Objective To assess stromal fibrosis in epidermal growth factor receptor(EGFR)mutant lung adenocarcinoma and its association with resistance to targeted therapy and patient prognosis.Methods Medical records of 207 patients diagnosed with EGFR-mutant advanced lung adenocarcinoma who received treatment at a hospital between January 2021 and December 2022 were reviewed.A total of 86 patients were ultimately included based on their prognosis and survival duration.These patients were categorized into a resistance group(32 cases)and a non-resistance group(54 cases),depending on whether they developed resistance to targeted therapy within one year.Additionally,patients were classified into mild,moderate,and severe fibrosis groups according to the extent of fibrosis observed.Clinical and pathological characteristics,as well as fibrosis levels,were compared between the two groups.Factors influencing the development of resistance to targeted therapy in patients with EGFR-mutant lung adenocarcinoma were analyzed,and the survival outcomes of patients with varying degrees of fibrosis were evaluated during follow-up.Results In the resistance group,the prevalence of EGFR exon 20 insertion mutations,elevated CA125 levels,and the presence of moderate-to-severe fibrosis were significantly higher compared to the non-resistance group(P<0.05).Multivariate logistic regression analysis revealed that EGFR exon 20 inser-tion mutation(OR=3.691,95%CI:1.043～13.057),elevated CA125 levels(OR=4.104,95%CI:1.160～14.517),and moderate-to-severe fibrosis(OR=3.959,95%CI:1.410～11.115)were independent risk factors associated with resistance to targeted therapy among patients with EGFR-mutant lung adenocarcinoma(P<0.05).The Cox proportional hazards model demonstrated a C-index of 0.72(95%CI:0.65～0.79),with area under the curve(AUC)values for 1-year and 2-year survival predictions of 0.781 and 0.734,respectively.EGFR exon 20 insertion mutation(HR=3.691),moderate-to-severe fibrosis(HR=3.959),and elevated CA125 levels(HR=4.104)were identified as independent prognostic factors for overall survival in these patients following targeted therapy.The median progression-free survival(PFS)for patients with mild,moderate,and severe fibrosis was 10.5 months,7.2 months,and 3.9 months,respectively,while the median overall survival(OS)was 21.4 months,16.1 months,and 11.5 months,respectively.Statistically significant differences in both PFS and OS were observed across the three fibrosis severity groups.(P<0.05).Conclusion The extent of stromal fibrosis in EGFR-mutant lung adenocarcinoma influences resistance to targeted therapy,and the progression of fibrosis is correlated with an unfavorable prognosis.

As the incidence of autism rises annually,its unknown pathogenesis makes it challenging to treat the varied repetitive and stereotyped behaviors that characterize its core symptoms.The striatum is an important brain region for the control of locomotor behaviors,featuring a unique mosaic structure,complex neural origin,and finely regulated developmental process that is highly susceptible to genetic and environmental influences.Both clinical and basic studies have indicated that abnormal development of the striatal nuclei may contribute to the pathogenesis of these repetitive stereotyped behaviors in autism.Clinical imaging data have primarily identified gross anatomical variations in the stratum(e.g.,its general outline),but lack the resolution necessary to detect the cellular and subcellular alterations within the region.By introducing the abnormalities in the spatiotemporal development of the striatum and their links to the characteristic behaviors of autism,this review aims to advance our understanding of the role of the striatum in autism pathogenesis and to inform future animal studies and clinical research.

Objective To assess stromal fibrosis in epidermal growth factor receptor(EGFR)mutant lung adenocarcinoma and its association with resistance to targeted therapy and patient prognosis.Methods Medical records of 207 patients diagnosed with EGFR-mutant advanced lung adenocarcinoma who received treatment at a hospital between January 2021 and December 2022 were reviewed.A total of 86 patients were ultimately included based on their prognosis and survival duration.These patients were categorized into a resistance group(32 cases)and a non-resistance group(54 cases),depending on whether they developed resistance to targeted therapy within one year.Additionally,patients were classified into mild,moderate,and severe fibrosis groups according to the extent of fibrosis observed.Clinical and pathological characteristics,as well as fibrosis levels,were compared between the two groups.Factors influencing the development of resistance to targeted therapy in patients with EGFR-mutant lung adenocarcinoma were analyzed,and the survival outcomes of patients with varying degrees of fibrosis were evaluated during follow-up.Results In the resistance group,the prevalence of EGFR exon 20 insertion mutations,elevated CA125 levels,and the presence of moderate-to-severe fibrosis were significantly higher compared to the non-resistance group(P<0.05).Multivariate logistic regression analysis revealed that EGFR exon 20 inser-tion mutation(OR=3.691,95%CI:1.043～13.057),elevated CA125 levels(OR=4.104,95%CI:1.160～14.517),and moderate-to-severe fibrosis(OR=3.959,95%CI:1.410～11.115)were independent risk factors associated with resistance to targeted therapy among patients with EGFR-mutant lung adenocarcinoma(P<0.05).The Cox proportional hazards model demonstrated a C-index of 0.72(95%CI:0.65～0.79),with area under the curve(AUC)values for 1-year and 2-year survival predictions of 0.781 and 0.734,respectively.EGFR exon 20 insertion mutation(HR=3.691),moderate-to-severe fibrosis(HR=3.959),and elevated CA125 levels(HR=4.104)were identified as independent prognostic factors for overall survival in these patients following targeted therapy.The median progression-free survival(PFS)for patients with mild,moderate,and severe fibrosis was 10.5 months,7.2 months,and 3.9 months,respectively,while the median overall survival(OS)was 21.4 months,16.1 months,and 11.5 months,respectively.Statistically significant differences in both PFS and OS were observed across the three fibrosis severity groups.(P<0.05).Conclusion The extent of stromal fibrosis in EGFR-mutant lung adenocarcinoma influences resistance to targeted therapy,and the progression of fibrosis is correlated with an unfavorable prognosis.

