Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Lingguizhugan Decoction (LGZG) demonstrates significant efficacy in treating various cardiovascular diseases clinically, yet its precise mechanism of action remains elusive. This study aimed to elucidate the potential mechanisms and effects of LGZG on isoproterenol (ISO) continuous stimulation-induced chronic heart failure (CHF) in mice, providing direct experimental evidence for further clinical applications. In vivo, continuous ISO infusion was administered to mice, and ventricular myocytes were utilized to explore LGZG?s potential mechanism of action on the ?1-adrenergic receptor (?1-AR)/Gs/G protein-coupled receptor kinases (GRKs)/?-arrestin signaling deflection system in the heart. The findings reveal that LGZG significantly reduced the messenger ribonucleic acid (mRNA) expression of hypertrophy-related biomarkers [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] and improved cardiac remodeling and left ventricular diastolic function in mice with ISO-induced CHF. Furthermore, LGZG inhibited the overactivation of Gs/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling and downregulated the downstream transcriptional activity of cAMP-response element binding protein (CREB) and the expression of the coactivator CBP/P300. Notably, LGZG downregulated the expression of ?-arrestin1 and GRK 2/3/5 while upregulating the expression of ?1-AR and ?-arrestin2. These results suggest that LGZG inhibits Gs/cAMP/PKA signaling and ?-arrestin/GRK-mediated desensitization and internalization of ?1-AR, potentially exerting cardioprotective effects through the synergistic regulation of the ?1-AR/Gs/GRKs/?-arrestin signaling deflection system via multiple pathways.
Animals ; Heart Failure/genetics* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Mice ; Male ; G-Protein-Coupled Receptor Kinases/genetics* ; Mice, Inbred C57BL ; Humans ; Isoproterenol ; Arrestins/genetics* ; Chronic Disease

Objective:By analyzing the genetic risk of triglyceride-glucose index(Tyg)and insulin resistance(IR)for cardiovascular disease(CVD), to elucidate the extent to which the contribution of Tyg to the risk of CVD development is influenced by IR genetic risk.Methods:In this study, we selected data from a cohort of elderly people in the Kunshan community, screened 7, 385 individuals with both clinical and genomic data, and calculated the polygenic risk score of insulin resistance(IRPRS)for each participant based on publicly available IR genome-wide association data, and assessed the effect of genetic risk and Tyg level on the risk of developing CVD using a multivariate Cox proportional risk model.Calculating interactions to assess the effects of genetic risk and Tyg levels on the risk of developing CVD, the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD were assessed using a multivariate Cox proportional risk model, and subgroup analyses were performed for gender to assess the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD by gender.Results:In the univariate Cox model, Q3 and IRPRS with the highest TYG levels were significantly associated with the risk of CVD, respectively( HR=1.59, 95% CI: 1.33-1.89; P<0.001; HR=1.61, 95% CI: 1.18-2.20; P=0.003).After adjusting for multiple confounders, the Q3 Group with the highest TYG level was still significantly associated with the risk of CVD( HR=1.28, 95% CI: 1.05-1.57; P=0.014), the Association of TYG with the risk of CVD did not change significantly( HR=1.29, 95% CI: 1.05-1.57; P=0.014).We conducted a subgroup analysis by sex and found that among older men, 13, the highest levels of TYG and IRPRS were significantly associated with CVD risk, respectively( HR=1.70, 95% CI: 1.31.2.20; P<0.001; HR=1.98, 95% CI: 1.24-3.15; P=0.004).After adding IRPRS to the model, the Association of TYG with the risk of CVD remained unchanged( HR=1.69, 95% CI: 1.31-2.19; P<0.001).After adjusting for various confounders, Tyg remained significantly associated with the risk of CVD( HR=1.39, 95% CI: 1.04-1.88; P=0.028), the results showed that TYG remained significantly associated with the risk of CVD( HR=1.41, 95% CI: 1.05-1.90; P=0.023), and the association did not decrease.No Association of IRPRS with CVD risk was found in older women. Conclusions:IRPRS and TYG are the risk factors of CVD, and diet, exercise, drugs and other external factors on TYG are the main risk factors of CVD.For individuals with high genetic factors, the risk of CVD can still be reduced by lifestyle adjustments such as diet, exercise and drug intervention.

