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Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The drug-induced diverse response among patients is a severe problem for improving hemorheological character. However, there is no validated method for personalized therapy to the best of our knowledge. Here, we apply a gravity-driven deformability cytometry platform (GD-DCP) to profile the drug response of the red cell deformability (RCD) at the single-cell level using pentoxifylline (PTX) as a model drug, the effect of different concentrations of PTX (0, 2, 20, 200 μg mL -1 , the clinical dosage of PTX is 20 μg mL -1 ) on RCD in patients with cardiovascular disease was explored. Based on the GD-DCP, about 38 and 56% of the acute phase of acute myocardial infarction (AMI) patients in the acute phase and coronary heart disease (CHD) patients respond positively to PTX, respectively, indicating that PTX has a strong patient dependency on RCD. Moreover, RCD is observed to be significantly inversely correlated with the activation of membrane protein kinase C (PKC) as well as the concentration of Ca 2+ (both P < 0.001). The results of animal experiments show that the protective effects of PTX on myocardial ischemia rats have substantial individual variation, too. It is noted that the effect of PTX is highly consistent between RCD in vitro and in vivo outcomes (blood viscosity, myocardial injury, and electrocardiogram (ECG)) in the same rat. All these new findings suggest that the GD-DCP is a promising method that uses deformability in vitro as one of the important criteria in personalized medicine, and our study provides unique insight into the individual-dependent mechanisms of PTX for improving RCD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: Although most risk factors for cardiac valve calcification (VC) are similar to those for coronary artery disease (CAD), they differ regarding lesions and clinical symptoms. Recently, increasing evidence suggests that intestinal bacteria play essential roles in cardiovascular disease (CVD). It is plausible that the gut microbiota is linked to the occurrence of different CVDs under similar risk factors. Thus, we aimed to explore the gut microbiomes in patients with VC or CAD and determine their underlying connections., Methods: We collected samples from 119 subjects and performed 16S rRNA gene sequencing to analyze the gut microbiomes in VC and CAD patients and in control volunteers., Results: The gut microbiomes of VC and CAD patients were significantly different in terms of beta-diversity. Bacteria from Veillonella dispar, Bacteroides plebeius and Fusobacterium were enriched in the VC group, while members of Collinsella aerofaciens, Megamonas, Enterococcus, Megasphaera, Dorea and Blautia were decreased. According to the association with dyslipidemia, seven operational taxonomic units (OTUs), including Parabacteroides distasonis, Megamonas, Fusobacterium, Bacteroides sp., Bacteroides plebeius, Lactobacillus and Prevotella copri, were regarded as potential pathogens for CVDs. Additionally, Prevotella copri might be a keystone of CVDs, especially in VC patients, while Collinsella aerofaciens is a possible keystone of CAD, based on the multi-correlations of these bacteria with other OTUs in microbial communities., Conclusions: Patients with VC and CAD suffer from different gut microbial dysbiosis. The gut microbiomes are associated with the clinical characteristics in these diseases and might be potential therapeutic targets., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) plays key roles in controlling cardiac metabolism and function. Myocardial energy expenditure (MEE) can reflect myocardial energy metabolism and cardiac function. Whether the variation of PGC-1α can influence MEE levels in chronic heart failure (CHF) is unclear. Therefore, we investigated the relationship between PGC-1α and MEE., Material and Methods: We studied 219 patients with CHF and 66 healthy controls. MEE was measured according to echocardiographic parameters. Serum PGC-1α, N-terminal pro-B-type natriuretic peptide and other parameters were detected. Patients with CHF were divided into different groups according to the left ventricular ejection fraction (LVEF) and the tertile range of MEE., Results: Serum PGC-1α was lower in the MEE 2 and 3 groups compared with controls (both P < 0.05). Patients in the MEE 2 (1.73 ± 0.83 versus 2.16 ± 0.82 ng/mL, P = 0.001) and 3 groups (1.65 ± 0.73 versus 2.16 ± 0.82 ng/mL, P < 0.001) possessed lower levels of PGC-1α than those in the MEE 1 group. Compared with high LVEF, patients with low LVEF had higher MEE (median, 167 versus 73 cal/minute, P < 0.05) and lower PGC-1α (1.71 ± 0.65 versus 1.95 ± 0.91 ng/mL, P = 0.032). Multivariate logistic regression analysis showed that MEE (OR = 0.517, 95% CI = 0.267-0.998, P = 0.049) and creatinine (OR = 2.704, 95% CI = 1.144-6.391, P = 0.023) were independently associated with increased PGC-1α., Conclusions: Serum PGC-1α was related to MEE and LVEF in patients with CHF and can reflect the degree of MEE and the systolic function of the left ventricle., (Copyright © 2018. Published by Elsevier Inc.)

