ObjectiveThe purpose of this study was to determine whether fQRS is associated with increased ventricular arrhythmic event in patients with Acute ST- elevation Myocardial Infarction.Methods 12-lead ECG, 24h-Holter monitoring and biochemical markers detection were performed in sixty cases with acute ST-elevation myocardial infarction, which were divided into two groups[fQRS group and nonfQRS group]according to Fragmented QRS (fQRS) on 12-lead ECG.Then ventricular arrhythmic events were analyzed.ResultsVentricular premature beats (24 h, 3140 +555 vs 1226 + 142, P ＜0.01) and the incidence of complex ventricular arrhythmic events(34.4％ vs 10.7％, P ＜0.05) in fQRS group were significantly higher than that in non- fQRS group.ConclusionsFragmented QRS may be used to predict ventricular arrhythmic events in patients with acute ST- elevation myocardial infarction.

MicroRNAs(miRNAs)are a class of small(22 nucleotides)non-coding RNAs which play important roles in diverse biological and pathological processes.The dysregulation of miRNA expression is closely related to the development and progression of malignant tumors in humans.DNA methylation is a kind of epigenetic modification in human genome.Both hypermethylation and hypomethylation of DNA are closely related to different kinds of tumors,including gastric cancer.

Objective To test the hypothesis that perceived organizational support(POS) plays a moderate role in the process of personality' s effect on emotional exhaustion.Methods Using POS,Revised NEO Personality Inventory and Emotional Exhaustion Inventory,376 special combat soldiers were tested from the Chinese Armed Police Force.Then SPSS 16.0 was used to conduct descriptive analysis,correlational analysis and hierarchical regression analysis.Results The interaction of neuroticism and POS as well as the interaction of conscientiousness and POS were significant or marginally significant,respectively.POS significantly moderated the relationship between neuroticism and emotional exhaustion(β=-0.19,t=-2.82,P＜0.01)as well as the relationship between conscientiousness and emotional exhaustion(β=-0.12,t=-1.95,P=0.052).Conclusion Neuroticism and conscientiousness are more strongly related with emotional exhaustion among individuals with low POS than high POS.

ObjectiveTo study the biological characterization and the genetic background of circulating CA16 strains in mainland of China for the purpose of CA16 vaccine development in the future.MethodsCA16 strains were isolated from throat swabs of patients with hand-foot-mouth disease and identified by neutralization assay and RT-PCR.The genotype of these isolates were determined by sequence alignment and phylogenetic analysis of VP1 gene.The proliferation dynamics and the plaque morphology were observed when propagated in Vero cells.The pathogenicity of these CA16 isolates was evaluated by challenging newborn mice.ResultsIn this study,six CA16 circulating isolates,BJ-1-6 were obtained.The RT-PCR products were 150 bp amplified with the general enterovirus primers and 210 bp with CA16 primers respectively,which cannot be amplified by EV71 primers.Additionally,these isolates were identified to display some obvious proliferation dynamics and plaque morphology when propagated for 96 h in Vero cells.The diameter of plaques were about 1.5 to 2 mm for BJ-1,BJ-2,BJ-4,BJ-6,4-5 mm for BJ-3 and 3 mm for BJ5,the plaques were regular except BJ-3.All the six isolates can be neutralized by the convalescent serum of patient infected with CA16.The virus titer of different isolates propagated for five passages in Vero cells was 7.0LgCCID50/ml.The sequence alignment of VP1 gene demonstrated that the genotypes of BJ-2,BJ-4,BJ5 were C1 and BJ-1,BJ-3,B J-6 were C,3 comparatively.The genetic distance of the VPI gene from theseisolates suggested that they were highly genetic identity with the homology of 90％ in nucleotide and 99％ in dedicated amino acid respectively.However,a distinctive difference in pathogenic ability in neonatal mice was found that the suckling mice challenged with BJ-3 & BJ-5 were paralyzed 4-5 d and dead 6-7d postchallenge,compared with the control group without any abnormality in the during of 14 d.ConclusionThe circulating CA16 isolates in China have different biological characteristics,different pathogenic ability and similar genetic backgrounds,which is helpful for the development of a CA16 vaccine in the future.

