ObjectiveTo evaluate pharmacological effects of Shengmai injection（SMI）on cerebral ischemia and study its neuroprotective mechanism. MethodsMale specific pathogen-free （SPF） Sprague-Dawley （SD） rats were randomly divided into a sham group， a model group， a low-dose SMI group（3 mL·kg^-1）， a middle-dose SMI group（6 mL·kg^-1）， a high-dose SMI group（12 mL·kg^-1）， and a Ginaton group（4 mL·kg^-1）according to the random number table method， with 12 rats in each group. The rat model of cerebral ischemia-reperfusion（MCAO/R）was prepared via the suture method. The administration groups were intraperitoneally injected with corresponding concentrations of SMI or Ginaton injection after reperfusion， which was conducted for 3 consecutive days. The sham group and model group were administered the equivalent volume of physiological saline. The pharmacological effects of SMI on brain injury in MCAO/R rats were evaluated by neurological function scores， cerebral infarction area， hematoxylin-eosin （HE） staining， Nissl staining， terminal deoxynucleotidyl transferase dUTP nick-end labeling （TUNEL） staining， and Western blot. The dominant link and key protein of SMI treating cerebral injury were explored using proteomic analysis. The related mechanisms of SMI were further validated using enzyme-linked immunosorbent assay （ELISA）， Western blot， and chloride ion fluorescence probe with oxygen-glucose deprivation/reoxygenation（OGD/R）-treated PC12 cells and MCAO/R rats. ResultsCompared with the sham group， the model group showed significantly increased neurological function scores， cerebral infarction area， neuronal apoptosis rate， and expression levels of apoptosis related proteins （P<0.05， P<0.01）and significantly decreased density of Nissl bodies and neurons（P<0.01）. Compared with the model group， the SMI groups exhibited significantly decreased neurological function scores， cerebral infarction area， neuronal apoptosis rate， and expression levels of apoptosis related proteins （P<0.05， P<0.01）and significantly increased density of Nissl bodies and neurons （P<0.05）. The proteomic analysis results showed that oxidative stress and inflammatory response were important processes of SMI intervening in MCAO/R injury， and the chloride intracellular channel protein 1 （CLIC1） was one of key proteins in its action network. The levels of representative indicators of oxidative stress and inflammatory response in the MCAO/R rats of the SMI groups were significantly reduced， compared with those in the model group（P<0.05， P<0.01）， and the expression levels of CLIC1 and downstream NOD-like receptor protein 3 （NLRP3） decreased （P<0.01）. In addition， the experimental results based on the OGD/R PC12 cells showed that SMI significantly increased the cell survival rate（P<0.01） and significantly decreased the intracellular chloride ion concentration（P<0.05）. ConclusionSMI has neuroprotective effects. Oxidative stress and inflammatory response are key processes of SMI intervening in MCAO/R injury. The potential mechanism is closely related to the regulation of CLIC1.

OBJECTIVE To evaluate the efficacy and safety of guideline-directed medical therapy （GDMT） combined with vericiguat in treating heart failure with reduced ejection fraction （HFrEF）. METHODS A retrospective study was conducted on 346 patients with HFrEF who received standardized diagnosis and treatment at the First People’s Hospital of Changzhou from January 2023 to May 2024. They were divided into standard treatment group （n＝215） and vericiguat group （n＝131）. Patients in the standard treatment group received GDMT， while patients in the vericiguat group received GDMT combined with vericiguat. Propensity score matching （PSM） was used to balance confounding factors between two groups， and the effectiveness （including outcome and prognostic indicators） and safety （occurrence of adverse events） of both groups were evaluated. Kaplan-Meier survival curves for primary and secondary outcome events were drawn， and the influential factors of primary outcome events were screened through univariate and multivariate Cox regression analysis. RESULTS After PSM， there were 100 patients in the standard treatment group and 100 patients in the vericiguat group， and there was no statistically significant differences in baseline data between two groups （P＞0.05）. During a 1-year follow-up， there were statistically significant differences in the cumulative incidence of major outcome events between the standard treatment group and the vericiguat group， cumulative incidence of hospitalization events due to heart failure， changes in N-terminal pro-B-type natriuretic peptide levels before and after treatment between the standard treatment group and the vericiguat group （P＜0.05）. There was no statistically significant difference in the incidence of adverse events between the two groups （P＞0.05）. Multivariate Cox regression analysis results showed that left ventricular ejection fraction ≤35% was a risk factor for the occurrence of major outcome events within 1 year [hazard ratio （HR）＝ 2.090， 95% confidence interval （CI）： 1.175-3.718， P＝0.012]， while the use of vericiguat was a protective factor for the occurrence of major outcome events within 1 year （HR＝0.505， 95%CI： 0.284-0.899， P＝0.020）. CONCLUSIONS Compared with GDMT， GDMT combined with vericiguat can improve the clinical symptoms and prognosis of HFrEF patients， and has good safety.

Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Objective To investigate the correlation between thyroid hormone levels and cognitive function in schizophrenia(SCZ)patients with metabolic syndrome(MetS),as well as the mediating role of thyroid hormones in the relationship between MetS-related indicators and cognitive function.Methods A cross-sectional trial was conducted on 120 SCZ inpatients and outpatients(40 cases of MetS and 80 cases of non-MetS)and 80 healthy controls admitted in the Chongqing Mental Health Center from August 2023 to December 2024.Thyroid function indicators[Thyroid-stimulating hormone(TSH),triiodothyronine(T3),thyroxine(T4),free triiodothyronine(FT3),and free thyroxine(FT4)],MetS-related parameters[blood glucose,triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),and waist circumference],Positive and Negative Syndrome Scale(PANSS)score,and Montreal Cognitive Assessment(MoCA)scores were collected.One-way ANOVA or Kruskal-Wallis rank sum test was applied to analyze the differences among the 3 groups,and LSD test or Bonferroni correction was performed for post hoc analysis.Pearson correlation analysis was conducted to assess the relationship between thyroid hormone levels and metabolic parameters as well as cognitive/clinical scale scores(MoCA,PANSS)in the MetS group.Results The MetS group exhibited significantly lower FT4 level(P<0.05)and MoCA score(P=0.001),but higher TSH level(P<0.05)and PANSS negative symptom score(P<0.001)when compared to the non-MetS group.Correlation analysis indicated that in the MetS group,TSH level was positively correlated with TG(r=0.672,P<0.001)and PANSS negative symptom score(r=0.458,P<0.05),and negatively with HDL-C(r=-0.377,P=0.017)and MoCA score(r=-0.667,P<0.001);FT4 level was positively correlated with MoCA score(r=0.534,P<0.001).In the non-MetS group,TSH level was positively correlated with PANSS negative symptom score(r=0.267,P=0.017)and negatively with HDL-C(r=-0.236,P=0.036),T3 was positively with waist circumference(r=0.268,P=0.017).No correlation was observed in FT4 level with HDL-C(r=-0.207,P=0.067)or MoCA score(r=0.216,P=0.055).Mediation analysis revealed that TSH partially mediated the association between TG and MoCA score,with a mediation effect accounting for 29.91%of the total effect.The mediating effect was not significant in the non-MetS group.Conclusion Abnormal elevation of TSH may serve as a critical link between MetS and cognitive impairment in SCZ patients,which providing novel insights into the mechanisms underlying cognitive dysfunction in the patients.

