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Background: Symptomatic intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS) are different in many aspects. Here, we explored the association between the location or severity of atherosclerotic stenosis and pro- or antiangiogenic factors, specifically vascular endothelial growth factor (VEGF) and endostatin (ES).Methods: We evaluated 198 consecutive patients with acute ischemia stroke: 132 with large-artery atherosclerosis (LAA) and 66 with small-artery occlusion (small-vessel occlusion). The LAA group was subclassified into 102 patients with ICAS and 30 with ECAS. Independent associations of VEGF, ES levels, and VEGF/ES ratio with the location of cerebral stenosis and the severity or short-term prognosis (14th day modified Rankin Scale) of ICAS were evaluated.Results: Plasma concentrations of VEGF and ES were lower (P < .05) in ICAS (38.07, 32.76-46.28 pg/mL and 58.95, 55.04-59.77 ng/mL) than those in ECAS (45.00, 34.30-83.34 pg/mL and 140.74, 85.63-231.21 ng/mL). Logistic regression analysis showed that VEGF concentrations and dyslipidemia were independently associated with ICAS, with odds ratios of .987 [95% CI = (.976, .998)] and .265 [95% CI = (.103, .792)], respectively. Moreover, plasmatic VEGF levels increased gradually along with the severity of ICAS (P = .003), and lower levels of ES (P = .040) or a higher VEGF/ES ratio (P = .048) were related to unfavorable short-term prognosis of ICAS.Conclusion: Lower VEGF levels are associated with the presence of symptomatic ICAS, but not with ECAS. Furthermore, the severity of ICAS is positively correlated with the levels of VEGF, and lower ES levels or a predominance of VEGF over ES are predictors of poor short-term prognosis of ICAS. [ABSTRACT FROM AUTHOR]

Purpose: To study the clinical characteristics of patients with game-induced seizures in the Chinese population.Method: We assessed 51 patients with various game-induced epileptic seizures. Based on whether they had spontaneous seizures, these 51 patients were classified as two groups. Twenty-seven patients who had both game-induced and spontaneous seizures were referred to as Group I, whereas twenty-four patients that had experienced seizures exclusively while playing specific games were assigned to Group II. All of the related clinical data of the patients was collected and evaluated.Results: The patients in Group I presented with adolescent-onset and related to photosensitive idiopathic generalized epilepsy (IGE), were responsive to valproic acid (VPA) or magnesium valproate (VPA-Mg) therapy, and presented a major seizure-precipitating factor in response to electronic games. While patients in Group II were adult onset and not associated with IGE, showed uncertain responses to VPA and a benign prognosis, and presented major seizure-precipitating factors in response to non-electronic games.Conclusion: There are obvious genetic differences between patients with game-induced epilepsy. It is necessary to differentiate between various types of game-induced seizures and select the corresponding treatment. [ABSTRACT FROM AUTHOR]

Background Cortical networks undergo large-scale switching between states of increased or decreased activity in normal sleep and cognition as well as in pathological conditions such as epilepsy. We previously found that focal hippocampal seizures in rats induce increased neuronal firing and cerebral blood flow in subcortical structures including the lateral septal area, along with frontal cortical slow oscillations resembling slow wave sleep. In addition, stimulation of the lateral septum in the absence of a seizure resulted in cortical deactivation with slow oscillations. Hypothesis We hypothesized that lateral septal activation might cause neocortical deactivation indirectly, possibly through impaired subcortical arousal. But how does subcortical stimulation cause slow wave activity in frontal cortex? How do arousal neurotransmitter levels (e.g. acetylcholine) change in cortex during the excitation of inhibitory projection nuclei? Methods and results In the current study, we used simultaneous electrophysiology and enzyme-based amperometry in a rat model, and found a decrease in choline, along with slow wave activity in orbital frontal cortex during lateral septal stimulation in the absence of seizures. In contrast, the choline signal and local field potential in frontal cortex had no significant changes when stimulating the hippocampus, but showed increased choline and decreased slow wave activity with an arousal stimulus produced by toe pinch. Conclusions These findings indicate that the activation of subcortical inhibitory structures (such as lateral septum) can depress subcortical cholinergic arousal. This mechanism may play an important role in large-scale transitions of cortical activity in focal seizures, as well as in normal cortical function. [ABSTRACT FROM AUTHOR]