Objective To investigate the effects of a Chinese medicine Xiao Aiping injection on the pathological changes of liver tissues in rat models, the migration ability of cancer cells in hypoxic tumor microenvironment, and explore their mechanism of action. Methods Sixty SPF 5-week old male Sprague-Dawley rats were randomly divided into model group (n=48) and blank control group (n=12). The model group was intraperitoneally injected with diethylnitrosamine to establish hepatocellular carcinoma model, and the blank control group was injected equal amount of normal saline. After 14 weeks, the model group was equally divided into three groups, two of them received the Xiao Aiping injection at a low and high dose, respectively, and the rest of model group and the blank control group were injected with normal saline once per day for five days, lasting for consecutive four weeks. Liver specimens were collected at the nineteenth week, and the rat liver cancer and liver tissues were examined by pathology. In the hypoxic environment induced by CoCl2, the effect of Xiao Aiping injection on the migration ability of hepatocellular cancer SMMC-7721 and HepG2 cells was assessed by wound healing experiment, and the expression of IL-6 mRNA was detected by real-time PCR assay. Results Compared with the blank control group, hepatic tissue of the model group showed obvious hepatocellular carcinoma-like-changes indicating the successful establishment of hepatocellular carcinoma model. After treatment, compared with the model group, the pathological alterations of hepatic tissue of Xiao Aiping injection low and high doses groups were reduced, and were more obvious in the high dose group. Under hypoxic condition, Xiao Aiping injection obviously inhibited the migration of HepG2 cells and inhibited IL-6 expression in the liver tissues. With the same concentration, Xiao Aiping injection obviously inhibited the migration of SMMC-7721 cells, and showed an inhibiting trend of IL-6 mRNA expression, but the difference was not statistically significant. Conclutions Xiao Aiping injection can reduce the pathological changes of hepatocellular carcinoma in rat models induced by intermittent intraperitoneal injection of diethylnitresamine. In the chemically induced hypoxic environment, the effects of Xiao Aiping injection on the migration of SMMC-7721 and hepG2 cells are different. Downregulating the expression of IL-6 mRNA may be one of the mechanisms of migration inhibiting effects.

Objective:To analyze the diagnostic value of metabolic makers in cerebrospinal fluid in advanced lung adenocarcinoma patients with leptomeningeal metastases (LM) .Methods:A total of 46 cerebrospinal fluid samples (LM group) from lung adenocarcinoma patients with LM admitted to Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School from December 2019 to December 2021 were collected, and 48 cerebrospinal fluid samples (control group) from patients with benign neurological diseases during the same period were collected. Metabolomics analysis of cerebrospinal fluid was carried out by high-performance liquid chromatography-mass spectrometry. Principle component analysis (PCA) and orthogonal to partial least squares discriminant analysis (OPLS-DA) were used for modeling. Multi-criteria assessment was used to identify the different metabolites between the two groups. Receiver operating characteristic (ROC) curve, pathway enrichment analysis and other methods were used to screen metabolites and pathways related to LM from lung adenocarcinoma.Results:There were no statistically significant differences in the proportions of age ( Z=-0.41, P=0.210) , gender ( χ2=1.19, P=0.275) , history of smoking ( χ2=2.86, P=0.091) , Karnofsky performance status score ( χ2=0.65, P=0.419) and increased intracranial pressure ( χ2=0.65, P=0.419) between the LM group and control group. The models of PCA (R2X was 0.608 and 0.583, Q2 was 0.462 and 0.513 in electrospray ion positive and negative modes, respectively) and OPLS-DA (R2Y was 0.967 and 0.889, Q2 was 0.959 and 0.852 in electrospray ion positive and negative modes, respectively) showed that the overall data quality was good. Meanwhile, the model interpretation rate and prediction rate were effective. The permutation tests duplicated for 200 times and showed no over-fitting of the established model. The metabolic profiles of the two groups were significantly different. A total of 30 endogenously differential metabolites were screened by using multi-criteria assessment. Six potential biomarkers with larger area under the curve (AUC) were identified through ROC curve analysis, including tyrosine (AUC=0.967, 95% CI: 0.906-1.000) , phenylalanine (AUC=0.992, 95% CI: 0.973-1.000) , pyruvate (AUC=0.976, 95% CI: 0.935-1.000) , tryptophan (AUC=0.935, 95% CI: 0.880-0.973) , glucose (AUC=0.932, 95% CI: 0.880-0.975) and adenosine monophosphate (AUC=0.993, 95% CI: 0.987-1.000) . The 30 selected differential metabolites were enriched and analyzed for metabolic pathways, and 20 relevant metabolic pathways were matched. Among them, the four metabolic pathways most likely to cause changes in metabolites were glycolysis and glucose metabolic synthesis, pyruvate metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis. Conclusion:Untargeted metabolomics analysis can effectively screen specific cerebrospinal fluid metabolites in lung adenocarcinoma patients with LM. Six potential metabolites such as tyrosine, phenylalanine, pyruvate, tryptophan, adenosine monophosphate, glucose and their metabolic pathways may be involved in the pathogenesis of LM from lung adenocarcinoma.

