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BACKGROUND@#Drug resistance is the main cause of high mortality of lung cancer. This study was conducted to investigate the effect of folic acid (FA) on the resistance of non-small cell lung cancer (NSCLC) cells to Osimertinib (OSM) by regulating the methylation of dual specificity phosphatase 1 (DUSP1).@*METHODS@#The OSM resistant NSCLC cell line PC9R was establishd by gradually escalation of OSM concentration in PC9 cells. PC9R cells were randomly grouped into Control group, OSM group (5 μmol/L OSM), FA group (600 nmol/L FA), methylation inhibitor decitabine (DAC) group (10 μmol/L DAC), FA+OSM group (600 nmol/L FA+5 μmol/L OSM), and FA+OSM+DAC group (600 nmol/L FA+5 μmol/L OSM+10 μmol/L DAC). CCK-8 method was applied to detect cell proliferation ability. Scratch test was applied to test the ability of cell migration. Transwell assay was applied to detect cell invasion ability. Flow cytometry was applied to measure and analyze the apoptosis rate of cells in each group. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) method was applied to detect the expression level of DUSP1 mRNA in cells. Methylation specific PCR (MSP) was applied to detect the methylation status of the DUSP1 promoter region in each group. Western blot was applied to analyze the expression levels of DUSP1 protein and key proteins in the DUSP1 downstream mitogen-activated protein kinase (MAPK) signaling pathway in each group.@*RESULTS@#Compared with the Control group, the cell OD450 values (48 h, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of extracellular regulated protein kinases (ERK) were obviously increased (P<0.05); the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the DAC group were obviously increased (P<0.05); the apoptosis rate, the expression of p38 MAPK protein, the phosphorylation level of ERK, and the methylation level of DUSP1 were obviously reduced (P<0.05). Compared with the OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously increased (P<0.05). Compared with the FA+OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM+DAC group were obviously increased; the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously reduced (P<0.05).@*CONCLUSIONS@#FA may inhibit DUSP1 expression by enhancing DUSP1 methylation, regulate downstream MAPK signal pathway, then promote apoptosis, inhibit cell invasion and metastasis, and ultimately reduce OSM resistance in NSCLC cells.
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Humans , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Dual Specificity Phosphatase 1/pharmacology , Cell Proliferation , p38 Mitogen-Activated Protein Kinases/pharmacology , Methylation , Apoptosis , Cell Line, TumorABSTRACT
ObjectiveTo investigate the efficacy and safety of sofosbuvir/velpatasvir alone or in combination with ribavirin in Chinese patients with genotype 3B HCV/HIV infection. MethodsA total of 299 patients with genotype 3B HCV/HIV infection who attended The Third People’s Hospital of Kunming from January 2017 to December 2020 were enrolled and treated with sofosbuvir/velpatasvir alone or in combination with ribavirin for 12 weeks， and they were followed up for 12 weeks after drug withdrawal. The patients were evaluated in terms of sustained virologic response at 12 weeks after treatment （SVR12） and adverse reactions. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between two groups； the Agresti-Coull method was used to evaluate the 95% confidence interval （CI） of SVR12； univariate and multivariate non-conditional logistic regression analyses were used to investigate the influencing factors for SVR. ResultsThe 299 patients with genotype 3B HCV/HIV infection had a mean age of 43.92±6.84 years， among whom the male patients accounted for 77.3% （231/299）， the patients with liver cirrhosis accounted for 36.5% （109/299）， the patients with a history of antiviral therapy accounted for 13.4% （40/299）， and the patients receiving sofosbuvir/velpatasvir combined with ribavirin accounted for 27.8% （83/299）. The overall SVR was 87.0% （260/299） for all patients， and there was no significant difference in SVR12 between the patients receiving sofosbuvir/velpatasvir alone and those receiving sofosbuvir/velpatasvir combined with ribavirin （87.5% vs 85.5%， χ2=0.203， P=0.653）. There was a significant difference in SVR12 between the patients without liver cirrhosis and those with liver cirrhosis （90.0% vs 81.7%， χ2=4.256， P=0.039）， and the patients receiving antiviral therapy for the first time had a significantly higher SVR12 than the treatment-experienced patients （93.4% vs 45.0%， χ2=71.670， P<0.001）. The univariate and multivariate logistic regression analyses showed that platelet count （odds ratio ［OR］=0.957， 95%CI： 0.931 — 0.984， P=0.002）， liver stiffness measurement （OR=1.446， 95%CI： 1.147 — 1.822， P=0.002）， and experience in treatment （OR=13.807， 95%CI： 2.970 — 64.174， P=0.001） were independent influencing factors for SVR in patients with genotype 3B HCV/HIV infection. There were 41 cases of serious adverse events， all of which occurred within 2 weeks after antiviral therapy， and 28 cases were resolved without drug withdrawal or active treatment， while 13 cases were not resolved after active treatment and were resolved after the antiviral drugs were stopped for 2 — 5 days， with no similar reactions observed when the drugs were used again after remission. ConclusionSofosbuvir/velpatasvir alone or in combination with ribavirin has relatively good efficacy and safety in patients with genotype 3B HCV/HIV infection.