Background: Mitochondrial quality control is crucial to the development of angiotensin II (AngII)-induced cardiac hypertrophy. PTEN induced putative kinase 1 (PINK1) is rapidly degraded in normal mitochondria but accumulates in damaged mitochondria, triggering autophagy to protect cells. PINK1 mediates mitophagy in general, but whether PINK1 mediates AngII-induced mitophagy and the effects of PINK1 on AngII-induced injury are unknown. This study was designed to investigate the function of PINK1 in an AngII stimulation model and its regulation of AngII-induced mitophagy., Methods: We studied the function of PINK1 in mitochondrial homeostasis in AngII-stimulated cardiomyocytes via RNA interference-mediated knockdown and adenovirus-mediated overexpression of the PINK1 protein. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, adenosine triphosphate (ATP) content, cell apoptosis rates and cardiomyocyte hypertrophy were measured. The expression of LC3B, Beclin1 and p62 was measured. Mitochondrial morphology was examined via electron microscopy. Mitophagy was detected by confocal microscopy based on the co-localization of lysosomes and mitochondria. Additionally, endogenous PINK1, phosphorylated PINK1, mito-PINK1, total Parkin, cyto-Parkin, mito-Parkin and phosphorylated Parkin protein levels were measured., Results: Cardiomyocytes untreated by AngII had very low levels of total and phosphorylated PINK1. However, in the AngII stimulation model, the MMP was decreased, and the levels of total and phosphorylated PINK1 were increased. After PINK1 was knocked down, Parkin translocation to the mitochondria was inhibited. Moreover, levels of phosphorylated Parkin were reduced, and autophagy markers were downregulated. MMP and ATP contents were further reduced, ROS production and the apoptotic rate were further increased, and myocardial hypertrophy was further aggravated compared with those in the AngII group. However, PINK1 overexpression promoted Parkin translocation and phosphorylation, autophagy markers were upregulated, and myocardial injury was reduced. In addition, the effects of PINK1 overexpression were reversed by autophagy inhibitors., Conclusion: Decreased MMP induced by AngII maintains the stability of PINK1, causing PINK1 autophosphorylation. PINK1 activation promotes Parkin translocation and phosphorylation and increases autophagy to clear damaged mitochondria. Thus, PINK1/Parkin-mediated mitophagy has a compensatory, protective role in AngII-induced cytotoxicity., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: microRNA223 (miR-223) plays an important role in the development of atherosclerosis and ischemic stroke. It is involved in regulation of multiple physiological and pathophysiological processes such as cholesterol metabolism, endothelial cell (EC) function, and thrombosis. Here we investigated the role of methylation regulation of MIR-223 promoter region in atherosclerotic cerebral infarction (ACI) patients., Methods: A total of 23 patients with ACI and 32 healthy individuals were recruited. We performed bisulfite sequencing PCR and real-time PCR to detect methylation levels of MIR-223 promoter region and miR-223, respectively, in genomic DNA isolated from peripheral blood leukocytes., Results: Mean methylation levels of a total of nine CpGs of MIR-223 promoter were significantly lower in ACI patients than in healthy individuals (p < 0.01), and were also significantly lower in individuals with carotid atherosclerosis than those without carotid atherosclerosis (p < 0.05). Meanwhile, miR-223 expression in leukocytes was significantly higher in ACI patients than in healthy individuals (p < 0.05). miR-223 level was negatively correlated with mean methylation levels of MIR-223 promoter (r = -0.4451, p < 0.01). The methylation level of MIR-223 promoter revealed a positive correlation with the circulating total cholesterol level (r = 0.318, p = 0.019)., Conclusions: Hypomethylation of MIR-223 promoter is associated with atherosclerotic cerebral infarction., (Copyright © 2017. Published by Elsevier B.V.)