Objective To evaluate the safety and efficacy of interventional embolization of middle meningeal artery(MMA)for the treatment of chronic subdural hematoma(CSDH).Methods The clinical data of 14 patients with CSDH(17 lesions in total),who were treated with simple embolization of MMA at the Yijishan Hospital of Wannan Medical College of China between July 2021 and July 2022,were retrospective analyzed.After superselective catheterization of MMA using a microcatheter was accomplished,Onyx-18 glue,a liquid embolization agent,was used to embolize the main trunk and the branches of MMA.Imaging follow-up was adopted at 30 days and 90 days after discharge from hospital to evaluate the absorption of hematoma,and the improvement of clinical symptoms was defined as the modified Rankin Scale score(mRS)being decreased≥1 point from the baseline value.Results Successful embolization of MMA was accomplished for all the 17 lesions in the 14 patients,and no procedure-related complications occurred.During the follow-up period,the clinical symptoms and signs were remarkably improved in all patients.The postoperative 90-day hematoma volume was reduced by more than 90%in 11 patients and by more than 40%in one patient,and in 2 patients the postoperative 30-day hematoma volume was reduced by more than 30%.Complete absorption of hematoma was seen in 11 patients,and partial absorption of hematoma was observed in 3 patients.Conclusion For the treatment of newly-developed or recurrent CSDH,interventional embolization of MMA is clinically safe and effective.(J Intervent Radiol,2024,32:12-16)

AIM:To investigate the effects of overexpressing α-Klotho(KL)in RAW264.7 cells stimulated by oxidative stress on the proliferation, migration, tube-formation and tight junction of human umbilical vein endothelial cells(HUVECs).METHODS:RAW264.7 cells were categorized into control, 4-hydroxynonenal(4HNE), and 4HNE+KL groups, with F4/80 expression assessed via immunofluorescence staining. Three groups of conditional media were prepared for HUVECs and culture divided into Mø-NC, Mø-4HNE, and Mø-4HNE+KL groups. Cell proliferation was evaluated using CCK8 assay, while scratch test and Transwell assays were employed to measure cell migration. Additionally, tube-formation assay was conducted to assess cell tubule formation, and Western blot assay was utilized to detect the protein expression levels of Claudin 5, Occludin and ZO 1.RESULTS:The results of immunofluorescence staining showed that the fluorescence intensity of F4/80 of RAW264.7 cells in the 4HNE group was significantly enhanced compared with the control group, while that of F4/80 in the 4HNE+KL group was significantly decreased compared with the 4HNE group(all P<0.05). The CCK8 assay results revealed a significant increase in the proliferation of HUVECs in the Mø-4HNE group compared with the Mø-NC group. Conversely, the proliferation of the Mø-4HNE+KL group exhibited a significant decrease compared with that in the Mø-4HNE group(all P<0.01). The results of scratch test and Transwell assays demonstrated a significant increase in the migration of HUVECs in the Mø-4HNE group compared with the Mø-NC group, while the migration of the Mø-4HNE+KL group exhibited a significant decrease compared with the Mø-4HNE group(all P<0.01). In the tube-formation assay, it was observed that the number of tubes formed by HUVECs in the Mø-4HNE group was significantly increased compared with the Mø-NC group, while that of tubes formed in the Mø-4HNE+KL group was significantly decreased compared with the Mø-4HNE group(all P<0.01). Additionally, the Western blot results revealed a significant decrease in the relative expression levels of Claudin 5, Occludin, and ZO 1 in the Mø-4HNE group compared with the Mø-NC group. Conversely, in the Mø-4HNE+KL group, there was a significant increase in the relative expression levels of Claudin 5, Occludin, and ZO 1 compared to the Mø-4HNE group(all P<0.01).CONCLUSIONS: KL inhibits the proliferation, migration, and tube-formation of HUVECs while enhancing the tight junction by changing the activation state of macrophages in the diabetic oxidative stress environment.