Objective:To evaluate the effects of intrathecal infusion chemotherapy on intracranial pressure (ICP) in non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM) by ultrasound measurement of the optic nerve beside the bed of optic nerve sheath diameter (ONSD) .Methods:A total of 31 NSCLC-LM patients who underwent intrathecal infusion chemotherapy at Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School from June 10, 2021 to December 25, 2022 were collected. The ONSD values were measured before and after the first lumbar puncture by bedside optic nerve ultrasound, and measured dynamically 30 min before intrathecal infusion chemotherapy (T0) , 30 min (T1) , 1 h (T2) , 2 h (T3) , 4 h (T4) , 6 h (T5) , and 24 h (T6) after intrathecal infusion chemotherapy. ICP ONSD was calculated, with differences between ICP LP and ICP ONSD, and differences between ONSD and ICP ONSD series at different time being compared separately. Mean arterial pressure (MAP) , heart rate, and headache score were assessed and compared respectively at T0, T1, T2, T3, T4, T5 and T6. Spearman analysis was used to evaluate the correlation between the response assessment in neuro-oncology (RANO) score and ICP. Results:Before the first lumbar puncture for cerebrospinal fluid drainage, ICP LP was (218.55±63.83) mmH 2O, left eye, right eye, and binocular eyes ICP ONSD were (217.28±57.17) mmH 2O, (223.64±51.13) mmH 2O, and (220.46±52.50) mmH 2O respectively, in NSCLC-LM patients, with no statistically significant difference ( F=0.77, P=0.463) . After first lumbar puncture for cerebrospinal fluid drainage, ICP LP was (214.68±58.01) mmH 2O, left eye, right eye, and binocular eyes ICP ONSD were (216.71±48.96) mmH 2O, (216.62±47.18) mmH 2O, and (216.67±47.86) mmH 2O respectively, with no statistically significant difference ( F=0.12, P=0.757) . At T0, T1, T2, T3, T4, T5, and T6, the MAP during intrathecal infusion chemotherapy was 89.80 (83.40, 93.67) mmHg, 95.00 (80.83, 99.37) mmHg, 91.86 (79.88, 100.14) mmHg, 90.15 (79.04, 100.55) mmHg, 105.14 (88.55, 114.74) mmHg, 98.96 (81.72, 111.81) mmHg, and 89.29 (85.45, 100.38) mmHg, with a statistically significant difference ( χ2=16.11, P=0.013) ; heart rates were 80.00 (75.00, 84.50) times/min, 80.00 (72.50, 87.50) times/min, 74.00 (66.00, 87.50) times/min, 82.00 (72.00, 90.00) times/min, 80.00 (70.50, 90.00) times/min, 77.00 (68.00, 91.00) times/min, 77.00 (71.50, 88.50) times/min, with no statistically significant difference ( χ2=2.18, P=0.902) ; headache scores were 2.00 (0.50, 3.00) score, 2.00 (1.00, 3.00) score, 2.00 (2.00, 3.00) score, 2.00 (1.00, 3.00) score, 2.00 (1.00, 2.00) score, 2.00 (1.00, 2.00) score, and 2.00 (0.00, 2.00) score, with no statistically significant difference ( χ2=11.64, P=0.071) . At T0, T1, T2, T3, T4, T5, and T6, left eye, right eye, and binocular ONSD were (5.85±0.64) mm, (5.72±0.68) mm, (7.11±1.11) mm, (6.42±0.78) mm, (5.69±0.63) mm, (5.61±0.64) mm, (5.65±0.88) mm, (5.85±0.12) mm, (5.89±0.12) mm, (6.93±0.20) mm, (6.40±0.14) mm, (5.71±0.12) mm, (5.66±0.12) mm, (5.33±0.14) mm, (5.85±0.64) mm, (5.81±0.64) mm, (7.02±1.03) mm, (6.41±0.75) mm, (5.70±0.63) mm, (5.64±0.63) mm, (5.49±0.76) mm, with statistically significant differences ( F=58.48, P<0.001; F=49.34, P<0.001; F=78.05, P<0.001) ; ICP ONSD were (222.81±56.81) mmH 2O, (211.89±60.29) mmH 2O, (335.12±98.32) mmH 2O, (274.17±68.87) mmH 2O, (208.77±56.12) mmH 2O, (201.75±56.79) mmH 2O, (205.59±78.36) mmH 2O, (223.26±58.33) mmH 2O, (227.08±61.68) mmH 2O, (319.36±101.10) mmH 2O, (272.33±69.61) mmH 2O, (211.21±57.73) mmH 2O, (206.51±57.22) mmH 2O, (177.22±68.98) mmH 2O, (223.03±57.24) mmH 2O, (219.49±57.24) mmH 2O, (327.24±91.56) mmH 2O, (273.25±67.04) mmH 2O, (209.99±56.26) mmH 2O, (204.13±56.29) mmH 2O, (191.40±67.95) mmH 2O, with statistically significant differences ( F=58.48, P<0.001; F=49.34, P<0.001; F=78.13, P<0.001) . The ONSD of the left eye, right eye, and binocular eyes and the corresponding ICP ONSD increased significantly at T2 compared with T0, T1, T3, T4, T5, and T6, with statistically significant differences (all P<0.05) . Pre- and post-treatment RANO scores were 4.00 (3.00, 7.00) score and 3.00 (2.00, 6.00) score respectively. Pre- and post-treatment RANO scores were positively correlated with ICP ONSD in the left eye ( r=0.55, P=0.001; r=0.60, P<0.001) , right eye ( r=0.54, P=0.001; r=0.46, P=0.009) and binocular eyes ICP ONSD ( r=0.45, P=0.010; r=0.37, P=0.043) . Conclusion:Intrathecal infusion chemotherapy for NSCLC-LM patients can cause a transient increase in ONSD and ICP, with the greatest effect at 1 hour after intrathecal infusion chemotherapy. RANO score is positively correlated with ICP ONSD before and after treatment, which can provide an important reference for evaluating the efficacy of intrathecal infusion chemotherapy.