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., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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 © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: DNA repair gene X-ray repair cross complementing group 1 (XRCC1) Arg194Trp polymorphism has been investigated widely on lung cancer risk. However, the results are inconclusive. To derive a more precise estimation of the relationship between XRCC1 Arg194Trp polymorphism and lung cancer risk, we performed this meta-analysis., Methods: An electronic search of the database PubMed, Embase, and Chinese National Knowledge Infrastructure was performed. The odds ratio (OR) was pooled by STATA 10.1. Subgroup analyses by ethnicity, gender, smoking, and histologic types of lung cancer were performed., Results: Twenty-two studies including 7515 cases and 9560 controls were identified ultimately. The pooled OR for total population showed that homozygous Trp/Trp variant genotype could increase lung cancer risk compared with the homozygous wild Arg/Arg genotype (OR = 1.22, 95% confidence interval [CI] = 1.04-1.44, p = 0.01); however, heterozygote Arg/Trp variant genotype could decrease lung cancer risk (OR = 0.91, 95% CI = 0.85-0.99, p = 0.02). Subgroup analyses by ethnicity confirmed the result that homozygous Trp/Trp variant genotype increased lung cancer risk in Asians (OR = 1.19, 95% CI = 1.01-1.41, p = 0.04) but not in whites. It was interesting to find that both the heterozygote Arg/Trp and the combined Trp/Trp + Arg/Trp variant genotypes could decrease the risk of lung cancer in whites (OR = 0.83, 95% CI = 0.72-0.96, p = 0.01; OR = 0.85, 95% CI = 0.74-0.98, p = 0.03, respectively) but not in Asians. Subgroup analyses by gender, smoking, and histologic types of lung cancer did not indicate any significant difference between cases and controls, excepted for male population, which carried heterozygote Arg/Trp variant genotype that could decrease lung cancer risk (OR = 0.54, 95% CI = 0.31-0.95, p = 0.03)., Conclusions: Homozygous Trp/Trp variant genotype of XRCC1 Arg194Trp polymorphism could increase lung cancer risk in total population, especially in Asians. However, the heterozygote Arg/Trp variant genotype might decrease the risk of lung cancer, especially in whites.

Purpose: To compare the efficacy and toxicities of irinotecan/ platinum (IP) with etoposide/platinum (EP) in patients with previously untreated extensive-stage small cell lung cancer (E-SCLC)., Methods: The PubMed database, the Cochrane Library, conference proceedings, databases of ongoing trials, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted data. The relative risk for overall response to treatment, hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios for the different types of toxicity were pooled by STATA package., Results: Six trials involving 1476 patients with previously untreated E-SCLC were ultimately analyzed. The intention-to-treatment analysis indicated that IP regimens could acquire more overall response than EP regimens (relative risk = 1.10, 95% confidence interval [CI]: 1.00 -1.21, p = 0.043). The pooled HR showed that IP could prolong OS (HR = 0.81, 95% CI: 0.66 -0.99, p = 0.044). Nevertheless, the pooled HR failed to show a favorable PFS in IP regimens (HR = 0.82, 95% CI: 0.64 -1.06, p = 0.139). IP regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than EP regimens. Treatment-related deaths were comparable between the two groups., Conclusion: Although the PFS was similar from this meta-analysis, our results suggest that IP might have an advantage in overall response and OS compared with EP with less hematological toxicities. The IP regimens may be an alternative of EP regimens in the first-line treatment of E-SCLC.