations in surface and groundwater. A negative binomial regression analysis was performed to investigate the association between central nervous system (CNS) tumors, leukemia, lymphoma, and atrazine and nitrate mean concentrations in groundwater. The age-adjusted brain and other CNS cancer incidence was higher than the national average in 63% of the Nebraska counties. After controlling for the counties socio-economic status and nitrate concentrations in groundwater, counties with groundwater atrazine concentrations above 0.0002 µg/L had a higher incidence rate for pediatric cancers (brain and other CNS, leukemia, and lymphoma) compared to counties with groundwater atrazine concentrations in the reference group (0.0000-0.0002 µg/L). Additionally, compared to counties with groundwater nitrate concentrations between 0 and 2 mg/L (reference group), counties with groundwater nitrate concentrations between 2.1 and 5 mg/L (group 2) had a higher incidence rate for pediatric brain and other CNS cancers (IRR = 8.39; 95% CI: 8.24-8.54), leukemia (IRR = 7.35; 95% CI: 7.22-7.48), and lymphoma (IRR = 5.59; CI: 5.48-5.69) after adjusting for atrazine groundwater concentration and the county socio-economic status. While these findings do not indicate a causal relationship, because other contaminants or cancer risk factors have not been accounted for, they suggest that atrazine and nitrate may pose a risk relative to the genesis of pediatric brain and CNS cancers, leukemia, and lymphoma.

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Pediatric brain tumors represent the most common types of childhood cancer and novel diagnostic and therapeutic solutions are urgently needed. The gold standard treatment option for brain cancers in children, as in adults, is tumor resection followed by radio- and chemotherapy, but with discouraging therapeutic results. In particular, the last two treatments are often associated to significant neurotoxicity in the developing brain of a child, with resulting disabilities such as cognitive problems, neuroendocrine, and neurosensory dysfunctions/deficits. Nanoparticles have been increasingly and thoroughly investigated as they show great promises as diagnostic tools and vectors for gene/drug therapy for pediatric brain cancer due to their ability to cross the blood-brain barrier. In this review we will discuss the developments of nanoparticle-based strategies as novel precision nanomedicine tools for diagnosis and therapy in pediatric brain cancers, with a particular focus on targeting strategies to overcome the main physiological obstacles that are represented by blood-brain barrier.

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Gene expression profiling has been shown to be comparable to other molecular methods for glioma classification. We sought to validate a gene-expression based glioma classification method. Formalin-fixed paraffin embedded tissue and flash frozen tissue collected at the Augusta University (AU) Pathology Department between 2000-2019 were identified and 2 mm cores were taken. The RNA was extracted from these cores after deparaffinization and bead homogenization. One hundred sixty-eight genes were evaluated in the RNA samples on the nCounter instrument. Forty-eight gliomas were classified using a supervised learning algorithm trained by using data from The Cancer Genome Atlas. An ensemble of 1000 linear support vector models classified 30 glioma samples into TP1 with classification confidence of 0.99. Glioma patients in TP1 group have a poorer survival (HR (95% CI) = 4.5 (1.3-15.4), p = 0.005) with median survival time of 12.1 months, compared to non-TP1 groups. Network analysis revealed that cell cycle genes play an important role in distinguishing TP1 from non-TP1 cases and that these genes may play an important role in glioma survival. This could be a good clinical pipeline for molecular classification of gliomas.

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Glioblastoma (GBM) is the most aggressive, malignant primary brain tumor in adults. GBM is notoriously resistant to immunotherapy mainly due to its unique immune microenvironment. High dimensional data analysis reveals the extensive heterogeneity of immune components making up the GBM microenvironment. Myeloid cells are the most predominant contributors to the GBM microenvironment; these cells are critical regulators of immune and therapeutic responses to GBM. Here, we will review the most recent advances on the characteristics and functions of different populations of myeloid cells in GBM, including bone marrow-derived macrophages, microglia, myeloid-derived suppressor cells, dendritic cells, and neutrophils. Epigenetic, metabolic, and phenotypic peculiarities of microglia and bone marrow-derived macrophages will also be assessed. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in GBM patients.

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AIM: To identify the sensory changes and lipoprotein ratios and their relationship in brain cancer patients during cancer-related therapy (CRT). METHODS: This was a prospective cross-sectional study with three observation times: before CRT, at 2-3 weeks, and 4-6 weeks after beginning CRT. The changes in patients' symptoms were evaluated using the Memorial Symptom Assessment Scale, and lipoprotein ratios were measured using total cholesterol/ high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol/HDL-c, and triglyceride/HDL-c at the three time points. RESULTS: Sensory changes such as itching, swelling of the arms and legs, numbness in the hands or feet, tingling in the hands or feet, and changes in the way food tastes and lipoprotein ratios were altered in patients with brain cancer during CRT. The lipoprotein ratios showed a significant positive correlation with sensory changes at each observation time (p < .05). CONCLUSION: Sensory changes and lipoprotein ratios varied, and their significant relationship was identified during CRT. Lipoprotein ratios should be considered as an indicator for symptom management in patients with malignant brain cancer during CRT.

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Calcium signaling, in addition to its numerous physiological roles, is also implicated in several pathological conditions including cancer. An increasing body of evidence suggest critical roles of calcium signaling in the promotion of different aspects of cancer, including cell proliferation, therapy resistance and metastatic-related processes. In many cases, this is associated with altered expression and/or activity of some calcium channels and pumps. Brain cancers have also been the subject of many of these studies. In addition to diverse roles of calcium signals in normal brain function, a number of proteins involved in calcium transport are implicated to have specific roles in some brain cancers including gliomas, medulloblastoma, neuroblastoma and meningioma. This review discusses research that has been conducted so far to understand diverse roles of Ca2+-transporting proteins in the progression of brain cancers, as well as any attempts to target these proteins towards a therapeutic approach for the control of brain cancers. Finally, some knowledge gaps in the field that may need to be further considered are also discussed.