Objective:To investigate the pharmacokinetics of cerebrospinal fluid pemetrexed following intrathecal injection chemotherapy in patients with leptomeningeal metastasis (LM) from lung adenocarcinoma and provide a basis for clinical intrathecal injection chemotherapy.Methods:A total of 21 patients with lung adenocarcinoma LM who underwent pemetrexed intrathecal injection chemotherapy via Ommaya capsule at Nanjing Drum Tower Hospital, Aiffilitated Hospital of Nanjing University Medical School from November 2019 to November 2022 were collected, and divided into 30, 40 and 50 mg groups ( n=10, n=4, n=7) according to pemetrexed dose. Cerebrospinal fluid was collected at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy, and day 8 of each cycle for three groups. Reversed phase high performance liquid chromatography was used to determine the drug concentration in cerebrospinal fluid, to clarify the drug-related pharmacokinetic parameters, and to compare the differences in pemetrexed concentration among groups. Finally, cerebrospinal fluid pemetrexed concentration changes were observed and compared after different intrathecal injection chemotherapy cycles. Results:There were statistically significant differences in cerebrospinal fluid drug concentrations of patients in three groups at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy (30 mg group: F=20.56, P<0.001; 40 mg group: F=27.06, P<0.001; 50 mg group: F=28.63, P<0.001), and there were statistically significant differences in the concentration of cerebrospinal fluid drugs in each dose group at 0.5, 1, 2, 4, 6 and 12 h compared to 0 h after intrathecal injection chemotherapy (all P<0.05). Compared to the 30 mg group, cerebrospinal fluid drug concentrations in the 50 mg group increased at 1, 2, 4, 6, 12 and 24 h after intrathecal injection chemotherapy, with statistically significant differences (all P<0.05). Pharmacokinetic analysis of cerebrospinal fluid pemetrexed showed that area under the concentration-time curve (AUC) 0-∞ of the 30, 40 and 50 mg groups were (5 696.12±283.32), (7 886.29±396.57), and (14 202.70±440.19) h·mg/L, respectively, with a statistically significant difference ( F=1 159.00, P<0.001) ; AUC 0-∞ increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; AUC 0-∞ increased in the 40 mg group compared to the 30 mg group ( P<0.05). The half-lives of three groups were (8.75±0.23), (11.29±0.59) and (16.42±1.23) h, respectively, with a statistically significant difference ( F=206.80, P<0.001) ; half-life was longer in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; half-life was longer in the 40 mg group compared to the 30 mg group ( P<0.05). The peak time of three groups were (1.55±0.10), (1.00±0.01), (1.43±0.11) h, respectively, with a statistically significant difference ( F=48.11, P<0.001) ; the peak time was shorter in the 40 and 50 mg groups compared to the 30 mg group (both P<0.05). Clearance of three groups were (7.02±2.46), (5.80±1.25) and (3.66±1.32) L/h, respectively, with a statistically significant difference ( F=6.02, P=0.009) ; clearance was decreased in the 50 mg group compared to the 30 mg group ( P<0.05). The peak concentration of three groups were (540.45±32.25), (820.75±46.47) and (1 014.78±64.96) mg/L, respectively, with a statistically significant difference ( F=207.70, P<0.001) ; peak concentration increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; peak concentration increased in the 40 mg group compared to the 30 mg group ( P<0.05). Cerebrospinal fluid drug concentrations were dynamically monitored after 4 cycles of intrathecal injection chemotherapy, in which cerebrospinal fluid pemetrexed concentrations in 30 mg group were (13.76±4.79), (11.41±7.08), (9.41±2.59) and (7.86±4.02) mg/L, respectively; 40 mg group were (14.45±6.59), (12.87±15.73), (11.24±2.48) and (9.09±3.38) mg/L, respectively; 50 mg group were (12.94±10.34), (9.72±7.62), (8.15±8.17) and (4.34±4.21) mg/L, respectively. There was a statistically significant difference in cerebrospinal fluid drug concentrations among different intrathecal injection chemotherapy cycles in 30 mg group ( F=4.04, P=0.016), and the cerebrospinal fluid drug concentration decreased in cycles 3 and 4 compared to cycle 1 (both P<0.05). There were no statistically significant differences in cerebrospinal fluid drug concentrations among different treatment cycles in 40 and 50 mg groups ( F=0.28, P=0.837; F=3.57, P=0.066) . Conclusion:Reversed phase high performance liquid chromatography method can effectively detect the pemetrexed concentration in cerebrospinal fluid; dynamic monitoring of cerebrospinal fluid pemetrexed concentration can provide a basis for the dosage and the treatment cycle of intrathecal injection chemotherapy in LM patients with lung adenocarcinoma.

Leptomeningeal metastasis (LM) is one of the most severe complications of non-small-cell lung cancer (NSCLC), and its incidence is increasing gradually with the progress of targeted therapies. There are currently no standard guidelines for the therapy of LM. Intrathecal chemotherapy is the mainstay of treatment for NSCLC patients with LM, but the optimal drug, administration route and mode, and dosage remain unclear. We report a case of LM from NSCLC, who received the intrathecal chemotherapy with pemetrexed by Ommaya reservoir after prior targeted therapies. This local treatment improved the quality of life, and obtained the clearing of CSF cytology and stable lesions of LM without any notable side effects. After confirmation of LM, the patient has survived 17 months until now. Here we report the first case to demonstrate the potential effectiveness of intrathecal pemetrexed by Ommaya reservoir for the treatment of LM of NSCLC, summarize the safety and effectiveness of intrathecal chemotherapy in combination with related literatures, and provide a new strategy for local treatment of LM in clinical.
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BACKGROUND: Tumor markers (TM) in cerebrospinal fluid (CSF) are useful for diagnosing leptomeningeal metastasis (LM). It has not been fully exploited the diagnostic possibilities of the CSF levels since the basic fact that the TM concentration of CSF depends strongly upon the serum levels as well as upon the condition of the blood brain barrier (BBB). To analyze the intrathecal TM synthesis and evaluate the integrity of BBB can be helpful for the definitive diagnosis of LM. Therefore, the aim of this study was to further explore the clinical value of intrathecal TM synthesis and BBB in the diagnosis for the lung cancer patients with LM. METHODS: Twenty-five lung cancer patients with LM and 57 patients with nonmalignant neurological diseases (NMNDs) admitted to Nanjing Drum Tower Hospital from December 2016 to March 2020 were included. We compared the integrity of BBB and intrathecal TM synthesis between two groups, analyzed the correlation of CSF TM between the detection and intrathecal synthesis, and evaluated serial CSF cytology, the integrity of BBB and intrathecal TM synthesis when intrathecal chemotherapy for one patient. RESULTS: Ninety-four percent LM patients showed the dysfunction of BBB, and all LM patients showed at least one intrathecal synthesized TM in CSF. In one patient, the CSF cytology was negative for the first time, but LM was eventually diagnosed based on the the intrathecal TM synthesis and positive CSF cytology of repeated lumbar puncture. In LM group, no correlation was observed between the detection and intrathecal synthesized TM in CSF. In the control group, only 3.5% (2/57) NMNDs patients had the dysfunction of BBB and no patients had intrathecal TM synthesis, both the differences of which were statistically significant (P<0.05). Finally, evaluating the CSF cytology, integrity of BBB and intrathecal TM synthesis can be used to assess the intracranial treatment effect. Moreover, intrathecal TM synthesis changes earlier than cytology. CONCLUSIONS The evaluation of intrathecal TM synthesis and integrity of BBB are novel clinical diagnostic tools. In addition, serial measurement of intrathecal synthesized TM may play an important role in monitoring efficacy of lung cancer patients with LM, which is worthy of further promotion and clinical application.