Objective To explore the safety and effects of alpha-lipoic acid (ALA) in patients with ischemic heart failure (IHF). Methods A randomized, double-blind, placebo-controlled trial was designed (ClinicalTrial.gov registration number NCT03491969). From January 2019 to January 2023, 300 patients with IHF were enrolled in four medical centers in China, and were randomly assigned at a 1∶1 ratio to receive ALA (600 mg daily) or placebo on top of standard care for 24 months. The primary outcome was the composite outcome of hospitalization for heart failure (HF) or all-cause mortality events. The second outcome included non-fatal myocardial infarction (MI), non-fatal stroke, changes of left ventricular ejection fraction (LVEF) and 6-minute walking distance (6MWD) from baseline to 24 months after randomization. Results Finally, 138 patients of the ALA group and 139 patients of the placebo group attained the primary outcome. Hospitalization for HF or all-cause mortality events occurred in 32 patients (23.2%) of the ALA group and in 40 patients (28.8%) of the placebo group (HR＝0.753, 95%CI 0.473-1.198, P＝0.231; Figure 1A-1C). The absolute risk reduction (ARR) was 5.6%, the relative risk reduction (RRR) associated with ALA therapy was approximately 19.4% compared to placebo, corresponding to a number needed to treat (NNT) of 18 patients to prevent one event. In the secondary outcome analysis, the composite outcome of the major adverse cardiovascular events (MACE) including the hospitalization for HF, all-cause mortality events, non-fatal MI or non-fatal stroke occurred in 35 patients (25.4%) in the ALA group and 47 patients (33.8%) in the placebo group (HR＝0.685, 95%CI 0.442-1.062, P＝0.091; Figure 1D). Moreover, greater improvement in LVEF (β＝3.20, 95%CI 1.14-5.23, P＝0.002) and 6MWD (β＝31.7, 95%CI 8.3-54.7, P＝0.008) from baseline to 24 months after randomization were observed in the ALA group as compared to the placebo group. There were no differences in adverse events between the study groups. Conclusions These results show potential long-term beneficial effects of adding ALA to IHF patients. ALA could significantly improve LVEF and 6MWD compared to the placebo group in IHF patients.

Objective To explore the value of combined ultrasound parameters, including the hepatorenal index (HRI) and renal resistance index (RRI), with cystatin C (CysC) in monitoring early acute kidney injury (AKI) after liver transplantation. Methods Perioperative data from 121 liver transplant recipients who received organs from donation after brain death were collected. The HRI and RRI of the recipients were measured on postoperative days 1-7 and at 1 month, and the CysC levels were measured on postoperative day 1. The recipients were divided into the AKI group (n=53) and the non-AKI group (n=68) based on whether AKI occurred within 7 days after operation. The data of the two groups were compared, and the ultrasound parameters before and after recovery in the AKI group were analyzed. The value of combined HRI, RRI and CysC in monitoring AKI was also analyzed. Results AKI occurred in 53 recipients, with an incidence rate of 43.8%, including 30 cases of stage 1, 18 cases of stage 2, and 5 cases of stage 3. Among them, 49 cases occurred on postoperative day 1, and 4 cases occurred on postoperative day 2. Of these, 43 cases recovered within 7 days after surgery, 8 cases recovered within 2 months after surgery, 1 case was lost to follow-up, and 1 case received renal replacement therapy. The body mass index and preoperative CysC levels were higher in the AKI group than in the non-AKI group, and the operative time was longer in the AKI group than in the non-AKI group (all P < 0.05). The HRI on postoperative day 1 was lower in the AKI group than in the non-AKI group, while the RRI and CysC levels were higher (all P < 0.05). When AKI occurred, the HRI was lower than the baseline level, and the RRI was higher than the baseline level. As AKI recovered, the HRI gradually increased, and the RRI gradually decreased. The receiver operating characteristic curve analysis showed that the sensitivity and specificity of HRI ≤ 1.12 for predicting AKI were 0.623 and 0.878, respectively, with an area under the curve (AUC) of 0.801. The sensitivity and specificity of RRI ≥ 0.65 for predicting AKI were 0.878 and 0.676, respectively, with an AUC of 0.825. The sensitivity and specificity of CysC ≥ 1.38 mg/L for predicting AKI were 0.736 and 0.882, respectively, with an AUC of 0.851 (all P<0.01). The combination of HRI and CysC (AUC=0.897, P<0.01), RRI and CysC (AUC=0.910, P<0.01), and all three parameters combined (AUC=0.934, P<0.01) were more effective than using each parameter alone. Conclusions HRI and RRI may be used to monitor the occurrence and recovery of early AKI after liver transplantation. The combination of these two parameters with CysC has a high application value in monitoring early AKI after liver transplantation.

