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.

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 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 compare the macular retinal thickness characteristics of diabetic kidney disease(DKD)patients with different blood pressure levels and explore the relationship between blood pressure and macular retinal damage in DKD patients.Methods A total of 435 DKD patients were selected and divided into four groups based on medical history and blood pressure:the non-hypertensive group(NH group,n=100),the well-controlled blood pressure group(G0 group,n=176),the grade 1 hypertension group(G1 group,n=118)and the grade 2 hypertension group(G2 group,n=41).General information,routine laboratory test results as well as the average thickness of the macular retinal nerve fiber layer(RNFL),ganglion cell layer(GCL),ganglion cell complex(GCC),choroidal layer(CL)and central macular retinal thickness(CMT)were compared between the four groups.The correlation between macular retinal thickness in both eyes and clinical data was analyzed.Results Compared with the G1 group and the G2 group,the G0 group had a longer duration of hypertension.Compared to the NH group,the G2 group had higher fasting plasma glucose(FPG).Compared to the G0 group,the G1 group and the G2 group had higher FPG,and the G2 group had higher glycated hemoglobin(HbA1c)and lower estimated glomerular filtration rate(eGFR).Compared to the NH group,the G0 group had decreased thickness in the GCL and GCC(P<0.05).The macular retinal thickness of the GCL and GCC in both eyes was negatively correlated with diastolic blood pressure(r=-0.158 and-0.195,respectively,P<0.05).Conclusion Macular retinal thickness is helpful in assessing the long-term effects of hypertension on optic nerve and microvascular damage in DKD patients.

Objective To explore the regulatory role of N-methyl berbamine(N-MB)in intracellular calcium homeostasis in H9c2 car-diomyocytes,and,thereby,clarify the possible mechanism of the myocardial protective effect of N-MB.Methods Binding of N-MB to CaV1.2 channels was simulated using the MOE software,and the binding affinity and binding mode were determined.The hCaV1.2 gene was transfected into HEK293 cells,and the effect of N-MB(30 μmol/L)on the CaV1.2 current was detected using the whole-cell patch clamp technique.In addition,a Fluo 3-AM fluorescent probe was loaded into H9c2 cardiomyocytes,and the effect of N-MB(3,30 μmol/L)on intracellular calcium ion concentration was observed under a laser confocal microscope.The effect of N-MB(3,30 μmol/L)on the expression of Ca2+regulation-related genes Cacna1c,Cacnb2,Ryr2,Serca2a,and Ncx1 in H9c2 cardiomyocytes was examined using real-time quantitative PCR.Results N-MB was predicted to bind to CaV1.2 channels.The binding sites mainly involved Phe1191,Thr1420,and Asn771,and the binding modes were H-donor,pi-pi,and pi-H.N-MB(30 μmol/L)significantly inhibited CaV1.2 currents,with an inhibition rate of 76.09％±7.41％.The fluorescence intensity of intracellular Ca2+level in H9c2 cardiomyocytes was significantly enhanced with N-MB treatment(3,30 μmol/L,P＜0.01).Compared with the control group,differences in the expression of Cacna1c,Serca2a,and Ncx1 in H9c2 cardiomyocytes were not significant after N-MB(3,30 μmol/L)intervention(P＞0.05),whereas the expression of Cacnb2 significantly reduced(P＜0.001)and the expression of Ryr2 significantly increased(P＜0.05).Conclusion N-MB binds to CaV1.2 calcium channels.N-MB may regulate intracellular calcium homeostasis by inhibiting calcium currents by decreasing the gene expression of CaV1.2 calcium channels.Additionally,N-MB may also increase intracellular Ca2+concentration by promoting the expression of Ryr2,which could be the mechanism underlying the myocardial protective effect of N-MB.

Objective:To explore the correlation between water-soluble vitamin levels and clinical indicators and provide a theoretical basis for precise nutrition treatment of chronic kidney disease (CKD) .Methods:Clinical data of CKD patients who underwent water-soluble vitamin (B1, B2, B6, B9, B12, C) level tests at the First Affiliated Hospital, Army Medical University from Jan. 2016 to Dec. 2023 were collected and analyzed to investigate the relationship between water-soluble vitamin levels and clinical indicators.Results:The median values of B1 and B2 were 47.52 (range 41.65-135.36) and 184.52 (range 178.52-192.53), which were below the normal range. The results showed that age, serum creatinine, and fasting blood glucose in the low-level group for all vitamins were higher than those in the high-level group ( P<0.05). However, hemoglobin and estimated glomerular filtration rate were lower in the low-level group than those in the high-level group ( P<0.05). In the low-level group of B1, the percentage of neutrophils (NEUT%) was higher than that in the high-level group ( P<0.05). In CKD stage 5, the levels of all vitamins were lower than those of CKD stage 1 ( P<0.05). Spearman correlation analysis showed that the levels of all vitamins were negatively correlated with CKD stage, with correlation coefficients of -0.329, -0.357, -0.345, -0.373, -0.386 and-0.351, respectively ( P<0.01) . Conclusions:Metabolic abnormalities of watersoluble vitamins are common in CKD, which are closely related to the progression of CKD, inflammation and anemia. Timely evaluation and intervention may be beneficial to prevent the progression of CKD and provide a new treatment strategy for precise nutrition intervention in CKD.