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AIM: To quantify early changes of macular capillary parameters in type 2 diabetic patients using optical coherence tomography angiography(OCTA).METHODS: Retrospective case study. A total of 49 healthy subjects, 52 diabetic patients without retinopathy(noDR)patients, and 43 mild nonproliferative diabetic retinopathy(mNPDR)patients were recruited. Capillary perfusion density, vessel length density(VLD), and average vessel diameter(AVD)were calculated from macular OCTA images(3 mm×3 mm)of the superficial capillary plexus after segmenting large vessels and the deep capillary plexus. Parameters were compared among control subjects, noDR, and mNPDR patients. The area under the receiver operating characteristic curve estimated the abilities of these parameters to detect early changes of retinal microvascular networks.RESULTS: Significant differences were found in the VLD and AVD among the three groups(P&#x003C;0.001). Compared with the control group, the noDR group had significantly higher AVD(P&#x003C;0.05). VLD of both layers in patients of mNPDR group was significant decreased compared with that of noDR group(all P&#x003C;0.01). Deep AVD had a higher area under the curve(AUC)of 0.796 than other parameters to discriminate the noDR group from the healthy group. Deep AVD had the highest AUC of 0.920, followed by that of the deep VLD(AUC=0.899)to discriminate the mNPDR group from the healthy group.CONCLUSIONS: NoDR patients had wider AVD than healthy individuals and longer VLD than mNPDR patients in both layers. When compared with healthy individuals, deep AVD had a stronger ability than other parameters to detect early retinal capillary impairments in noDR patients.
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Objective The volume and cortical thickness of gray matter in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) were compared and analyzed by voxel⁃based morphometry (VBM) and surface⁃based morphometry (SBM), and the differences in the structural changes of gray matter in the two diseases were discussed. Methods A total of 21 MS patients, 16 NMO patients and 19 healthy controls were scanned by routine MRI sequence. The data were processed and analyzed by VBM and SBM method based on the statistical parameter tool SPM12 of Matlab2014a platform and the small tool CAT12 under SPM12. Results Compared with the normal control group (NC), after Gaussian random field (GRF) correction, the gray matter volume in MS group was significantly reduced in left superior occipital, left cuneus, left calcarine, left precuneus, left postcentral, left central paracentral lobule, right cuneus, left middle frontal, left superior frontal and left superior medial frontal (P<0. 05). After family wise error (FWE) correction, the thickness of left paracentral, left superiorfrontal and left precuneus cortex in MS group was significantly reduced (P<0. 05). Compared with the NC group, after GRF correction, the gray matter volume in the left postcentral, left precentral, left inferior parietal, right precentral and right middle frontal in NMO group was significantly increased (P<0. 05). In NMO group, the volume of gray matter in left middle occipital, left superior occipital, left inferior temporal, right middle occipital, left superior frontal orbital, right middle cingulum, left anterior cingulum, right angular and left precuneus were significantly decreased (P<0. 05). Brain regions showed no significant differences in cortical thickness between NMO groups after FWE correction. Compared with the NMO group, after GRF correction, the gray matter volume in the right fusiform and right middle frontal in MS group was increased significantly(P<0. 05). In MS group, the gray matter volume of left thalamus, left pallidum, left precentral, left middle frontal, left middle temporal, right pallidum, left inferior parietal and right superior parietal were significantly decreased (P<0. 05). After FWE correction, the thickness of left inferiorparietal, left superiorparietal, left supramarginal, left paracentral, left superiorfrontal and left precuneus cortex in MS group decreased significantly (P<0. 05). Conclusion The atrophy of brain gray matter structure in MS patients mainly involves the left parietal region, while NMO patients are not sensitive to the change of brain gray matter structure. The significant difference in brain gray matter volume between MS patients and NMO patients is mainly located in the deep cerebral nucleus mass.
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ObjectiveTo explore the impact of autonomic nerve function on motor function in patients with post-stroke depression (PSD) from the perspective of regional homogeneity (ReHo). MethodsFrom January to December, 2020, a total of 60 inpatients and outpatients with cerebral infarction in the Affiliated Brain Hospital of Nanjing Medical University were divided into control group (n = 30) and PSD group (n = 30). Two groups were assessed using Fugl-Meyer Assessment (FMA), modified Barthel Index (MBI) and Hamilton Depression Scale (HAMD). Heart rate variability (HRV) was measured. Ten patients in each group were selected randomly to undergo resting state functional magnetic resonance imaging (rs-fMRI) to calculate ReHo. ResultsAll HRV indices were lower in PSD group than in the control group (|t| > 2.092, P < 0.05). In PSD group, FMA and MBI scores showed positive correlations with 24-hour standard deviation of normal-to-normal R-R intervals (SDNN), the root mean square of successive differences between normal heartbeats over 24 hours (RMSSD), the percentage of differences between adjacent normal R-R intervals over 24 hours that were greater than 50 ms (PNN50), total power (TP), very low frequency power (VLF) and low frequency power (LF) (r > 0.394, P < 0.05), and showed negative correlations with HAMD scores (|r| > 0.919, P < 0.001). HAMD scores in PSD group were negatively correlated with SDNN, RMSSD, PNN50, TP and VLF (|r| > 0.769, P < 0.001). Compared with the control group, the ReHo increased in PSD group in the right rectus gyrus (142 voxels, t = 6.575), the left medial and paracingulate gyri (204 voxels, t = 4.925) (GRF correction, P-Voxel < 0.005，P-Cluster < 0.05); and reduced in the right cerebellum (191 voxels, t = -6.487), the left middle temporal gyrus (140 voxels, t = -5.516), and the left precentral gyrus (119 voxels, t = -4.764) (GRF correction, P-Voxel < 0.005，P-Cluster < 0.05) in PSD group. ConclusionAutonomic nerve function is related to motor dysfunction in patients with PSD. The modulation of emotional, cognitive and motor brain regions by the autonomic nervous system may play a role in influencing the motor function in patients with PSD.