Objective To compare the therapeutic efficacy of a self-locking zero-notch interbody fusion device for long-segment cervical spondylosis in elderly patients with traditional titanium plate combined with interbody fusion device.Methods From Jan 2019 to Jan 2021,elderly patients(>60 years)with 3-4 segments(C3-C7)radiculopathy,myelopathy,or mixed-type cervical spondylosis underwent anterior cervical discectomy and fusion(ACDF)using a zero-notch interbody fusion device(Group A,n=24)and ACDF using a titanium plate combined with an interbody fusion device(Group B,n=18).We recorded the surgery duration,blood loss,incision length and hospital stay,measure preoperative and postoperative intervertebral height,functional segment height and cervical lordosis,and also observe treatment outcomes and postoperative complications between the two groups.Results There were no statistically significant differences between the two groups in terms of gender,age,Japanese Orthopaedic Association(JOA)score,visual analogue scale(VAS)of upper limb,Neck Disability Index(NDI),preoperative intervertebral height,functional segment height and cervical lordosis.Blood loss,surgery time and hospital stay were similar in both groups,but Group A had shorter incision length(P<0.01)compared with Group B.There were no significant differences between the two groups in JOA scores,upper limb VAS and postoperative NDI,and even in postoperative intervertebral height,functional segment height and cervical lordosis recovery.Conclusion The zero-notch interbody fusion device is effective for treating long-segment cervical spondylosis.Compared with the traditional titanium plate combined with an interbody fusion device,it can avoid postoperative dysphagia with smaller incision and shorter surgery time,which makes it more suitable for elderly patients.

Objective To explore the mechanism by which Pulsatilla saponin D(PSD)inhibits invasion and metastasis of triple-negative breast cancer(TNBC).Methods The public databases were used to identify the potential targets of PSD and the invasion and metastasis targets of TNBC to obtain the intersection targets between PSD and TNBC.The"PSD-target-disease"interaction network was constructed and protein-protein interaction(PPI)analysis was performed to obtain the core targets,which were analyzed for KEGG pathway and GO functional enrichment.Molecular docking study of the core targets and PSD was performed,and the therapeutic effect and mechanism of PSD were verified using Transwell assay and Western blotting in cultured TNBC cells.Results Network pharmacology analysis identified a total of 285 potential PSD targets and 26 drug-disease intersection core targets.GO analysis yielded 175 entries related to the binding of biomolecules(protein,DNA and RNA),enzyme activities,and regulation of gene transcription.KEGG analysis yielded 46 entries involving pathways in cancer,chemical carcinogenesis-receptor activation,microRNAs in cancer,chemical carcinogenesis-reactive oxygen species,PD-L1 expression and PD-1 checkpoint pathway in cancer.Molecular docking showed high binding affinities of PSD to MTOR,HDAC2,ABL1,CDK1,TLR4,TERT,PIK3R1,NFE2L2 and PTPN1.In cultured TNBC cells,treatment with PSD significantly inhibited cell invasion and migration and lowered the expressions of MMP2,MMP9,N-cadherin and the core proteins p-mTOR,ABL1,TERT,PTPN1,HDAC2,PIK3R1,CDK1,TLR4 as well as NFE2L2 expressionin the cell nuclei.Conclusion The inhibitory effects of PSD on TNBC invasion and metastasis are mediated by multiple targets and pathways.