[Display omitted] • The Dongcuo batholith was constructed during ca. 225–204 Ma by three stages of magmatism. • Peak magmatism occurred at ca. 220–216 Ma and recycled early-formed zircons. • Incorporation of antecrysts results in large zircon age spans (∼20 Myr) in granitic samples. Large and homogeneous plutons can assemble incrementally over millions of years, yielding large age spans. Determination of the age span is crucial to constrain the timing and nature of the batholith assembly. This paper reports comprehensive whole-rock geochemical data, LA-ICP-MS zircon U-Pb age, and zircon Hf isotopic data to constrain the timing and assembly process of the Late Triassic Dongcuo batholith, the largest batholith in the Yidun Terrane, eastern Tibetan Plateau. Samples from the batholith consist of metaluminous to weakly peraluminous granitoids (SiO 2 = 69.91–79.85 wt%). These granitoids show large variation of zircon Hf isotopic compositions with ε Hf (t) of -17.15 to +0.13. The multiple zircon populations in single hand specimens revealed by kernel density estimation spread over 20 Myr (ca. 225–204 Ma), which is also confirmed by core-rim ages of single zircon grains, suggesting prolonged magmatism of the Dongcuo batholith. Our data indicate that the assembly of the batholith resulted from emplacement of discrete magma batches which derived from spatially varied sources and underwent variable differentiation. The assembly mainly involved three stages, including an early episode of magmatism (ca. 228 Ma), a high-flux magmatism between ca. 220 Ma and ca. 216 Ma, and a late-stage thermal event (ca. 211–204 Ma) possibly related to high temperature and localized remelting of the batholith. This study highlights the complexity of zircon populations in composite granitic batholith, showing that the search for single crystallization ages for a sample is fraught with difficulties and may mask rather than elucidate the crystallization history of the magmatic body. [ABSTRACT FROM AUTHOR]

Abstract: Background: and purpose: Matrix metalloproteinases 9 (MMP-9) has been reported to play a critical role in the pathophysiology of atherosclerotic cerebral infarction (ACI). Here we assessed association of MMP-9 polymorphisms with ACI susceptibility and the function of SNPs through microRNA mediated regulation. Methods: Genotyping was performed using MALDI-TOF mass spectrometry. Reporter gene plasmids with the MMP-9 3′UTR carrying either the mutant or the wild-type MMP-9 allele were constructed. Also, we constructed pcDNA-3.1-miR-491-5p recombinant plasmid, which transiently co-transfected human umbilical vein endothelial cells (HUVEC) with the reporter plasmids. Reporter plasmids, miR-491-5p mimics and inhibitor were transfected into HUVE cells line by lipofectamine. MMP-9 mRNA expression in HUVEC was detected by RT-PCR and protein level by ELISA. Results: The rs1802908 and rs2664517 polymorphisms were not observed in all subjects from Hunan Han Chinese. No significant difference in genotype distribution of rs20544 and rs9509 between cases and controls were observed (p＞0.05). The rs1056628CC genotype had a significantly increased risk for ACI as compared with carries of the rs1056628 A allele (total χ 2 = 12.041, P = 0.002). Reporter gene assay revealed that the rs1056628 A allele showed lower reporter activity than the rs1056628C allele. Hsa-miR-491-5p had effect on modulation of MMP-9 gene in vitro. The rs1056628 A→C variant in the 3′-UTR of the MMP-9 increased MMP-9 protein expression in cultured HUVECs. Conclusions: Our data suggested that the rs1056629A→C variation contributes to an increased risk of ACI by increasing MMP-9 expression through affecting binding of miR-491 to the polymorphic site in the 3′-UTR of MMP-9. [Copyright &y& Elsevier]

Abstract: The phosphatase and tensin homologue (PTEN) gene is critical to the pathological development of atherosclerosis, a major risk factor for atherosclerotic cerebral infarction (ACI). However, it remains unclear whether genetic polymorphism in the PTEN gene can affect the risk of developing ACI. In the present haplotype-based case-control study, we investigated whether polymorphisms of the PTEN gene were associated with ACI in a Han Chinese population. Using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS), we genotyped 300 patients with ACI and 204 matched healthy controls for five single nuclear polymorphisms (SNP) of the PTEN gene (rs2299939, rs17431184, rs555895, rs12357281 and rs2673836). Linkage disequilibrium and haplotype construction were analyzed using SHEsis software. We found that the rs2299939 PTEN intronic polymorphism was significantly associated with a risk of ACI in our Han Chinese population. The rs555895 and rs17431184C/T variants were not associated with risk of ACI. Two other polymorphisms were not detected in any subject in this study. The rs2299939C/rs17431184T/rs555895T PTEN haplotype was also significantly associated with risk of ACI. Our study provides the first evidence of an association between a PTEN intronic variant and the risk of ACI. It also provides new a new line of evidence for the critical role of PTEN in the development of stroke. [Copyright &y& Elsevier]

Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients. We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment approaches, LM progression-free survival (LM PFS) and overall survival (OS) after the diagnosis of LM (OS LM) were analyzed. The median OS LM was 16.0 months and the 3-year OS rate was 22.5%. The PFS LM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was significantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P = 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P = 0.024). Better Eastern Cooperative Oncology Group performance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS. The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive. [ABSTRACT FROM AUTHOR]

Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. While aortic valve interstitial cells (AVICs) are the main cells that express osteogenic mediators, the molecular mechanism that mediates AVIC osteogenic responses is incompletely understood. This study aims to identify pro-osteogenic factors in human AVICs affected by CAVD. Methods and results Microarray analysis identified 11 up-regulated genes in AVICs of diseased valves. Among these genes, mRNA levels of neurotrophin 3 (NT3) increased by 2 fold. Higher levels of NT3 protein in diseased aortic valves and diseased AVICs were confirmed by immunofluorescent staining and immunoblotting, respectively. An exposure of AVICs of normal valves to recombinant human NT3 (0.025–0.10 μg/mL) up-regulated the production of Runx2, TGF-β1 and BMP-2 in a dose-dependent fashion. NT3 also promotes calcium deposit formation. The pro-osteogenic effect of NT3 was not affected by neutralization of Toll-like receptor 2 or 4. Interestingly, mRNA encoding neural growth factor receptors (TrkA, TrkB, TrkC and p75 NTR) was detectable in human AVICs. Inhibition of Trk receptors markedly reduced the effects of NT3 on Runx2, TGF-β1 and BMP-2 production, calcium deposit formation and Akt phosphorylation. Further, inhibition of Akt also reduced the pro-osteogenic effects of NT3. Conclusions AVICs of diseased human aortic valves express higher levels of NT3. NT3 up-regulates the production of Runx2, TGF-β1 and BMP-2, and promotes calcium deposit formation in human AVICs via the Trk–Akt pathway. Thus, NT3 is a novel pro-osteogenic factor in aortic valves and may play a role in valvular calcification. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Whether platinum plus gemcitabine or vinorelbine are equally effective in the treatment of advanced non-small-cell lung cancer (NSCLC) is still controversial, a meta-analysis was performed to compare the gemcitabine plus platinum with vinorelbine plus platinum regimens in first-line treatment of advanced NSCLC. Methods: A literature search was performed in PubMed database, the Cochrane Central Register of Controlled Trials (CENTRAL) database, the Physician Data Query (PDQ) database, EMBASE and the American Society of Clinical Oncology (ASCO) annual meeting abstracts. The following keywords were used: “non small cell lung cancer,” or “Carcinoma, Non-Small-Cell Lung”. Reference lists of original articles and review articles were also examined. The published languages and years were not limited. The trials searched were evaluated for eligibility and quality, and then the data were abstracted and analyzed. Endpoints were overall survival, overall response, and toxicity. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. Results: Nine randomized controlled trials involving 2186 patients were identified from 453 reports. They were all published as full-text articles. The intention-to-treatment (ITT) analysis demonstrated that the patients with gemcitabine plus platinum regimens had an equal overall response rate in comparison with vinorelbine plus platinum regimens (RR, 0.91; 95%CI, 0.81–1.03; P =0.15). Furthermore, the 1-year survival rate for the two platinum-based regimens were comparable (RR, 1.06; 95%CI, 0.96–1.18; P =0.27). Subgroup analysis comparing the cisplatin plus gemcitabine or vinorelbine had achieved the same results. Vinorelbine plus platinum regimens led to more frequent grade 3 or 4 of neutropenia, nephrotoxicity, constipation and phlebitis (OR, 0.37; 95%CI, 0.26–0.52; P <0.00001; OR, 0.38; 95%CI, 0.25–0.57; P <0.00001; OR, 0.50; 95%CI, 0.27–0.92; P =0.03 and OR, 0.13; 95%CI, 0.05–0.32; P <0.00001, respectively), while gemcitabine plus platinum chemotherapy inclined to developing more grade 3 or 4 thrombocytopenia (OR, 11.37; 95%CI, 4.56–28.38; P <0.00001). The incidence of grade 3 or 4 anemia, nausea and vomiting were almost comparable between the two arms (OR, 1.12; 95%CI, 0.62–2.02; P =0.71 and OR, 0.72; 95%CI, 0.41–1.28; P =0.27, respectively). Similar results were also achieved in subgroup analyses between the gemcitabine and vinorelbine in combination with the cisplatin. Conclusion: It could be concluded that the efficacy were similar between the platinum plus gemcitabine or vinorelbine regimens. The choice of platinum plus gemcitabine or vinorelbine depends on the toxicity of the drugs and patients’ tolerance. [Copyright &y& Elsevier]

Ferulic acid, a main ingredient of Ligusticum, exhibits anti-oxidant and anti-inflammation effects in heart diseases. Some studies indicate that gut microbiome is associated with the generation of ferulic acid. Whether the beneficial effect of ferulic is raised by the alteration of gut microbiota is still unknown. This study examined the effect of sodium ferulate on gut microbiome and cardiac function in TAC mice. Cell Counting Kit-8 (CCK8) assay verified that ferulic acid has low toxicity in vitro and that ferulic acid inhibited the up-regulation of β-MHC and ANP induced by Angiotensin II. In addition, daily supplement of 50 mg/kg sodium ferulate improved the ejection fraction and changed the gut microbiota composition of TAC mice. Relative abundance of Lactobacillus and Parabacteroides are increased in TAC mice gavaged with sodium ferulate. In addition, Lactobacillus is negatively correlated with HW/BW and LW/BW ratio. These results suggest that the beneficial effect of ferulic in TAC mice is probably through the regulation of gut microbiota. [ABSTRACT FROM AUTHOR]