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Simple Summary: Subependymal giant cell astrocytoma is a slow-growing brain tumor affecting children and young adults. Despite the characteristic molecular and clinical features, the severity of the disease varies from patient to patient, and, in addition, tumors in their early stages can be asymptomatic for a long time. Morbidity and mortality are due to the location of the tumor, which can obstruct the flow of cerebrospinal fluid, leading to progressive hydrocephalus and even death. The etiology and the response to treatment are still poorly understood due to the diversity of the background and the course of the disease. Therefore, this review aims to present and discuss the latest research on SEGA, its diagnosis, and treatment. Subependymal giant cell astrocytoma (SEGA) is most often found in patients with TSC (Tuberous Sclerosis Complex). Although it has been classified as a benign tumor, it may create a serious medical problem leading to grave consequences, including young patient demise. Surgery and chemotherapy belong to the gold standard of treatment. A broader pharmacological approach involves the ever-growing number of rapalogs and ATP-competitive inhibitors, as well as compounds targeting other kinases, such as dual PI3K/mTOR inhibitors and CK2 kinase inhibitors. Novel approaches may utilize noncoding RNA-based therapeutics and are extensively investigated to this end. The purpose of our review was to characterize SEGA and discuss the latest trends in the diagnosis and therapy of this disease. [ABSTRACT FROM AUTHOR]

Protein kinase CK2 has become a target of experimental antiglioma therapies as laboratory data are almost uniformly favorable and the number of synthetized CK2 inhibitors is rapidly growing. The evidence of their use for other brain tumors is on the increase as well. Great expectations are entrusted in naturally occurring compounds capable of inhibiting CK2 kinase. These compounds are extracted and purified by means of biochemistry methods and are amenable for innovative drug delivery systems as well. CK2 kinase inhibitors have been proven suitable for combined therapies with other investigational antiglioma agents and treatment modalities. However, a greater share of efforts should be undertaken towards inhibiting functions relatively specific for glial tumors, including infiltrative growth and invasiveness or maintenance of glioma initiating cells. Many of these functions appear to converge on the mTOR and JAK/STAT pathways, which are being meticulously studied in this respect. Protein kinase CK2 holds therapeutic promise, especially when combined with other agents aimed at molecular signatures of gliomas. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the involvement of the proteasome in the mechanism of preconditioning with hyperbaric oxygen (HBO-PC). Methods: The experiments were performed on male Wistar rats subjected to a transient global cerebral ischemia of 5 min duration (2-vessel occlusion model) and preconditioned or not with HBO for 5 preceding days (1 h HBO at 2.5 atmosphere absolute [ATA] daily). In subgroups of preconditioned rats, the proteasome inhibitor MG132 was administered 30 min prior to each preconditioning session. Twenty-four hours and 7 days post-ischemia, after neurobehavioral assessment, the brains were collected and evaluated for morphological changes and quantitative immunohistochemistry of cell markers and apoptosis-related proteins. Results: We observed reduced damage of CA1 pyramidal cells in the HBO preconditioned group only at 7 days post-ischemia. However, both at early (24 h) and later (7 days) time points, HBO-PC enhanced the tissue expression of 20S core particle of the proteasome and of the nestin, diminished astroglial reactivity, and reduced p53, rabbit anti-p53 upregulated modulator of apoptosis (PUMA), and rabbit anti-B cell lymphoma-2 interacting mediator of cell death (Bim) expressions in the hippocampus and cerebral cortex. HBO-PC also improved T-maze performance at 7 days. Proteasome inhibitor abolished the beneficial effects of HBO-PC on post-ischemic neuronal injury and functional impairment and reduced the ischemic alterations in the expression of investigated proteins. Significance: Preconditioning with hyperbaric oxygen-induced brain protection against severe ischemic brain insult appears to involve the proteasome, which can be linked to a depletion of apoptotic proteins and improved regenerative potential. [ABSTRACT FROM AUTHOR]