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ObjectiveTo qualitatively analyze the chemical constituents and their tissue distribution in Lujiao formula based on ultra performance liquid chromatography-quadrupole-electrostatic field orbitrap high resolution mass spectrometry（UPLC-Q-Orbitrap-MS）. MethodThe separation was performed on an ACQUITY UPLC® BEH C18 column（2.1 mm×100 mm， 1.7 μm） with the mobile phase of 0.1% formic acid aqueous solution（A）-methanol（B） in a gradient elution（0-2 min， 4%B； 2-6 min 4%-12%B； 6-38 min， 12%-70%B； 38-38.5 min， 70%B； 38.5-39 min， 70%-95%B； 39-43 min， 95%B； 43-43.1 min， 95%-4%B； 43.1-45 min， 4%B）， the flow rate was 0.3 mL·min-1 with the column temperature of 40 ℃ and the injection volume of 5 µL. The data were acquired by an electrospray ionization（ESI） in the full scanning mode of positive and negative ions， the scanning rang was set at m/z 100-1 500， the collision energies were 10， 20， 40 eV. Retention time， precise relative molecular mass and secondary mass spectrometry fragment ions were used to identify the compounds in Lujiao formula and analyze their tissue distribution， combing with self-established database and comparing with standard substances and published literature data. ResultA total of 260 compounds， including 156 flavonoids， 43 terpenoids， 18 coumarins， 13 organic acids， 7 phenylethanoids， 7 alkaloids and 16 others， were identified or hypothesized from Lujiao formula， 68 of which were identified by comparison with standard substances. And the results of tissue distribution showed that 100， 143， 129 and 126 prototype components were detected in blood， heart， liver and kidney， respectively. ConclusionThe chemical composition of Lujiao formula and their tissue distribution were systematic analyzed， which can provide reference for the quality control， clinical application， pharmacokinetics and pharmacodynamic material basis of Lujiao formula and its medicinal materials.
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Yigongsan is derived from Xiaoer Yaozheng Zhijue written by QIAN Yi in the Northern Song dynasty， which is the No. 3 formula in the Catalogue of Ancient Famous Classical Formulas（The Second Batch of Pediatrics） released by the National Administration of Traditional Chinese Medicine（TCM） in September 2022， and it can be developed as a class 3.1 new TCM drug. By referring to ancient medical books and modern literature， this study conducted herbal textual research on Yigongsan from five aspects， including historical evolution， origin and processing， dosage conversion， usage and preparation methods， and functional application， then formed the key information table of this formula， in order to provide reference for the development of reference samples and preparations of Yigongsan. Based on the results of the study， it is recommended that Panax ginseng should be removed the basal part of stem（rhizoma）， Poria cocos should be removed the peel， Citrus reticulata should be cut into shreds and Glycyrrhiza uralensis should be used. According to 4.13 g/Qian（钱）， 1 g/slice for ginger， 3 g for each jujube and 300 mL/Zhan（盏）， the doses of Ginseng Radix， Poria， Atractylodis Macrocephalae Rhizoma， Glycyrrhizae Radix et Rhizoma， Citri Reticulatae Pericarpium， Zingiberis Rhizoma Recens， Jujubae Fructus were 1.652， 1.652， 1.652， 1.652， 1.652， 5， 6 g， and the total amount was 19.26 g. The decocting method was to crush the medicinal materials into fine powder with 50-80 mesh， add 300 mL of water and decoct to 210 mL for each dose， then remove the dregs and take it warmly. This formula was recorded in ancient books as the main treatment for the cold-deficiency of spleen and stomach， and Qi stagnation in children with vomiting and diarrhea and lack of appetite. It has been flexibly applied by later generations of physicians， and is often used to treat anorexia， inflammation of the digestive tract， diarrhea and other diseases in children.
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Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APCmin/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.
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Objective@#To understand the current status of obesity and high blood pressure (HBP) comorbidity and their multidimensional influencing factors in children aged 7-12 years in Xiamen, so as to provide reference basis for subsequent preventive measures.@*Methods@#Based on the baseline survey of the Xiamen pubertal development cohort in 2017, a total of 4 798 primary school students from second to sixth grade were selected in the study by cluster random sampling method. And physical examination and questionnaires were conducted. The Logistic regression was used to screen potential variables for obesity combined with HBP. A multivariate Logistic regression model was used to analyse the factors influencing obesity combined with HBP.@*Results@#About 9.15 % children were found with obesity and 11.65% with HBP. The rate of obesity combined with HBP was 3.00% in boys and 1.80 % in girls. The rate of HBP was 8.28% in normal weight children and 26.88% in obese children. Multivariate Logistic regression models showed that consumption of sugary drinks at least once a week ( OR =2.50), daily consumption of salted or pickled vegetables ( OR =4.52), family history of obesity ( OR =3.09) were positively associated with obesity combined with HBP ( P <0.05). Girls ( OR =0.53), consumption of highenergy snacks at least once a week ( OR =0.40) and adequate physical activity ( OR =0.58) were negatively associated with comorbidity of obesity and HBP ( P <0.05).@*Conclusion@#Gender differences in comorbidity burden of obesity and HBP exist among children aged 7-12 years in Xiamen. Dietary behaviour and exercise behaviour are the main dimensions influencing the comorbidity of obesity and HBP. Prevention and control of obesity and HBP in children should be based on multiple dimensions, including diet and exercise behavioural environment, to prevent early the occurrence for comorbidity of obesity and HBP in children.