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RE-1 silencing transcription factor (REST) (known also as NRSF) is a well-known transcription repressor whose strong decrease induces the distinction of neurons with respect to the other cells. Such distinction depends on the marked increased/decreased expression of specific genes, accompanied by parallel changes of the corresponding proteins. Many properties of REST had been identified in the past. Here we report those identified during the last 5 years. Among physiological discoveries are hundreds of genes governed directly/indirectly by REST, the mechanisms of its neuron/fibroblast conversions, and the cooperations with numerous distinct factors induced at the epigenetic level and essential for REST specific functions. New effects induced in neurons during brain diseases depend on the localization of REST, in the nucleus, where functions and toxicity occur, and in the cytoplasm. The effects of REST, including cell aggression or protection, are variable in neurodegenerative diseases in view of the distinct mechanisms of their pathology. Moreover, cooperations are among the mechanisms that govern the severity of brain cancers, glioblastomas, and medulloblastomas. Interestingly, the role in cancers is relevant also for therapeutic perspectives affecting the REST cooperations. In conclusion, part of the new REST knowledge in physiology and pathology appears promising for future developments in research and brain diseases.

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AIM: In recent years, it is believed that Vitamin D may play a protective role in some cancer types. Certain regions of the Vitamin D receptor (VDR) gene may show a genetic difference in structure. The most frequent polymorphisms in this gene are in Taq-1, Fok-1, and Bsm-1 regions. Some adult cancer types are associated with VDR gene polymorphism such as; colorectal carcinoma, breast carcinoma, and prostate carcinoma. Reviewing the medical literature, no such study had been done on children so far. MATERIALS AND METHODS: We investigated the association of the three most common gene polymorphisms (Taq-1, Fok-1, and Bsm-1 regions) in VDR gene in 32 children with brain tumors and forty control healthy volunteers. RESULTS: We could not find any relationship between childhood brain tumors and VDR gene polymorphism in these three regions. CONCLUSION: The present results suggest that the Taq-1, Fok-1, and Bsm-1 polymorphism in the VDR gene and pediatric brain cancers have no association.

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PURPOSE: The purpose of this study was to identify the lipid profile ratios as factors affecting disease progress in patients with high-grade primary brain cancers undergoing concurrent chemoradiotherapy (CCRT) and adjuvant chemotherapy. METHODS: The levels of lipid profile ratios were evaluated by looking at the total cholesterol (TC) to high-density lipoprotein (HDL)-cholesterol (TC/HDL-c), low-density lipoprotein (LDL)-cholesterol to HDL-cholesterol (LDL-c/HDL-c), and triglycerides to HDL-cholesterol (TG/HDL-c). This descriptive research was conducted 7 months after the initiation of CCRT and adjuvant chemotherapy. RESULTS: A total of 36 patients with newly diagnosed primary malignant brain cancer were included in the study. The levels of lipid profile ratios such as TC/HDL-c, LDL-c/HDL-c, TG/HDL-c were significantly different between the patients with and without disease progress at 7 months after initiation of CCRT and adjuvant chemotherapy. CONCLUSION: The lipid profile ratios were indicators affecting disease prognosis with tumor-related factors at 7 months after initiation of CCRT and adjuvant chemotherapy. Therefore, lipid profile ratios indicating hyperlipidemia in patients with high-grade brain cancers should be carefully monitored during and after cancer-related therapy.

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The constitutional MisMatch Repair deficiency (CMMRD) syndrome is one of the inherited cancer predisposition syndromes. More than two-third patients belonging to a CMMRD family are diagnosed mainly in the first decade with brain cancers and/or hematological malignancies. This syndrome is due to bi-allelic germline mutations in genes of the MMR pathway (MLH1, MSH2, MSH6 or PMS2). Our family report begins with the index case presenting initially with a medulloblastoma, which was even the two relapses in complete remission, when she was diagnosed for an AML. She died after bone marrow transplantation from toxicity. The family history was progressively established when her uncle was diagnosed for a colonic cancer and a cousin for a brain tumor. Surprisingly, her father had an atypical sarcoma but her brother also presented a lymphoma followed by a gliomatosis cerebri. A new MLH1 bi-allelic mutation was identified in this family. More than the diagnostic difficulties, this family report illustrates the complexity of the microsatellite instability detection in CMMRD patients, which has to be discussed further to a more accurate diagnosis in the pediatric setting, and address the question of the proper diagnostic tool to use in such genetic background with hypermutated tumors.

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The target tracer carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives, N-(3-[(11)C]methoxy-4-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (3-[(11)C]4a) and N-(4-[(11)C]methoxy-3-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (4-[(11)C]4a); 2-((6-amino-9H-purin-8-yl)thio)-N-(3-[(11)C]methoxy-4-methoxyphenyl)acetamide (3-[(11)C]8a) and 2-((6-amino-9H-purin-8-yl)thio)-N-(4-[(11)C]methoxy-3-methoxyphenyl)acetamide (4-[(11)C]8a), were prepared by O-[(11)C]methylation of their corresponding precursors with [(11)C]CH3OTf under basic condition (2N NaOH) and isolated by a simplified solid-phase extraction (SPE) method in 50-60% radiochemical yields based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555GBq/µmol.

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