Objective:The incidence of early-onset colorectal cancer (EOCRC) is increasing globally; however, the molecular characteristics and prognosis of sporadic EOCRC are unclear. In this systematic review and meta-analysis, we aimed to investigate the incidence of gene mutations and their association with cancer survival in sporadic EOCRC, focusing on six common gene mutations ( TP53, BRAF, KRAS, NRAS, PTEN, and APC). Methods:Ovid Embase and Ovid Medline electronic databases were searched for studies involving patients with sporadic EOCRC (i.e., diagnosed with colorectal cancer before the age of 50 years and with no evidence of hereditary syndromes predisposing to colorectal cancer). The included articles were evaluated using quality assessment tools. Meta-analysis was performed using random-effects and fixed-effects models. Cochran's Q statistic and the I2 index were used to assess heterogeneity. The incidence of the six common gene mutations listed above in sporadic EOCRC and their association with cancer survival were evaluated.Results:(1) Incidence of specific gene mutations in sporadic EOCRC. A total of 34 articles were included in this meta-analysis. The incidence of APC gene mutation was 36% (from 13 articles, 95%CI: 19%-55%, P=0.043); of KRAS gene mutation 30% (from 26 articles, 95%CI: 24%-35%, P=0.190); of BRAF gene mutation 7% (from 18 articles, 95%CI: 5%-11%, P=0.422); of NRAS gene mutation 4% (from five articles, 95%CI: 3%-5%, P=0.586); of PTEN gene mutation 6% (from six articles, 95%CI: 4%-10%, P=0.968); and of TP53 gene mutation 59% (from 13 articles, 95%CI: 49%-68%, P=0.164). (2) Association between gene mutations and survival in sporadic EOCRC . A total of six articles were included in this meta-analysis. Compared with wild-type BRAF, mutant BRAF was significantly associated with increased overall mortality risk in patients with EOCRC (pooled HR=2.85, 95%CI: 1.45-5.60, P=0.002). Subgroup analysis showed that the incidence of BRAF gene mutation was higher in Eastern than in Western countries, whereas the incidence of TP53, KRAS, NRAS, and APC gene mutations was lower. There was no significant difference in the incidence of PTEN gene mutation between different regions. Conclusion:Compared with colorectal cancer occurring in the general population, the incidence of APC and KRAS mutations is lower in EOCRC, whereas the incidence of TP53 mutation remains consistent. BRAF mutation is associated with increased overall mortality risk in patients with EOCRC.

Objective:To investigate the effect of immune checkpoint inhibitors on reducing residual lymph node metastasis in patients with gastric cancer.Methods:The cohort of this retrospective study comprised patients from Nanfang Hospital of Southern Medical University and the First Affiliated Hospital of Xiamen University who had undergone systemic treatment prior to gastrectomy with D2 lymphadenectomy and had achieved Grade 1 primary tumor regression (TRG1) from January 2014 to December 2023. After exclusion of patients who had undergone preoperative radiotherapy, data of 58 patients (Nanfang Hospital: 46; First Affiliated Hospital of Xiamen University: 12) were analyzed. These patients were allocated to preoperative chemotherapy (Chemotherapy group, N=36 cases) and preoperative immunotherapy plus chemotherapy groups (Immunotherapy group, N=22 cases). There were no significant differences between these groups in sex, age, body mass index, diabetes, tumor location, pathological type, Lauren classification, tumor differentiation, pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, mismatch repair protein status, number of preoperative treatment cycles, or duration of preoperative treatment (all P>0.05). The primary outcome measure was postoperative lymph node downstaging. Secondary outcomes included postoperative depth of invasion by tumor, number of lymph nodes examined, and factors affecting residual lymph node metastasis status. Results:Lymph node downstaging was achieved significantly more often in the Immunotherapy group than the Chemotherapy group (pN0: 90.9% [20/22] vs. 61.1% [22/36]; pN1: 4.5% [1/22] vs. 36.1% [13/36]; pN2: 4.5% [1/22) vs. 0; pN3: 0 vs. 2.8% [1/36], Z=-2.315, P=0.021). There were no significant difference between the two groups in number of lymph nodes examined (40.5±16.3 vs. 40.8±17.5, t=0.076, P=0.940) or postoperative depth of invasion by primary tumor (pT1a: 50.0% [11/22] vs. 30.6% [11/36]; pT1b: 13.6% [3/22] vs. 19.4% [7/36]; pT2: 13.6% [3/22] vs. 13.9% [5/36]; pT3: 13.6% [3/22] vs. 25.0% [9/36]; pT4a: 9.1% [2/22] vs. 11.1% [4/36], Z=-1.331, P=0.183). Univariate analysis revealed that both preoperative treatment regimens were associated with residual lymph node metastasis status in patients whose primary tumor regression was TRG1 (χ 2=6.070, P=0.014). Multivariate analysis incorporated the following factors: pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, number of preoperative treatment cycles, and preoperative treatment duration. We found that a combination of immunotherapy and chemotherapy administered preoperatively was an independent protective factor for reducing residual lymph node metastases in study patients whose primary tumor regression was TRG1 (OR=0.147, 95%CI: 0.026–0.828, P=0.030). Conclusion:Compared with preoperative chemotherapy alone, a combination of preoperative immunotherapy and chemotherapy achieved greater reduction of residual lymph node metastases in the study patients who achieved TRG1 tumor regression in their primary lesions.