The genetic alterations related to many kinases are responsible for the formation of glial tumours. In addition it is the cell kinases that keep the cancerous signalling machinery in motion, thus enabling tumour cell growth, motility and invasion. Kinase inhibitors may have a potential to surpass the classical oncolytic treatment for gliomas. However, overcoming drug resistance mechanisms and limited blood-brain barrier (BBB) permeability are the remaining daunting issues. Latest research explores novel kinase inhibitors, yielding several promising results, including those from CK2 inhibition studies, as well as the possibility of relabelling the inhibitors previously approved for tumours other than glial tumours. [ABSTRACT FROM AUTHOR]

Tumours of astroglial origin, both malignant glioblastoma (GBM) and benign subependymal giant cell astrocytoma (SEGA), pose a serious medical problem. Casein kinase 2 (CK2), a member of the serine/threonine kinase family, has antiapoptotic properties and plays a vital role in glial tumour cell survival. It contributes to invasive cell growth and is often upregulated in malignant neoplastic cells; however, its role in benign tumours of astrocytic origin is less understood. In the present study we investigated the effects of small molecule CK2 inhibitors on proliferation and viability of glioma cells in vitro. The experiments were conducted on commercial T98G malignant glioma cell line and the SEGA cell line, derived from a paediatric case of tuberous sclerosis complex (TSC). Cell cultures were incubated with selected CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzimidazole (TBI), 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBB) at 0.1, 1, 10, 25, 50, 75 and 100 μM concentrations for 24 and 48 hours. Cell proliferation was assessed using a cell counter and cell viability was evaluated by MTT assay. TBB at 75 μM and 100 μM, and TBI starting from 25 μM, both reduced T98G cell proliferation after 24 hours, while DMAT was ineffective. All tested small molecule CK2 inhibitors appear to reduce T98G cell growth and viability after 48 hours, although TBI appeared to be the most effective and reduced cell growth in the 50-100 μM dose range. TBI also showed potential efficacy in reducing the number and viability of SEGA cells after 48 hours. Proliferation and viability of SEGA cells have proven resistant to TBB treatment. DMAT only reduced the viability of SEGA cells at 24 (at 100 μM) and 48 hours (10-100 μM). Importantly, normal human astrocyte cells were found to be moderately resistant to TBB, while their viability was mildly reduced at higher doses of DMAT and TBI. In conclusion, CK2 appears to play a role not only in malignant glioma cells but it can also sustain the viability and proliferation of benign astrocytoma cells. The obtained antitumor effects of CK2 inhibitors significantly exceeded their mild or no effect on normal astrocytes in control, which supports the therapeutic potential of these compounds against gliomas. [ABSTRACT FROM AUTHOR]

Treatment options for glioblastoma remain limited and unfortunately even with maximal resection and postoperative adjuvant treatments, the median overall survival of patients remains approximately 15 months. In the present study we investigated the effect of HBO (2ATA - atmospheres absolute) prolonged to 2 hours on antitumor efficacy of selected CK2 kinase inhibitors in two distinct human malignant glioma cell lines, T98G and U87MG. Tested compounds were administered in increasing concentrations within the range of 5-100µM either under normoxia or with the addition of HBO at the beginning of experiments. After 24 hour incubation, 2 hour HBO decreased the viability of T98G cells in response to CK2 kinase inhibitors 2-aminoetylo-amino-4,5,6,7-tetrabromo-1H-benzimidazol (TBIAEA), 2/ 4,5,6,7-tetrabromoN²metylo-N²hydroksyetylo 2 ami-nobenzimidazol (TMHA), and 3/ 1-(β-D-2'-deoxy-ribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazol(TDB), as compared to treatments with these inhibitors under normoxia. The 2 hour HBO-induced reductions of viability amounted up to 36% over pharmaceutics alone and occurred at 5-100µM of their concentration range. Notably, as compared with 1 hour HBO sessions combined with CK2 kinase inhibitors, 2 hour HBO sessions combined with these pharmaceuticals produced greater reductions of viability of T98G cells, resulting in the lowest numbers of surviving tumor cells in the whole experiment. In T98G cells, as compared with U87MG cells, 2 hour HBO caused more potent reductions over pharmaceuticals alone. Thus, the prolonged dosing of HBO may increase tumoricidal effect of antiglioma agents and hence deserves further study. Investigating even more prolonged HBO exposures and other kinase inhibitors combined with HBO against glioblastoma cells would be worth a while. This work was supported by the Foundation for Development of Diagnostic and Therapy Warsaw. [ABSTRACT FROM AUTHOR]