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Objective@#To understand the early life factors that influence cardiometabolic risk factors in children and adolescents, so as to provide effective measures to curb cardiometabolic risk factors such as hypertension and diabetes in children and adolescents.@*Methods@#Data were sourced from the 2020 follow up survey of the Xiamen Adolescent Development Cohort. The study involved 1 197 subjects for whom completed anthropometric examination and blood biochemistry testing data, as well as early life data. Early life and sociodemographic data were obtained through questionnaire surveys, while cardiometabolic indicator data were sourced through physical examinations and blood testing. Logistic regression analysis was performed to analyze the impact of early life factors on the cardiometabolic risk factors after adjusting for gender, age, and family history.@*Results@#The prevalence rate of cardiometabolic risk factors clustering in children and adolescents in Xiamen was 17.96%, with boys (26.67%) reporting higher rates than girls (9.64%), and the difference was statistically significant ( χ 2=57.69, P <0.01). For every additional early life risk factor, the risk factors of obesity increased 0.35 times ( OR=1.35, 95%CI=1.03-1.78, P <0.05). Post term pregnancy may be a primary early life risk factors for cardiometabolic risk factors, and it was associated with an increased risk of cardiometabolic risk factors clustering (OR=2.45, 95% CI =1.11-5.41) and high triglycerides ( OR=3.25, 95%CI =1.39-7.61)( P <0.05).@*Conclusion@#Increased cardiometabolic risk factors in youth is associated with early life adverse factors. It is crucial to pay greater attention to post term pregnancy as an early life factor and to consider obesity as a cardiometabolic risk factors. Controlling early life adverse factors is important for the prevention of cardiovascular disease.
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ObjectiveTo investigate the efficacy of Huangqintang on mouse models of colitis-associated colon cancer （CAC） and explore the mechanism of Huangqintang in regulating immune function and inflammatory response， inhibiting abnormal cell proliferation， and delaying or inhibiting CAC formation in CAC. MethodC57BL/6J mice were randomly divided into a normal group， model group， mesalazine group， and high- and low-dose Huangqintang groups according to body weight， with 12 mice in each group. Except for the normal group， the rest of the mice were given two intraperitoneal injections of 10 mg·kg-1 azomethane （AOM） and allowed to drink 1.5% dextran sodium sulfate （DSS） freely for seven days and water normally for two weeks. Then， two cycles of ''DSS-drinking water'' were repeated. During the administration of DSS， mice in the normal group and model group were given gavage in equal doses of pure water. Mice in the mesalazine group were given 150 mg·kg-1·d-1 mesalamine suspension for gavage， and mice in the high- and low-dose Huangqintang groups were given 18 and 9 g·kg-1·d-1 Huangqintang for gavage， respectively. Each group was given one dose daily until the end of three cycles. After the intervention， the body weight， colon length， and number of colon tumors in each group were measured， and disease activity index （DAI） scores were performed. The serum contents of interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， interleukin-10 （IL-10）， and gastrointestinal tumor marker carbohydrate antigen-199 （CA199） were detected by enzyme linked immunosorbent assay （ELISA）. The colonic lesions were observed by hematoxylin-eosin （HE） staining. The expression of proliferative cell-associated antigen （Ki67） was observed by immunohistochemistry. The expression of T lymphocyte subsets （CD3+， CD4+， CD8+， and CD49b+） in mouse plasma was detected by flow cytometry. Fluorescein isothiocyanate-D （FITC-D） content in mouse serum was detected by fluorescent labeling method. The Western blot method was used to detect the expression of Cyclin D1， cyclin-dependent kinase 2 （CDK2）， cyclin-dependent kinase 4 （CDK4）， and tightly junction-related Occludin and Claudin-1. ResultCompared with the normal group， the body weight of mice in the model group decreased. DAI score increased significantly， and the colon became shorter. Pro-inflammatory factors such as IL-6， TNF-α， and IL-1β increased， and IL-6 and TNF-α were significantly increased （P<0.05）. The inflammatory factor IL-4 （P<0.05） and IL-10 were significantly reduced， and the tumor marker CA199 was significantly increased （P<0.01）. HE staining showed that colon lesions， intestinal mucosal epithelial defects with a large number of inflammatory infiltrates， serious crypt structure damage， and glandular arrangement disorder were observed in the model group. Ki67 positive granules were expressed in large areas of colonic tissue. The serum CD4+ and CD4+/CD8+ of mice in the model group decreased significantly （P<0.05）， and CD8+ increased significantly （P<0.05）. The plasma content of FITC-D in the model group was significantly increased （P<0.05）， and the expression of Cyclin D1， CDK2， and CDK4 proteins in colon tissue was significantly increased （P<0.05， P<0.01）. In addition， the expression of Occludin and Claudin-1 was significantly decreased. Compared with the model group， the body weight of mice in the mesalazine group and the high- and low-dose Huangqintang groups increased. DAI score decreased， and the colon became longer. IL-6， TNF-α， and IL-1β expression decreased （P<0.05， P<0.01）， but there was no significant change in IL-4 and IL-10. The content of CA199 was significantly reduced （P<0.05）， and the colomatoid lesions and inflammatory infiltrates were reduced in the mesalazine group and the Huangqintang group. The crypt structure damage was lighter， and the positive expression of Ki67 was reduced. CD4+， CD4+/CD8+， and CD49b+ increased， and the difference was not statistically significant. FITC-D content decreased （P<0.05）. The expression of Cyclin D1， CDK2， and CDK4 decreased （P<0.05， P<0.01）， and Claudin-1 and Occludin protein expression increased in the high-dose Huangqintang group （P<0.05）. ConclusionHuangqintang has a certain delay and inhibitory effect on AOM/DSS-induced inflammatory cancer transformation， and its mechanism of action may be related to regulating immune function and inflammatory response， inhibiting the release of pro-inflammatory factors， repairing damaged intestinal barriers， inhibiting abnormal proliferation of colon cells， and intervening in the formation and development of CAC colon tumors.