As the incidence of autism rises annually,its unknown pathogenesis makes it challenging to treat the varied repetitive and stereotyped behaviors that characterize its core symptoms.The striatum is an important brain region for the control of locomotor behaviors,featuring a unique mosaic structure,complex neural origin,and finely regulated developmental process that is highly susceptible to genetic and environmental influences.Both clinical and basic studies have indicated that abnormal development of the striatal nuclei may contribute to the pathogenesis of these repetitive stereotyped behaviors in autism.Clinical imaging data have primarily identified gross anatomical variations in the stratum(e.g.,its general outline),but lack the resolution necessary to detect the cellular and subcellular alterations within the region.By introducing the abnormalities in the spatiotemporal development of the striatum and their links to the characteristic behaviors of autism,this review aims to advance our understanding of the role of the striatum in autism pathogenesis and to inform future animal studies and clinical research.

Objective:To observe the relationship between the response to anti-vascular endothelial growth factor (VEGF) drug treatment and single nucleotide polymorphism (SNP) genotype in patients with wet age-related macular degeneration (wAMD).Methods:A retrospective clinical study. From August 2019 to September 2020, 103 eyes of 103 wAMD patients diagnosed in Tianjin Medical University Eye Hospital were included in the study. Among them, there were 59 males (57.28%, 59/103) and 44 females (42.72%, 44/103); the average age was 68.74±7.74 years. The standard logarithmic visual acuity chart was used to detect the Best Corrected Visual Acuity of the affected eye and converted to the logarithmic minimum angle of resolution (logMAR) visual acuity during statistics. Optical coherence tomography was used to detect the central retinal thickness (CRT) of the affected eye. At the same time, the patient's high-density lipoprotein cholesterol (HDL-C) was tested. All eyes were treated with intravitreal injection of anti-VEGF drugs once a month for 3 months. Before the initial treatment, peripheral venous blood from the patient were collected. Interleukin-8 ( IL-8), complement C3 gene ( C3), complement factor H ( CFH), liver lipase ( LIPC), cholesterol ester transfer protein ( CETP), ATP binding cassette subfamily a member 1 ( ABCA1), lipoprotein lipase ( LPL), fatty acid desaturation gene cluster ( FADS1) SNP. According to gene frequency, genotypes are divided into wild type and mutant type were detected. Qualitative data such as the frequency difference of the genotype distribution in the clinical phenotype and the Hardy-Weinberg equilibrium of the genotype distribution were compared with the Chi-square test or Fisher's exact test. Results:There were fewer CRT responders in IL-8 rs4073 mutant (TA+AA) patients than wild-type (TT) [odds ratio ( OR)=0.310, 95% confidence interval ( CI) 0.106-0.910, P<0.05). Among them, after the drug stratification test, the proportion of patients with IL-8 rs4073 locus TT genotype in the conbercept treatment group was less CRT non-responders ( OR=0.179, 95% CI=0.034-0.960, P=0.033). Patients with LIPC rs2043085 mutant (CT+TT) with BCVA increased ≥0.2 logMAR are more likely than wild-type (CC) ( OR=3.031, 95% CI 1.036-8.867, P<0.05); HDL-C level was significantly lower Compared with wild type (CC), the difference was statistically significant ( t=2.448, P=0.016). There was no significant difference in logMAR BCVA and CRT between IL-8 rs4073, LIPC rs2043085 mutant and wild-type patients before treatment ( IL-8 rs4073: Z=-0.198, -1.651; P=0.843, 0.099; LIPC rs2043085: Z=-0.532, -0.152; P=0.595, 0.879). C3 rs 225066, CFH rs800292, CETP rs708272, ABCA1 rs1883025, FADS1 rs174547, LPL rs12678919 have no correlation with anti-VEGF drug treatment response. Conclusions:Patients with wAMD are treated with anti-VEGF drugs. Those with IL-8 rs4073 locus A genotype may be less responsive to CRT. LIPC rs2043085 locus T genotypes may be relatively more responsive to BCVA.