Objective:To explore the feasibility and effectiveness of full free-breathing cardiac magnetic resonance (CMR) in clinical practice.Methods:The study prospectively included patients who underwent full free-breathing CMR and traditional breath-holding cine imaging between June 1 and June 30, 2024. An analysis and comparison were conducted on the image acquisition time, image quality, and left ventricular function parameters under two scanning methods, including left ventricular ejection fraction (LVEF), left ventricular cardiac output (LVCO),left ventricular end diastolic volume (LVEDV), left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic volume (LVESV), left ventricular end systolic volume index (LVESVI), left ventricular stroke volume (LVSV), and left ventricular mass (LVM). In addition, the study conducted both quantitative and qualitative analyses of other sequences in full free-breathing CMR, including T 1 mapping, T 2 mapping, flow imaging, and late gadolinium enhancement (LGE). Group comparisons were performed using the Wilcoxon signed-rank test or paired t-test. Consistency assessments included Bland-Altman analysis, intraclass correlation coefficient ( ICC), and linear regression analysis. Results:Totally, 150 patients were recruited into the study. The average acquisition time of full free-breathing CMR was (22.1±3.1) min, with an average short axis cine sequence examination time of (2.7±0.4) min; The average acquisition time of short axis images in a breath-holding state was (4.9±1.4) min, which was significantly longer than the cine scan in the free-breathing state ( P0.001). The cine and LGE images quality scores obtained from full free-breathing CMR were 4 (4, 4) points and 5 (4, 5) points, respectively, while the cine image quality score obtained in a breath-holding state was 5 (4, 5) points. Compared with traditional breath-hold CMR, free-breathing CMR measurements showed slightly higher LVESV, and LVESVI, while LVEDV, LVEDVI, LVSV, LVCO, LVEF, and LVM were slightly lower, except for LVSV and LVCO, which showed no statistically significant difference, the differences in other cardiac function parameters were statistically significant ( P0.05). However, the two methods demonstrated good consistency( ICC0.947) and correlation (0.808 r0.993, P0.001). The Bland-Altman analysis showed that the bias for all cardiac function parameters was within 8.0%. The Native T 1 and T 2 values for free-breathing CMR were (1 277.5±57.0) ms and 40.1 (38.5, 41.4) ms, respectively, and the results of flow imaging and echocardiography were basically consistent. Conclusions:Free-breathing CMR is feasible and effective in clinical practice, showing a high level of consistency with left ventricular functional parameters obtained from traditional breath-hold scanning. It significantly shortens examination time and holds great clinical value for the promotion and widespread use of CMR.

Objective:To investigate the views of doctors on the incidence and treatment tactics of mild progression after epithelial growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)treatment in lung adenocarcinoma and provide suggestions to optimize the counter-measure strategies.Methods:Convenience sampling was used to conduct an online questionnaire survey for doctors specializing in onco-logy and respiratory diseases.Results:584 valid questionnaires were collected,and all the doctors expressed concerns regarding mild tumor progression after EGFR-TKI treatment.The coping strategies included maintaining the original TKI treatment,adding other treatments to the original TKI,changing the regimen,and performing secondary tissue biopsy,among which,most doctors chose to add other treatments to the original TKI.Conclusions:Doctors have noticed the enlargement of target lesions in still stable disease(SD)and most frequently chose to add other treatments to the original TKI as a coping strategy.This finding can provide a reference for framing future guidelines for large sample prospective clinical studies that are needed to find the most effective synergistic treatment options.