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Objective:To investigate the factors influencing the prognosis of hepatitis B-related hepatocellular carcinoma treated with programmed death receptor 1 (PD-1) inhibitors, and to construct a prognostic nomogram model for these patients and evaluate its clinical significances.Methods:The clinical data of 121 patients with hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors at the First Affiliated Hospital of Xinxiang Medical College from July 2018 to July 2021 were retrospectively analyzed. Follow-up was performed from the beginning of PD-1 inhibitor use, and the Kaplan-Meier method was used to analyze the overall survival of patients. The variables screened by the univariate Cox proportional hazards model analysis and variables clinically believed to be related to the prognosis were included in the multivariate Cox proportional hazards model for overall survival, and the stepwise regression method was used to screen the independent factors influencing overall survival. Based on the independent influencing factors of overall survival, R 3.5.1 software was used to construct a prognostic nomogram model for overall survival of hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors. Calibration curve was used to the consistency of model prediction and practice. The Harrell consistency index and receiver operating characteristic (ROC) curve (with imaging diagnosis as the gold standard) were used to analyze the efficacy of model in predicting the 1-year and 2-year overall survival rates.Results:The median follow-up time of 121 patients was 12.40 months, and the median overall survival time was 14.30 months, with overall survival rates of 82.60% and 62.30% at 6 and 12 months. Multivariate Cox regression analysis showed that albumin (ALB) ( HR = 0.946, 95% CI 0.901-0.992), international normalized ratio (INR) ( HR = 32.034, 95% CI 5.046-203.362), aspartate aminotransferase (AST) ( HR = 1.010, 95% CI 1.007-1.012) were independent influencing factors for overall survival of patients. According to the three factors, a prognostic nomogram model for hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors was constructed. The slope of the calibration curve of the model predicting 1-year and 2-year overall survival rates was close to 1. The Harrell consistency index of the nomogram model was 0.809 (95% CI 0.760-0.858). ROC curve analysis showed that the area under the curve (AUC) of the nomogram model predicting 1-year and 2-year overall survival rates of patients was 0.794 (95% CI 0.744-0.887, P < 0.001) and 0.791 (95% CI 0.708-0.860, P = 0.002). Conclusions:ALB, INR and AST are the influencing factors of prognosis of hepatitis B-related hepatocellular carcinoma patients treated with PD-1 inhibitors, and the nomogram model constructed based on prognostic influencing factors has a good effect on predicting the 1-year and 2-year overall survival rates of patients, which can be used to screen the population suitable for immunotherapy and is conducive to the clinical formulation of individualized and precise treatment plans.
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Objective:To observe any effect of combining low-frequency transcranial magnetic stimulation (rTMS) with interactive virtual scenario training on the recovery of upper limb motor function after a stroke.Methods:Ninety stroke survivors were randomly divided into a pseudo-rTMS group, an rTMS group and a combination group, each of 30. In addition to basic medication, conventional rehabilitation and nursing care, the pseudo-rTMS, rTMS and combination groups received either sham rTMS treatment, 1Hz rTMS or virtual situational interaction along with 1Hz rTMS 5 days a week for 4 weeks. Before and after the 4 weeks their motor evoked potentials, cortical latency and central motor conduction time were measured, and surface electromyography was applied to the affected biceps brachii and triceps brachii. Meanwhile, the National Institutes of Health Stroke Scale, the Fugl-Meyer upper extremity assessment and the modified Barthel index were employed to assess the degree of neurological deficit, upper extremity motor function and ability in the activities of daily living (ADL).Results:After the 4-week intervention, a significant improvement was observed in all of the outcome measurements with all three groups. At that time the average scores of the rTMS group were significantly better than the pseudo-rTMS group′s averages but the average scores of the combination group were significantly better than those of either of the other two groups.Conclusion:Repeated application of low-frequency transcranial magnetic stimulation combined with virtual scenario interactive training can effectively improve the upper limb motor function and ADL performance of stroke survivors, and relieve the symptoms of neurological deficit. The combined therapy is worthy of application in clinical practice.
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Objective:To analyze the status of neonatal respiratory distress syndrome (RDS) management in 10 hospitals in Northwest China over the past five years and to investigate the strategies for improving the prevention and treatment of RDS.Methods:This retrospective study involved premature infants with RDS who were admitted to the neonatal intensive care units (NICU) of 10 hospitals (six in Shaanxi Province, three in Gansu Province, and one in Xinjiang Uygur Autonomous Region) of the Northwest China Neonatal Collaborative Group within 3 d after birth from January 1 to December 31, 2016, and from January 1 to December 31, 2021. Basic information, perinatal condition, treatment approaches, complications, and prognosis of the patients were compared. T-test, rank sum, and Chi-square tests were used for statistical analysis. Result:(1) This study enrolled 322 premature