In recent years, the subthreshold micropulse laser is a kind of laser mode which is characterized by long intermittence. It achieves effective therapeutic effect while minimizes the damage to tissues. At present, it has been used to treat diabetic macular edema. Early studies suggested that the laser selectively acts on retinal pigment epithelial cells to reduce macular edema by regulating the expression of inflammatory biomarkers, growth factors, heat shock proteins and other substances. In recent years, with the development of research, more and more emphasis has been placed on the role of retinal glial cells. Müller cells are also considered as one of the target cells affected by micropulse laser, but there is no evidence of direct or indirect effects of micropulse laser on Müller cells. In the near future, it is expected that we will have more clinical evidence to confirm the target cells of the micropulse laser, which may be further confirmed by in vitro experiments through Müller cells or Müller cells co-cultured with retina pigment epithelium cells, so as to make a more detailed statement on the mechanism of it.

OBJECTIVE：To study metabonomics of secondary components of Astragalus membranaceus injection on leukopenia model mice. METHODS ：The mice were divided into normal group ，model group ，A. membranaceus injection group （0.004 mL/g），secondary components low-dose ，medium-dose and high-dose groups （0.004，0.008，0.016 mL/g），with 7 mice in each group. Except for normal group ，other groups were given cyclophosphamide （80 mg/kg） intraperitoneally to induce leukopenia model. After modeling ，administration groups were given relevant medicine intraperitoneally ，and normal group and model group were given constant volume of sterile water for injection intraperitoneally ，once a day ，for consecutive 7 days. During the experiment ，the changes of body weight of mice were measured every 2 days. After the last administration ，the blood routine indexes [white blood cell （WBC），neutrophil（NE），lymphocyte（LY）and monocyte （MO）counts] of mice were detected by animal blood analyzer. UPLC-Q Exactive Orbitrap-HRMS combined with multivariate statistical analysis were used to analyze the metabonomics of mice serum. RESULTS ：Compared with model group ，body weight of mice in the secondary component low-dose group increased significantly on the 4th and 8th day of administration （P＜0.05），and the counts of WBC ，NE，LY and MO in serum of mice in secondary component groups increased significantly （P＜0.05 or P＜0.01）. Metabonomic analysis showed that the secondary components of A. membranaceus injection could significantly regulate the contents of 8 endogenous metabolites in serum， including spermidine ， uric acid ， citric acid ， nicotinamide， eicosapentaenoic acid ， linoleic acid ， erucamide and sphingosine-1-phosphate. Their effects involved linoleic acid metabolism pathway ，nicotinic acid and nicotinamide metabolism pathway and tricarboxylic acid cycle pathway. CONCLUSIONS ：The secondary components of A. membranaceus injection possess the effect of increasing white blood cells in leukopenia model mice ，the mechanism of which may be related to intervention of linoleic acid metabolism pathway ， nicotinic acid and nicotinamide metabolism pathway ，and tricarboxylic acid cycle pathway.

Objective:To compare the sedative and anti-anxiety effects of levo-tetrahydropalmatine (L-THP) and diazepam on conditioned fear model rats.Methods:According to the random number table method, 32 adult male rats were divided into blank group, model group, diazepam group and L-THP group(with 8 rats in each group). The conditioned fear model was reproduced by the plantar electric shock method. Four days after the modeling, the rats in diazepam group and L-THP group were given diazepam (3.6 mg/kg) and L-THP (25 mg/kg) were respectively gavaged once a day for 10 days, the rats in blank group and model group were given the same volume of saline. After the administration, the elevated plus maze test and the open field test were used to measure the anxiety behavior of the rats, and the sleep energy monitoring system was used to detect changes in sleep and energy-related indicators. SPSS 23.0 and Graphpad Prism 7.0 softwares were used for data analysis, multiple samples between groups were compared by one-way ANOVA, and LSD test was used for pairwise comparison.Results:The results of the elevated plus maze experiment showed that compared with the model group, the percentage of open-arm entry times ((11.27±8.78)%, (30.11±14.59)%, P<0.05) and the percentage of open-arm residence time ((1.94±1.48)%, (17.53±8.21)%, P<0.05) in diazepam group were all significantly increased. Compared with the model group, the open arm residence time, the percentage of open arm residence time and the percentage of open arm entry times in L-THP group showed an upward trend, but there was no statistical significance (all P>0.05). The results of the open field experiment showed that compared with the model group, the time of entering the central grid ((2.99±1.83) s, (6.94±3.52) s, P<0.05) and the time of entering the peripheral field ((297.01±1.83) s, (293.30±3.52) s, P<0.05) in diazepam group both increased. Compared with the model group, there was no significant difference in the changes of various indexes in L-THP group (all P>0.05). The results of locomotor activities showed that the autonomic activity times of model group in nighttime was significantly lower than that of blank group((758.79±375.37)times/h, (1 101.93±525.96)times/h, P<0.05). Compared with the model group, the number of autonomous activities of rats in L-THP group in daytime ((820.57±364.60) times/min, (502.40±228.54)times/min, P<0.05) decreased, and the number of autonomous activities in the nighttime ((758.79±375.37) times/min, (1 146.85±309.69)times/min, P<0.05) increased, but there was no significant change in the number of autonomous activities in the whole day. Correlation analysis of energy metabolism related indexes and sleep time of rats in each group were analyzed. The experimental results showed that the daytime sleep time were negatively correlated with heat value ( r=-0.335, P<0.05), and the night sleep time was positively correlated with daytime heat value ( r=0.352, P<0.05). Conclusion:L-tetrahydropalmatine has no significant anti-anxiety effect in the concentration range used in this study, but its sedative and improving sleep activity rhythm are better than diazepam.