Objective To investigate the histological and cellular bases for the improvement of portal hypertension(PH)by observing liver histopathological changes after treatment in patients with cirrhotic portal hypertension,and to provide a basis for clinical drug development.Methods A total of 322 patients with hepatitis B cirrhosis who completed 48 weeks of antiviral therapy or combined anti-fibrotic treatment in 20 hospitals across 12 provinces in China from September 2014 to October 2018 were enrolled,and the noninvasive diagnostic criteria for clinically significant portal hypertension(CSPH)from Baveno Ⅶ were used to assess the severity of PH;43 patients with a confirmed diagnosis of CSPH were identified based on liver stiffness measurement(LSM)≥25 kPa before treatment,and according to whether the severity of PH was reduced by≥2 grades after treatment,the patients were divided into PH improvement(n=19)group and PH non-improvement group(n=24).Related data were collected,including demographic data,laboratory tests.Liver fibrosis were assessed,including HE staining and reticular fiber staining;liver microvascular lesions were assessed,including obliterative portal venopathy(OPV),nodular regenerative hyperplasia(NRH),and incomplete septal fibrosis(ISF).Single immunohistochemical staining was performed for von Willebrand factor(vWF),and fibronectin;multiplex immunohistochemical staining was performed for fibrinogen,CD32b,CD31,alpha-smooth muscle actin(α-SMA).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.Results After 48 weeks of treatment,43 patients had significant improvements in red blood cell count,alanine aminotransferase,aspartate aminotransferase,aspartate aminotransferase-to-platelet ratio index score,liver fibrosis grade,and PH grade(all P<0.05),among whom 19 patients showed a reduction in PH severity by≥2 grades(PH improvement group),while the remaining patients were enrolled as the PH non-improvement group.There was no significant difference in the outcome of liver fibrosis between the two groups(χ2=3.380,P=0.066).Microvascular lesion assessment showed that compared with the PH non-improvement group,the PH improvement group had significantly lower OPV severity,microvascular density(the expression level of vWF),and expression of fibronectin(all P<0.05),while there were no significant differences in NRH severity,ISF severity,and the expression level of fibrinogen between the two groups(all P>0.05).Cytological evaluation showed no significant differences in the expression levels of CD32b,CD31,and α-SMA between the two groups before and after treatment(all P>0.05),and comparison of the expression levels before and after treatment showed that the PH improvement group had a significant increase in the expression level of CD32b(t=-2.007,P=0.045)and a significant reduction in the expression level of α-SMA(t=2.628,P=0.013).Conclusion The pathological features of PH improvement are associated with liver fibrosis regression and the improvement in liver microvascular lesions,and at the cellular level,PH improvement is associated with the dedifferentiation of liver sinusoidal endothelial cells and the activated phenotype of hepatic stellate cells.

PURPOSE: To investigate the protective effect of sub-hypothermic mechanical perfusion combined with membrane lung oxygenation on ischemic hypoxic injury of yorkshire brain tissue caused by traumatic blood loss. METHODS: This article performed a random controlled trial. Brain tissue of 7 yorkshire was selected and divided into the sub-low temperature anterograde machine perfusion group (n = 4) and the blank control group (n = 3) using the random number table method. A yorkshire model of brain tissue injury induced by traumatic blood loss was established. Firstly, the perfusion temperature and blood oxygen saturation were monitored in real-time during the perfusion process. The number of red blood cells, hemoglobin content, NA⁺, K⁺, and Ca²⁺ ions concentrations and pH of the perfusate were detected. Following perfusion, we specifically examined the parietal lobe to assess its water content. The prefrontal cortex and hippocampus were then dissected for histological evaluation, allowing us to investigate potential regional differences in tissue injury. The blank control group was sampled directly before perfusion. All statistical analyses and graphs were performed using GraphPad Prism 8.0 Student t-test. All tests were two-sided, and p value of less than 0.05 was considered to indicate statistical significance. RESULTS: The contents of red blood cells and hemoglobin during perfusion were maintained at normal levels but more red blood cells were destroyed 3 h after the perfusion. The blood oxygen saturation of the perfusion group was maintained at 95% - 98%. NA⁺ and K⁺ concentrations were normal most of the time during perfusion but increased significantly at about 4 h. The Ca²⁺ concentration remained within the normal range at each period. Glucose levels were slightly higher than the baseline level. The pH of the perfusion solution was slightly lower at the beginning of perfusion, and then gradually increased to the normal level. The water content of brain tissue in the sub-low and docile perfusion group was 78.95% ± 0.39%, which was significantly higher than that in the control group (75.27% ± 0.55%, t = 10.49, p < 0.001), and the difference was statistically significant. Compared with the blank control group, the structure and morphology of pyramidal neurons in the prefrontal cortex and CA1 region of the hippocampal gyrus were similar, and their integrity was better. The structural integrity of granulosa neurons was destroyed and cell edema increased in the perfusion group compared with the blank control group. Immunofluorescence staining for glail fibrillary acidic protein and Iba1, markers of glial cells, revealed well-preserved cell structures in the perfusion group. While there were indications of abnormal cellular activity, the analysis showed no significant difference in axon thickness or integrity compared to the 1-h blank control group. CONCLUSIONS Mild hypothermic machine perfusion can improve ischemia and hypoxia injury of yorkshire brain tissue caused by traumatic blood loss and delay the necrosis and apoptosis of yorkshire brain tissue by continuous oxygen supply, maintaining ion homeostasis and reducing tissue metabolism level.
Animals ; Perfusion/methods* ; Disease Models, Animal ; Brain Injuries/etiology* ; Swine ; Male ; Hypothermia, Induced/methods*