infants with RDS in 2016 and 349 in 2021. Premature infants at the gestational age of 30 to 33 weeks were mainly affected, and the majority were male [64.3% (207/322) and 57.3% (200/349)]. The average maternal age in 2021 was older than that in 2016 [(30.6±4.8) years vs (28.6±5.4) years, t=24.02, P<0.001], and the proportion of women at advanced maternal age was also higher in 2021 [19.2% (67/349) vs 12.4% (40/322), χ2=4.18, P<0.05]. (2) The proportions of pregnancies conceived with assisted reproductive technologies [11.7% (41/349) vs 1.9% (6/322), χ2=25.12], underwent routine prenatal examinations [58.5% (204/349) vs 30.4% (98/322), χ2=53.33], exposed to steroids [62.2% (217/349) vs 28.6% (92/322), χ2=82.58] and delivered by cesarean section or elective cesarean section [73.6% (257/349) vs 51.6% (166/322), χ2=35.06; 24.1% (84/349) vs 6.5% (21/322), χ2=39.07], as well as the ratio of cesarean scar pregnancy [7.4% (26/349) vs 3.4% (11/322), χ2=5.23] were all higher in 2021 than those in 2016 (all P<0.05). Moreover, the incidence of fetal distress [30.1% (105/349) vs 20.2% (65/322), χ2=8.68], gestational hypertension [24.6% (86/349) vs 13.0% (42/322), χ2=14.59], premature rupture of membranes [16.0% (56/349) vs 10.2% (33/322), χ2=4.89], meconium-stained amniotic fluid [12.6% (44/349) vs 5.6% (18/322), χ2=9.83], placental abruption [10.3% (36/349) vs 5.3% (17/322), χ2=5.84], gestational diabetes mellitus [10.3% (36/349) vs 1.6%(5/322), χ2=22.41], chorioamnionitis [4.6%(16/349) vs 0.9% (3/322), χ2=8.12], thyroid dysfunction [4.3% (15/349) vs 0.6% (2/322), χ2=7.88] and heart disease [4.3% (15/349) vs 0.3% (1/322), χ2=9.17] were higher in 2021 than in 2016 (all P<0.05). (3) In 2021, the rate of pulmonary surfactant (PS) usage, the dosage of porcine PS, and the proportion of bovine PS usage were all significantly higher than those in 2016 [73.6% (257/349) vs 67.1% (216/322), χ2=11.62; (178.5±38.0) mg/kg vs (165.2±42.8) mg/kg, t=7.85; 47.9% (123/257) vs 19.4% (42/216), χ2=41.72; all P<0.01]. No significant difference in the incidence of intubation-surfactant-extubation (INSURE), early PS administration (≤2 h after birth), or the arterial blood gas values before and after PS treatment was found between the cases enrolled in 2021 and 2016. The duration of antibiotic treatment [7.0 d (5.0-14.0 d) vs 5.0 d (1.0-8.0 d), Z=7.55] and assisted ventilation [144 h (81-264 h) vs 73 h (47-134 h), Z=8.20] and the median hospital stay [24 d(14-42 d) vs 16 d (10-25 d), Z=6.74] were significantly longer in 2021 than in 2016 (all P<0.01). More patients required nasal intermittent positive pressure ventilation [29.6% (100/338) vs 1.0% (3/306), χ2=97.81] and conventional ventilation [42.6% (144/338) vs 30.1% (92/306), χ2=10.87] in 2021 as compared with those five years ago (both P<0.01). (4) In 2021, the incidence of patent ductus arteriosus [15.5% (54/349) vs 6.2% (20/322), χ2=63.40], bronchopulmonary dysplasia [9.2% (32/349) vs 2.8% (9/322), χ2=12.88], persistent pulmonary hypertension [5.4% (19/349) vs 0.6% (2/322), χ2=12.85], periventricular leukomalacia [4.3% (15/349) vs 1.2% (4/322), χ2=7.52] and pneumothorax [3.4% (12/349) vs 0.3% (1/322), χ2=9.68] increased as compared with those in 2016 (all P<0.05), while the incidence of nosocomial infection decreased significantly [7.4% (26/349) vs 19.6% (63/322), χ2=21.37, P<0.001]. (5) The cure rate of premature infants with RDS was 70.8% (247/349) in 2021, which was significantly higher than that in 2016 [56.2% (181/322), χ2=15.37, P<0.001]. Moreover, the rate of withdrawing treatment and the total mortality rate was lower in 2021 than in 2016 [7.7% (27/349) vs 14.3% (46/322), χ2=7.41; in-hospital: 1.4% (5/349) vs 5.6% (18/322), χ2=8.74; out of hospital: 8.3% (29/349) vs 13.7% (44/322), χ2=4.96; all P<0.05]. Conclusions:The clinical management of RDS in premature infants in the involved hospitals has been improved. However, there is room for improvement in prenatal examinations.
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Objective:To summarize the clinical features and gene mutation characteristics of a child with mitochondrial enoyl-CoA hydratase short chain 1 deficiency (ECHS1D) caused by enoyl-CoA hydratase short chain 1 ( ECHS1) gene mutation. Methods:The clinical characteristics and genetic test results of a child with ECHS1D who visited the Department of Neurology of Xuzhou Children′s Hospital in January 2021 were retrospectively analyzed, and the clinical features of the disease were also reviewed by searching relevant domestic and foreign literature.Results:The child was a 6 months and 4 days old male, with acute onset, the main clinical manifestation being limb movement disorder after admission. The child had slow motor development, his head was still upright and cannot turn over, the child also cannot sit alone, follow up and make a laugh, and the muscle tension of limbs was increased. The child′s blood lactate was increased to 6.2 mmol/L, which suggested metabolic acidosis, and magnetic resonance imaging (MRI) of the head showed abnormal signals in the basal ganglia on both sides, abnormal enhancement of the meninges of the left cerebral hemisphere. Whole exome sequencing revealed that the child had compound heterozygous mutations in ECHS1 gene, c.563C>T (p.A188V) and c.5C>T (p.A2V), respectively. The child′s father carried c.563C>T mutation, the mother carried c.5C>T mutation, all of which were missense mutations. Conclusions:ECHS1 gene mainly has missense mutations, most of which are compound heterozygous mutations, and a few are homozygous mutations. The ECHS1D caused by ECHS1 gene mutation often affects infants and young children. MRI suggests abnormal signals in the basal ganglia; for cases with the above clinical manifestations and abnormal signals in the basal ganglia on MRI, genetic testing should be considered to confirm the diagnosis.
