Journal of Neuropathology and Experimental Neurology最新文献

Hemorrhagic transformation can complicate ischemic strokes after recanalization treatment within a time window that requires early intervention. To determine potential therapeutic effects of matrilin-3, rat cerebral ischemia-reperfusion was produced using transient middle cerebral artery occlusion (tMCAO); intracranial hemorrhage and infarct volumes were assayed through hemoglobin determination and 2,3,5-triphenyltetrazoliumchloride (TTC) staining, respectively. Oxygen-glucose deprivation (OGD) modeling of ischemia was performed on C8-D1A cells. Interactions between matrilin-3 and YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) were determined using RNA immunoprecipitation assay and actinomycin D treatment. Reperfusion after tMCAO modeling increased hemorrhage, hemoglobin content, and infarct volumes; these were alleviated by matrilin treatment. Matrilin-3 was expressed at low levels and YTHDF2 was expressed at high levels in ischemic brains. In OGD-induced cells, matrilin-3 was negatively regulated by YTHDF2. Matrilin-3 overexpression downregulated p-PI3K/PI3K, p-AKT/AKT, ZO-1, VE-cadherin and occludin, and upregulated p-JNK/JNK in ischemic rat brains; these effects were reversed by LY294002 (a PI3K inhibitor). YTHDF2 knockdown inactivated the PI3K/AKT pathway, inhibited inflammation and decreased blood-brain barrier-related protein levels in cells; these effects were reversed by matrilin-3 deficiency. These results indicate that YTHDF2-regulated matrilin-3 protected ischemic rats against post-reperfusion hemorrhagic transformation via the PI3K/AKT pathway and that matrilin may have therapeutic potential in ischemic stroke.

Recombinant human erythropoietin (rh-EPO) has been shown to stimulate neurogenesis and angiogenesis, both of which play crucial roles in the repair of brain injuries. Previously, we observed that rh-EPO treatment effectively reduced brain damage and enhanced angiogenesis in a neonatal rat model of periventricular white matter damage (PWMD). The objective of this research is to investigate the specific mechanism through which rh-EPO regulates angiogenesis following PWMD in premature neonates. We conducted experiments utilizing a neonatal PWMD model. Following rh-EPO treatment, the levels of erythropoietin receptor (EPOR) were found to be increased in the damaged brain of rats. Although the total amount of extracellular signal-regulated kinase (ERK), a downstream protein in the EPO signaling pathway, remained unchanged, there was clear upregulation of phosphorylated ERK1 (p-ERK1) levels. The increase in levels of p-ERK1 was inhibited by an ERK kinase inhibitor, while the total amount of ERK remained unchanged. Conversely, the levels of EPOR were not affected by the inhibitor. Notably, the introduction of rh-EPO led to a significant increase in the frequency of angiogenesis-related cells and the expression levels of angiogenic factors. However, these effects were nullified when the ERK pathway was blocked. These findings indicate that rh-EPO enhances angiogenic responses through the EPOR-ERK1 pathway in a neonatal PWMD model.

Isocitrate dehydrogenase (IDH)-mutant astrocytoma with microvascular proliferation, necrosis, CDKN2A/B homozygous deletion, or any combination of these features corresponds to World Health Organization grade 4 according to current criteria. However, the prognostic significance of CDKN2A hemizygous deletion in IDH-mutant astrocytoma is not well established. We undertook a comprehensive study that included assessments of histological and genetic approaches to prognosis for these tumors. Samples from a cohort of 114 patients with extended observation were subjected to histological review and molecular analysis. CDKN2A (9p21) deletion was detected by fluorescence in situ hybridization. Overall survival (OS) was calculated via Kaplan-Meier estimation using the log-rank test. Histological grade, Ki-67 index, and the extent of surgical resection correlated with the OS of IDH-mutant astrocytoma patients. Both CDKN2A homozygous deletion and hemizygous deletion were detectable. Patients with CDKN2A homozygous-deletion tumors had the poorest OS; those with CDKN2A hemizygous-deletion tumors had an intermediate OS (p < .001). We then established a novel grading system that combined CDKN2A homozygous and hemizygous deletions with histological grade; the combined grading system was an independent prognostic factor for IDH-mutant astrocytomas. We conclude that CDKN2A homozygous and hemizygous deletion should be combined in a grading system for IDH-mutant astrocytomas.

Pilocytic astrocytomas (PA) typically exhibit distinct clinical, radiological, histopathological, and genetic features. DNA-methylation profiling distinguishes PA according to their location (infratentorial, midline, hemispheric, or spinal). In the hemispheric location, distinguishing PA from glioneuronal tumors remains a common diagnostic challenge for neuropathologists. Furthermore, the current version of the DKFZ classifier seems to have difficulty separating them from gangliogliomas. In this study, after central radiological review, we identified a histopathologically defined set of PA (histPA, n = 11) and a cohort of DNA-methylation defined PA (mcPA, n = 11). Nine out of the 11 histPA matched the methylation class of hemispheric PA, whereas 2 cases were classified at the end of the study as dysembryoplastic neuroepithelial tumors. Similarly, the mcPA cohort contained tumors mainly classified as PA (7/11), but 4 cases were classified as glioneuronal. The analysis of the 16 tumors with an integrated diagnosis of PA revealed that they affect mainly children with a wide spectrum of radiological, histopathological (i.e. a predominantly diffuse growth pattern), and genetic characteristics (large range of mitogen-activated protein kinase alterations). Based on these results, we consider hemispheric PA to be different from their counterparts in other locations and to overlap with other glioneuronal tumors, reinforcing the necessity of interpreting all data to obtain an accurate diagnosis.