OBJECTIVE To investigate the clinical incidence and severity of adverse reactions related to nano-albumin-bound paclitaxel(Nab-P) and traditional solvent-based paclitaxel chemotherapy, and analyze the improvement of adverse reactions of paclitaxel treatment by nano-albumin delivery system. METHODS A hospital information system was used to retrospectively investigate 326 cancer patients received Nab-P chemotherapy and 303 paclitaxel chemotherapy patients who were diagnosed in the Department of Oncology of the Affiliated Hospital of Jiangnan University from July 2019 to December 2021. The information of the adverse reactions related to Nab-P and paclitaxel treatment was extracted from the electronic medical records and nursing record sheets, to explore the effect and clinical status of the nano albumin drug delivery system to improve the adverse reactions of chemotherapy. RESULTS Nab-P and paclitaxel-related adverse reactions such as nausea, vomiting, allergic reactions, myelosuppression, liver injury, paresthesias, phlebitis and others were significantly different in incidence and severity(P<0.05). The incidence and severity of Nab-P-related myelosuppression was higher than that of paclitaxel, while the incidence and severity of all other adverse reactions treated with Nab-P were lower. CONCLUSION Except for myelosuppression, Nab-P-related adverse reactions are significantly lower than traditional paclitaxel. Therefor, for patients undergoing Nab-P chemotherapy, more attention should be paid to the occurrence of myelosuppression.

Objective:The incidence of early-onset colorectal cancer (EOCRC) is increasing globally; however, the molecular characteristics and prognosis of sporadic EOCRC are unclear. In this systematic review and meta-analysis, we aimed to investigate the incidence of gene mutations and their association with cancer survival in sporadic EOCRC, focusing on six common gene mutations ( TP53, BRAF, KRAS, NRAS, PTEN, and APC). Methods:Ovid Embase and Ovid Medline electronic databases were searched for studies involving patients with sporadic EOCRC (i.e., diagnosed with colorectal cancer before the age of 50 years and with no evidence of hereditary syndromes predisposing to colorectal cancer). The included articles were evaluated using quality assessment tools. Meta-analysis was performed using random-effects and fixed-effects models. Cochran's Q statistic and the I2 index were used to assess heterogeneity. The incidence of the six common gene mutations listed above in sporadic EOCRC and their association with cancer survival were evaluated.Results:(1) Incidence of specific gene mutations in sporadic EOCRC. A total of 34 articles were included in this meta-analysis. The incidence of APC gene mutation was 36% (from 13 articles, 95%CI: 19%-55%, P=0.043); of KRAS gene mutation 30% (from 26 articles, 95%CI: 24%-35%, P=0.190); of BRAF gene mutation 7% (from 18 articles, 95%CI: 5%-11%, P=0.422); of NRAS gene mutation 4% (from five articles, 95%CI: 3%-5%, P=0.586); of PTEN gene mutation 6% (from six articles, 95%CI: 4%-10%, P=0.968); and of TP53 gene mutation 59% (from 13 articles, 95%CI: 49%-68%, P=0.164). (2) Association between gene mutations and survival in sporadic EOCRC . A total of six articles were included in this meta-analysis. Compared with wild-type BRAF, mutant BRAF was significantly associated with increased overall mortality risk in patients with EOCRC (pooled HR=2.85, 95%CI: 1.45-5.60, P=0.002). Subgroup analysis showed that the incidence of BRAF gene mutation was higher in Eastern than in Western countries, whereas the incidence of TP53, KRAS, NRAS, and APC gene mutations was lower. There was no significant difference in the incidence of PTEN gene mutation between different regions. Conclusion:Compared with colorectal cancer occurring in the general population, the incidence of APC and KRAS mutations is lower in EOCRC, whereas the incidence of TP53 mutation remains consistent. BRAF mutation is associated with increased overall mortality risk in patients with EOCRC.