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Objective:To compare Da-vinci robotic surgical system with laparoscopic surgery for the repair of hiatal hernia.Methods:The clinical data of 115 patients undergoing minimally invasive Nissen fundoplication at the Department of Hernia and Abdominal Wall Surgery, the Affiliated Hospital,Xuzhou Medical University from Dec 2019 to May 2022 were retrospectively studied. After propensity score matching (PSM), 46 cases in each group were included:Robot-assisted surgery (RS group) and laparoscopic surgery (LS group). Postoperative complications were collected and GERD Questionnaire (GERDQ) were used as the standard in evaluation of the results.Results:Patients in RS group had less intraoperative bleeding ( P<0.001), shorter postoperative gastrointestinal recovery time ( P<0.001), and shorter postoperative hospital stay ( P=0.002). The LS group had a shorter operative time ( P<0.001) and lower total hospital cost ( P<0.001). GERD-Q scores decreased significantly in both groups at 3 and 6 months postoperatively compared with preoperative scores ( P<0.001). There was no statistically significant difference between the two groups in the incidence of postoperative complications ( P>0.05). No recurrence was seen in both groups during postoperative follow-up. Conclusion:Da-vinci robot-assisted repair of hiatal hernia is as safe and feasible as laparoscopic procedures, with less intraoperative trauma and quicker, earlier recovery.
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Objective:To explore the association between dietary patterns and the incidence of type 2 diabetes mellitus(T2DM), so as to provide insights for the prevention and management of T2DM.Methods:Participants were recruited from the " The Tianjin Chronic Inflammation and Health Cohort Study(TCLSIH)" cohort study from 2013 to 2018, who had completed the modified semiquantitative food frequency questionnaire(FFQ) and blood glucose testing( n=26 425), free of cardiovascular disease, cancer, or diabetes at baseline. The relevant information collected includes food frequency, blood glucose concentration, and other confounding factors. In this study, the correlation between dietary patterns and T2DM was tested using Cox proportional risk regression model, and the gender stratification analysis and body mass index stratification analysis of different gender groups were carried out. All statistical analysis was performed using SAS 9.3 software. Results:The age of all participants was (41.0±11.5)years, and the cumulative incidence was 3.84% for T2DM. The cumulative incidence of T2DM in male population was 5.29%, while that in female population was 2.16%. There were significant differences in the incidence of T2DM among different genders( P <0.001). The multivariable-adjusted hazard ratios( HR) and corresponding 95% CI of T2DM across the plant-based dietary pattern score were 1.09(95% CI 0.91-1.31), 0.80(95% CI 0.66-0.97), and 0.76(95% CI 0.62-0.94; Ptrend =0.010). Moreover, no statistically significant differences were observed between animal and traditional northern Chinese diets with the incidence of T2DM. Conclusions:The plant-based dietary patterns were associated with substantially lower risk of developing T2DM, and there were no significant association between animal and traditional northern Chinese dietary patterns with T2DM. Plant-based dietary patterns characterized by a variety of fruit, leeks, onions, seaweed may be beneficial to the prevention and control of T2DM.
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Objective:To evaluate the relationship between intestinal microbiota heterogeneity and acquired myasthenia in septic mice.Methods:Eighty SPF healthy male C57BL/6 mice, weighing 18-20 g, aged 6-8 weeks, were included. Forty mice were selected to prepare a sepsis model by intraperitoneal injection of lipopolysaccharide (LPS) 10 mg/kg. Sepsis-sensitive mice (state of dying or even death within 24 h after developing the model) and sepsis-resistant mice (survival for 7 days and recovery) were screened. The feces from donor mice were collected to make fecal bacteria fluid. Forty mice were selected and divided into 4 groups ( n=10 each) by the random number table method: control group (C group), antibiotic group (ABX group), resistant group (Res group), and sensitive group (Sen group). Group C received no treatment. In ABX group, compound antibiotics were given by intragastric gavage once a day for 5 consecutive days. In Res group, the fecal solution from sepsis-resistant mice 150 μl was given by gavage once a day for 3 consecutive days starting from 5 days after gavage administration of compound antibiotics, and then LPS 15 mg/kg was intraperitoneally injected. In Sen group, the fecal solution from sepsis-sensitive mice was given by gavage for 3 days (using the same method as previously described in Res group) starting from 5 days after gavage administration of compound antibiotics, and then LPS 15 mg/kg was intraperitoneally injected. The severity of sepsis was assessed and scored at 24 h after developing the model. The four limb grip strength was measured after fecal bacteria transplantation and at 24 h after developing the sepsis model. The Compound Muscle Action Potential (CMAP) of the gastrocnemius was measured at 24 h after developing the sepsis model. Then blood samples were collected for determination of the levels of interleukin-1 (IL-1), IL-6 and tumor necrosis factor α (TNF-α) in serum by enzyme-linked immunosorbent assay. The tissues of anterior tibial muscle and gastrocnemius muscle were obtained for determination of the expression of muscle-specific ring finger protein 1 (MuRF-1) and muscle atrophy box F protein (MAFbx) by Western blot. The diameter and cross-sectional area of gastrocnemius muscle fibers were measured after HE staining. The feces of mice were collected at 3 days after fecal bacteria transplantation, and DNA was extracted from mouse fecal samples for 16S rDNA sequencing and untargeted metabolomics analysis. Results:Compared with C group, the score for severity of sepsis was significantly increased, the four limb grip strength was decreased after developing the sepsis model, the serum IL-6 concentration was increased, and the diameter and cross-sectional area of gastnemius muscle fibers were decreased ( P<0.05), and no statistically significant changes were found in the other parameters in Res group, and no statistically significant changes were found in the indexes mentioned above in ABX group ( P>0.05). Compared with C group and Res group, the score for severity of sepsis was significantly increased, the four limb grip strength was decreased, the latency of CMAP was prolonged, and the amplitude of CMAP was decreased, the serum concentrations of IL-1, IL-6 and TNF-α were increased, the diameter and cross-sectional area of gastrocnemius muscle fibers were decreased, and the expression of MuRF-1 and MAFbx in anterior tibial muscle was up-regulated after developing the sepsis model in Sen group ( P<0.05). 16S rDNA sequencing of intestinal flora: Compared with Sen group, no significant change was found in Chao1 index, Good-coverage index and Simpson index in Res group ( P>0.05), Shannon index was increased ( P<0.05), and no significant change was found in β diversity in Res group ( P>0.05). LDA analysis showed that f_Akkermarisiaceae, o_Verrucomicrobiales, g_Akmansia, c_Verrucomicrobiae and p_Verrucomicrobiota were significantly enriched in Sen group, and g_Enterococcus and f_Enterococcaceae were significantly enriched in Res group ( P<0.05). Nontargeted metabolic analysis: The metabolite profiles in Res group and Sen group suggested that the model was well developed (R2Y>Q2Y). Compared with Sen group, 90 metabolites was significantly up-regulated and 88 down-regulated, significantly up-regulated metabolic substances including vitamin K1, gamma-tocopherol, and taurine in Res group ( P<0.05). The differential metabolite KEGG enrichment pathway included 2-oxocarboxylic acid metabolism and ubiquinone and other terpenoid-quinone biosynthesis ( P<0.05). Conclusions:Intestinal flora heterogeneity may be involved in the pathogenesis of acquired myasthenia in septic mice.