OBJECTIVE: To investigate the expression and potential mechanism of calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ) in patients with acute myeloid leukemia (AML). METHODS: Peripheral blood samples were collected from 90 AML patients, and mononuclear cells were isolated. The expression of CaMKIIγ was measured using real-time quantitative PCR and Western blot. The diagnostic value of CaMKIIγ for AML was assessed, and its correlation with clinical characteristics was analyzed using the clinical data of patients. Additionally, the molecular mechanisms of CaMKIIγ were preliminarily explored. RESULTS: Compared with the control group, the expression of CaMKIIγ was significantly upregulated in AML patients. Receiver operating characteristic (ROC) curve analysis showed that CaMKIIγ could serve as a promising biomarker for distinguishing AML patients from healthy individuals. Furthermore, CaMKIIγ was significantly correlated with white blood cell (WBC) count and FLT3-ITD mutation. CaMKIIγ was highly expressed in both newly diagnosed and relapsed AML patients, while decreased during remission. In AML cell lines, the expression levels of CaMKIIγ were all elevated. Inhibition of phosphorylated CaMKIIγ by berbamine led to a decrease in pAKT and pSTAT5 expression. CONCLUSION CaMKIIγ is significantly upregulated in AML patients, and is associated with poor clinicopathological features and unfavorable prognosis. It may serve as a prognostic marker and potential therapeutic target in AML. Its expression may be related to the activation of pAKT and pSTAT5, suggesting that CaMKIIγ may contribute to the development and progression of AML through the activation of the AKT/STAT5 signaling pathway.
Humans ; Leukemia, Myeloid, Acute/metabolism* ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; STAT5 Transcription Factor/metabolism* ; Male ; Female ; Proto-Oncogene Proteins c-akt/metabolism* ; Mutation ; Middle Aged ; Adult ; Clinical Relevance

OBJECTIVES: To explore the mechanism by which Pulsatilla saponin D (PSD) inhibits invasion and metastasis of triple-negative breast cancer (TNBC). METHODS: The public databases were used to identify the potential targets of PSD and the invasion and metastasis targets of TNBC to obtain the intersection targets between PSD and TNBC. The "PSD-target-disease" interaction network was constructed and protein-protein interaction (PPI) analysis was performed to obtain the core targets, which were analyzed for KEGG pathway and GO functional enrichment. Molecular docking study of the core targets and PSD was performed, and the therapeutic effect and mechanism of PSD were verified using Transwell assay and Western blotting in cultured TNBC cells. RESULTS: Network pharmacology analysis identified a total of 285 potential PSD targets and 26 drug-disease intersection core targets. GO analysis yielded 175 entries related to the binding of biomolecules (protein, DNA and RNA), enzyme activities, and regulation of gene transcription. KEGG analysis yielded 46 entries involving pathways in cancer, chemical carcinogenesis-receptor activation, microRNAs in cancer, chemical carcinogenesis-reactive oxygen species, PD-L1 expression and PD-1 checkpoint pathway in cancer. Molecular docking showed high binding affinities of PSD to MTOR, HDAC2, ABL1, CDK1, TLR4, TERT, PIK3R1, NFE2L2 and PTPN1. In cultured TNBC cells, treatment with PSD significantly inhibited cell invasion and migration and lowered the expressions of MMP2, MMP9, N-cadherin and the core proteins p-mTOR, ABL1, TERT, PTPN1, HDAC2, PIK3R1, CDK1, TLR4 as well as NFE2L2 expressionin the cell nuclei. CONCLUSIONS The inhibitory effects of PSD on TNBC invasion and metastasis are mediated by multiple targets and pathways.
Humans ; Triple Negative Breast Neoplasms/metabolism* ; Saponins/pharmacology* ; Pulsatilla/chemistry* ; Female ; Molecular Docking Simulation ; Cell Line, Tumor ; Neoplasm Invasiveness ; Protein Interaction Maps ; Neoplasm Metastasis ; Signal Transduction/drug effects* ; Cell Movement/drug effects*