Hemorrhagic stroke, accounting for 10-30% of stroke cases, carries high rates of morbidity and mortality. This review presents the current knowledge on the efficacy of hyperbaric oxygen (HBO)-based modalities in the preclinical research on hemorrhagic stroke. Both preconditioning and post-treatment with HBO are considered as prospective therapeutic options. High efficacy of HBO therapy (HBOT) for brain hemorrhage has been noted. We found that moderate hyperbaric pressures appear optimal for therapeutic effect, while the therapeutic window of opportunity is short. HBO preconditioning offers more modest neuroprotective benefit as compared to HBO post-treatment for experimental intracerebral hemorrhage. We advocate for mandatory calculations of percent changes in the experimentally investigated indexes of HBO effectiveness and stress the need to design new clinical trials on HBO for hemorrhagic stroke. [ABSTRACT FROM AUTHOR]

The effectiveness and efficacy of hyperbaric oxygen (HBO) preconditioning and post-treatment modalities have been demonstrated in experimental models of ischemic cerebrovascular diseases, including global brain ischemia, transient focal and permanent focal cerebral ischemia, and experimental neonatal hypoxia-ischemia encephalopathy. In general, early and repetitive post-treatment of HBO appears to create enhanced protection against brain ischemia whereas delayed HBO treatment after transient focal ischemia may even aggravate brain injury. This review advocates the level of injury reduction upon HBO as an important component for translational evaluation of HBO based treatment modalities. The combined preconditioning and HBO post-treatment that would provide synergistic effects is also worth considering. [ABSTRACT FROM AUTHOR]

Pleomorphic xanthoastrocytoma (PXA) is a rare, low-grade astrocytic tumour corresponding to WHO grade II that is usually diagnosed in adolescents and young adults with epileptic seizures. Pleomorphic xanthoastrocytoma typically appears as a superficial, often cystic mass lesion predominantly affecting the temporal lobe. Cases with typical pathology and total tumour excision have a favourable prognosis. Occasionally, the tumour reveals anaplastic features and behaves more aggressively due to local recurrences or subarachnoid spread. The treatment of PXA includes gross total resection followed by neuroradiological monitoring. The association between vascular malformations and cerebral gliomas is rarely encountered, especially if both such lesions occur as separate parts of the same tumour. The vascular pathology of such changes most often refers to arteriovenous malformation (AVM), less frequently - cavernous angioma. The coexistence of PXA and AVM is extremely rare, especially when dealing with two distinct patterns found within the same tumour mass. We present a 36-year-old woman with tumour of parasagittal localization in the right occipital lobe that was composed of two different and clearly demarcated components: PXA and vascular lesion of AVM morphology. The pathogenesis of such coexistence remains still unclear. [ABSTRACT FROM AUTHOR]

In gliomas, casein kinase 2 (CK2) plays a dominant role in cell survival and tumour invasiveness and is upregulated in many brain tumours. Among CK2 inhibitors, benzimidazole and isothiourea derivatives hold a dominant position. While targeting glioma tumour cells, they show limited toxicity towards normal cells. Research in recent years has shown that these compounds can be suitable as components of combined therapies with hyperbaric oxygenation. Such a combination increases the susceptibility of glioma tumour cells to cell death via apoptosis. Moreover, researchers planning on using any other antiglioma investigational pharmaceutics may want to consider using these agents in combination with CK2 inhibitors. However, different compounds are not equally effective when in such combination. More research is needed to elucidate the mechanism of treatment and optimize the treatment regimen. In addition, the role of CK2 in gliomagenesis and maintenance seems to have been challenged recently, as some compounds structurally similar to CK2 inhibitors do not inhibit CK2 while still being effective at reducing glioma viability and invasion. Furthermore, some newly developed inhibitors specific for CK2 do not appear to have strong anticancer properties. Further experimental and clinical studies of these inhibitors and combined therapies are warranted. [ABSTRACT FROM AUTHOR]