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Objective:To investigate the relationship between the number of epithelial progenitor cells(EPCs)in peripheral blood and blood parameter values in order to clarify the relationship between peripheral blood EPCs and the length of survival in elderly individuals aged 75 and beyond.Methods:Analysis was conducted on 114 individuals ≥75 years recruited from the Department of Geriatrics, Tianjin Medical University General Hospital in 2008.Clinical data were collected with December 31, 2020 as the end of the follow-up.Associations between peripheral blood EPC numbers, blood parameter values and all-cause mortality were analyzed.Results:In low and high EPC groups based on orthogonal partial least squares-discriminant analysis(OPLS-DA), D-Dimer was found to be a potential classification marker[the variable importance in projection(VIP)=4.750], out of a panel of blood tests.Blood parameters such as red blood cells(RBC), hemoglobin(HGB), hematocrit(HCT), aspartate aminotransferase(AST), gamma-glutamyl transferase(GGT), lactate dehydrogenase(LDH)and D-Dimer showed statistically significant differences between groups with different levels of EPCs(all P<0.05). Blood EPC numbers were positively correlated with RBC, HGB and HCT and negatively correlated with GGT and D-Dimer in older individuals( r=0.364, 0.343, 0.336, -0.312, -0.312, P<0.05 for all). The number of circulating EPCs had a significant positive correlation with survival time in older individuals( r=0.234, P=0.017). Based on the data of the long-term(12-years)follow-up, Logistic regression analysis suggested that the number of EPCs, age, and HCT were associated with all-cause mortality events in older individuals( OR=0.971, 1.585, 1.231, P=0.013, 0.012, 0.029). Conclusions:EPCs in the peripheral circulation may be involved in the progression of various conditions such as anemia, cardiac, hepatic and renal injury, and coagulation.The number of circulating EPCs may influence the survival of elderly individuals ≥75 years.Age and HCT may be risk factors for all-cause mortality events, whereas the number of EPCs may be a protective factor.
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Objective:To investigate the effects and mechanisms of copper transporter 1 (CTR1) in radiation induced intestinal injury in vitro. Methods:Human small intestinal epithelial cells (HIEC) were irradiated with 2, 4, 6, 8 Gy of X-rays and rat intestinal epithelial cells (IEC-6) were irradiated with 5, 10, 15, 20 Gy of X-rays. At 2, 4, 8, 24, and 48 h after irradiation, the expression of CTR1 was detected by Western blot assay. In some experiments, HIEC and IEC-6 cells were transfected with CTR1 shRNA and then exposed to X-rays. Copper levels were detected by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The radiosensitivity of cells was verified by colonogenic assay, the cellular reactive oxygen species (ROS) level and DNA damage were detected to further explore the related mechanism. In addition, Western blot was applied to detect the expressions of antioxidants and cuproptosis associated proteins in enterocytes after silencing CTR1 or irradiation.Results:The expression of CTR1 was increased by X-ray irradiation in a dose-dependent manner ( t=3.53, 3.45, 6.37, 11.11, 11.13, P<0.05). CTR1 expression was successfully diminished by CTR1 shRNA adenovirus vectors. According to the survival curves, the enhancement ratios of the radiosensitivity of HIEC and IEC-6 cells with CTR1 knocking-down were 1.146 and 1.201, respectively. Radiation-induced copper accumulation was alleviated after CTR1 silencing in IEC-6 cells ( t=3.10, P<0.05). At 0.5 h after irradiation, the ROS production in the CTR1 knockdown group was significantly lower than that in the control group ( t=5.23, 2.96, P<0.05). At 1 h after irradiation, the protein expression of γ-H2AX in the CTR1 knockdown group was obviously lower than that in the control group ( t=7.50, 4.29, P<0.05). The expressions of Nrf2 and HO-1 were increased after irradiation, which could be further increased after CTR1 silencing. In addition, cuproptosis associated protein DLAT, LIAS and FDX1 were reduced post-irradiation, which were recovered after CTR1 silencing. Conclusions:The radioresistance of HIEC and IEC-6 cells was enhanced after CTR1 silencing, possibly through the intracellular ROS and cuproptosis pathway.