OBJECTIVE：To study the intervention effects of Huan gqi injecti on on leucopenia model mice. METHODS ： Kunming mice were randomly divided into normal group ，model group and drug group ，with 8 mice in each group. Model group and drug group were given intraperitoneal injection of cyclophosphamide to induce leukopenia model. Normal group was given intraperitoneal injection of equal volume of sterile water. After modeling successfully ，normal group and model group were given intraperitoneal injection of equal volume of sterile water ；drug group was given intraperitoneal injection of Huangqi injection 0.04 mL/10 g，once a day ，for consecutive 7 d. Based on the detection of blood routine indexes （leukocyte，lymphocyte，neutrophil， monocyte count ）of mice in each group ，the metabolites in serum were analyzed by LC-MS. Principal component analysis （PCA）， partial least squares discriminant analysis （PLS-DA），orthogonal partial least squares-discriminant analysis （OPLS-DA），HMDB， METLIN， KEGG and other databases as well as related literatures were used to identify the differential metabolites. The metabolic pathways of differential metabolites were analyzed with MetPA online tools ，and the correlation of blood routine indexes and differential metabolites were analyzed on the basis of Pearson correlation coefficient. RESULTS： Compared with normal group ， blood rountine indexes of model group were decreased significantly （P＜ 0.01）. Compared with model group ，above blood r ountine indexes of drug group were all increased siginificantly （P＜0.01）. LC-MS chromatogram of serum samples in normal group and model group were significantly different ，and LC-MS metabonomics data of serum samples in drug group were similar to those of normal group. Multivariate statistical analysis and correlated database analysis revealed that compared with normal group ，serum contents of 17 metabolites as L-isoleucine，eicosapentaenoic acid were increased significantly in model group ，while the contents of 4 metabolites as spermidine were decreased significantly （P＜0.05 or P＜0.01）. Compared with model group ，Huangqi injection could reverse the serum contents of 9 metabolites in mice ，such as citric acid ，L-proline，acetylcarnitine，L-isoleucine， L-phenylalanine，sphingosine-1-phosphate，lysophosphatidylinositol，eicosapentaenoic acid and linoleic acid （P＜0.05 or P＜ 0.01），which were associated with linoleic acid metabolism ，biosynthesis of phenylalanine ，tyrosine and tryptophan ，and phenylalanine metabolism （metabolism pathway influential values were all higher than 0.1）. Correlation analysis showed that there was a significant correlation between blood routine indexes and the contents of D-sphingosine，linoleic acid and citric acid in model group（the absolute values of r were generally greater than 0.5）. CONCLUSIONS ：Huangqi injection can increase the counts of leukocytes，lymphocytes，neutrophils and monocytes in leucopenia model mice. The increase of leukocytes may be related to linoleic acid metabolism ，biosynthesis of phenylalanine ，tyrosine and tryptophan ，and phenylalanine metabolism.

AIM To investigate the effects of ethyl acetate extract from Huangqi Injection (HQIEACE) on leucopenia mice.METHODS An experimental mouse model of leucopenia was induced by cyclophosphamide.NMR based metabolomic profiling technique coupled with multivariate statistical method was used for performing metabolomic analysis.RESULTS HQIEACE could elevate the levels of white blood cell,monocytes,neutrophils and lymphocyte in modeled mice.The levels of ten potential endogenous metabolites (lipid,leucine,3-D-hydroxybutyrate,lactate,alanine,pyruvate,creatine,scyllo-inositol,betaine and glucose) were reversed.CONCLUSION The metabolic pathways related to the pharmacological effects of HQIEACE on leucopenia are probably involved in body energy metabolism,amino acid metabolism,oxidative stress and choline metabolism.