Objective:To explore the correlation between water-soluble vitamin levels and clinical indicators and provide a theoretical basis for precise nutrition treatment of chronic kidney disease (CKD) .Methods:Clinical data of CKD patients who underwent water-soluble vitamin (B1, B2, B6, B9, B12, C) level tests at the First Affiliated Hospital, Army Medical University from Jan. 2016 to Dec. 2023 were collected and analyzed to investigate the relationship between water-soluble vitamin levels and clinical indicators.Results:The median values of B1 and B2 were 47.52 (range 41.65-135.36) and 184.52 (range 178.52-192.53), which were below the normal range. The results showed that age, serum creatinine, and fasting blood glucose in the low-level group for all vitamins were higher than those in the high-level group ( P<0.05). However, hemoglobin and estimated glomerular filtration rate were lower in the low-level group than those in the high-level group ( P<0.05). In the low-level group of B1, the percentage of neutrophils (NEUT%) was higher than that in the high-level group ( P<0.05). In CKD stage 5, the levels of all vitamins were lower than those of CKD stage 1 ( P<0.05). Spearman correlation analysis showed that the levels of all vitamins were negatively correlated with CKD stage, with correlation coefficients of -0.329, -0.357, -0.345, -0.373, -0.386 and-0.351, respectively ( P<0.01) . Conclusions:Metabolic abnormalities of watersoluble vitamins are common in CKD, which are closely related to the progression of CKD, inflammation and anemia. Timely evaluation and intervention may be beneficial to prevent the progression of CKD and provide a new treatment strategy for precise nutrition intervention in CKD.

Objective:To investigate the impact of the number of examined lymph nodes (ELN) on survival outcomes in gastric cancer patients with postoperative pathological stage pN3b.Methods:This retrospective cohort study included 279 pN3b gastric cancer patients who underwent D2 gastrectomy at Nanfang Hospital, Southern Medical University (September 2008 to April 2023), with 35 patients receiving combination chemotherapy and anti-PD-1 therapy (immunotherapy group) and 244 receiving adjuvant chemotherapy alone (nonimmunotherapy group). Additionally, 422 patients with pN3b from the SEER database (2005 to 2020) were collected as an external validation cohort to determine the optimal cutoff value for the number of lymph nodes examined in the nonimmunotherapy group. The primary endpoints were overall survival (OS) and recurrence-free survival (RFS) in the nonimmunotherapy group of the Nanfang Hospital cohort, stratified by whether the number of examined lymph nodes was above or below the ELN optimal cutoff value. These findings were subsequently validated in the SEER cohort.Results:The optimal ELN cutoff value (34 nodes) was determined using X-tile software and by constructing an ELN-HR fitting model with inflection point identification. In the nonimmunotherapy group, patients with ELN >34 exhibited significantly prolonged survival compared to ELN ≤34 (median OS: 25.0 (95%CI:20.5-29.5) to 17.0 (95%CI:12.7-21.3) months, P=0.004; median RFS: 19.0 (95%CI:15.6-22.4) to 13.0 (95%CI:9.5-16.5) months, P=0.048). Multivariate Cox analysis also showed ELN >34 to be an independent protective factor for both OS (HR=0.576, 95%CI: 0.397-0.836) and RFS (HR=0.701, 95%CI: 0.492-0.998). In the SEER cohort, ELN >34 was associated with a 5-month OS extension (19 to 14 months, P=0.065), with multivariate analysis supporting its independent prognostic significance (HR=0.729, 95%CI: 0.580-0.915, P=0.006). Notably, in the immunotherapy group, patients with ELN >34 ( n=30) achieved a median OS of 41 months, but the median OS had not been reached in the ELN ≤34 group ( n=5) (1 death at 48 months). Conclusion:Higher ELN (>34) correlates with improved survival in nonimmunotherapy-treated pN3b gastric cancer patients. However, in pN3b gastric cancer patients treated with immunotherapy, the optimal ELN threshold requires further exploration to determine.

Objective To compare the macular retinal thickness characteristics of diabetic kidney disease(DKD)patients with different blood pressure levels and explore the relationship between blood pressure and macular retinal damage in DKD patients.Methods A total of 435 DKD patients were selected and divided into four groups based on medical history and blood pressure:the non-hypertensive group(NH group,n=100),the well-controlled blood pressure group(G0 group,n=176),the grade 1 hypertension group(G1 group,n=118)and the grade 2 hypertension group(G2 group,n=41).General information,routine laboratory test results as well as the average thickness of the macular retinal nerve fiber layer(RNFL),ganglion cell layer(GCL),ganglion cell complex(GCC),choroidal layer(CL)and central macular retinal thickness(CMT)were compared between the four groups.The correlation between macular retinal thickness in both eyes and clinical data was analyzed.Results Compared with the G1 group and the G2 group,the G0 group had a longer duration of hypertension.Compared to the NH group,the G2 group had higher fasting plasma glucose(FPG).Compared to the G0 group,the G1 group and the G2 group had higher FPG,and the G2 group had higher glycated hemoglobin(HbA1c)and lower estimated glomerular filtration rate(eGFR).Compared to the NH group,the G0 group had decreased thickness in the GCL and GCC(P<0.05).The macular retinal thickness of the GCL and GCC in both eyes was negatively correlated with diastolic blood pressure(r=-0.158 and-0.195,respectively,P<0.05).Conclusion Macular retinal thickness is helpful in assessing the long-term effects of hypertension on optic nerve and microvascular damage in DKD patients.