Bruton’s tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors (n = 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors (p ≤ 0.05) and overall survival (OS) of patients with grade III gliomas (p ≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.
Ischemic stroke is characterized by a complex cascade of events starting from vessel occlusion. The term “penumbra” denotes the area of severely hypo-perfused brain tissue surrounding the ischemic core that can be potentially recovered if blood flow is reestablished. From the neurophysiological perspective, there are local alterations—reflecting the loss of function of the core and the penumbra—and widespread changes in neural networks functioning, since structural and functional connectivity is disrupted. These dynamic changes are closely related to blood flow in the affected area. However, the pathological process of stroke does not end after the acute phase, but it determines a long-term cascade of events, including changes of cortical excitability, that are quite precocious and might precede clinical evolution. Neurophysiological tools—such as Transcranial Magnetic Stimulation (TMS) or Electroencephalography (EEG)—have enough time resolution to efficiently reflect the pathological changes occurring after stroke. Even if they do not have a role in acute stroke management, EEG and TMS might be helpful for monitoring ischemia evolution—also in the sub-acute and chronic stages. The present review aims to describe the changes occurring in the infarcted area after stroke from the neurophysiological perspective, starting from the acute to the chronic phase.
The eight-and-a-half syndrome is a rare neuro-ophthalmological condition caused by a structural lesion in the dorsal portion of the pons, involving critical areas of the brainstem, i.e., medial longitudinal fasciculus (MLF), abducens nucleus, facial genu, and colliculus. It is characterized by internuclear ophthalmoplegia with horizontal gaze palsy and peripheral facial palsy. Although the syndrome is most frequently caused by vascular or demyelinating diseases, several different underlying causes might occur. Herein, we describe a case of the eight-and-a-half syndrome caused by a lung adenocarcinoma metastasis localized in the lower pontine tegmentum. Then, we review the current literature on the underlying causes of the eight-and-a-half syndrome.
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