Objective:To construct and validate a predictive model for postoperative pulmonary complications (PPCs) in patients undergoing robot-assisted laparoscopic urological surgery.Methods:This retrospective study included the medical records of 932 patients who underwent robot-assisted laparoscopic urological surgery at the First Affiliated Hospital of Zhejiang University School of Medicine from January 2020 to February 2022. The patients were divided into a training group ( n=559) and a validation group ( n=373) at a 6∶4 ratio. Logistic regression analysis was used to determine the independent risk factors for PPCs, and a nomogram prediction model was constructed based on these factors. The performance of the model was evaluated using the receiver operating characteristic curve and calibration curve, and the clinical benefit was assessed using the clinical decision curve analysis. Results:The independent risk factors for PPCs included advanced age (>60 yr), smoking history, respiratory tract infection within 1 month, preoperative low SpO 2 (<96%), and prolonged length of postoperative hospital stay ( P<0.05), and the body mass index (18.5-<28.0 kg/m 2) was a protective factor. The nomogram prediction model developed based on the aforementioned 6 influencing factors had an area under the receiver operating characteristic curve of 0.81 (95% confidence interval 0.76-0.86) in training group and 0.80 (95% confidence interval 0.75-0.86) in validation group. The calibration curve indicated a good consistency between the predicted and actual occurrence curves, and the clinical decision curve analysis showed good accuracy and net benefit of the prediction model. Conclusions:The predictive model for PPCs is successfully constructed based on age, low body mass index, smoking history, history of respiratory tract infection within 1 month, preoperative low SpO 2 and prolonged length of postoperative hospital stay and has good predictive performance in patients undergoing robot-assisted laparoscopic urological surgery.

Objective To investigate the impact of smoking cessation on high-resolution compu-ted tomography(HRCT)phenotypes in smokers with chronic obstructive pulmonary disease(COPD)and its relationship with the frequency of acute exacerbations.Methods A retrospective study was conducted in 237 smokers with COPD who could cooperate with a 1-year follow-up.Among them,160 patients underwent a comprehensive 1-year smoking cessation intervention,and were divided into smoking cessation failure group(87 patients)and smoking cessation success group(73 patients)based on whether they successfully quited smoking.The remaining 77 smokers with COPD who did not receive smoking cessation intervention were designated as smoking group.HRCT phenotypes,total lung volume(TLV),total emphysema volume(TEV),emphysema index(EI)and the number of acute exacerbation at different time points were compared among the three groups.Pearson correlation analysis was used to explore the correlation between smoking cessation and the number of acute exac-erbations.Results There was no statistically significant difference in the proportion of A phenotype patients among the three groups before intervention and at 3 and 6 months of intervention(P＞0.05).At the 9th and 12th months of intervention,the proportion of patients with A phenotype in the smoking group was lower than that in the smoking cessation failure group and smoking cessation success group(P＜0.05).Before the intervention and at the 3rd,6th and 9th months of interven-tion,there were no statistically significant differences in the proportion of patients with E phenotype among the three groups(P＞0.05).Before intervention and at the 3rd and 6th months of interven-tion,there were no statistically significant differences in the proportion of patients with M phenotype among the three groups(P＞0.05).At the 9th and 12th months of intervention,the proportion of patients with M phenotype in the smoking group was higher than that in the smoking cessation failure group and smoking cessation success group(P＜0.05).Before intervention,there were no statisti-cally significant differences in TLV,TEV and EI among the three groups(P＞0.05).One year af-ter the intervention,TLV,TEV and El in the smoking cessation failure group and smoking cessation success group were lower than those in the smoking group(P＜0.05).At the 3rd,6th,9th and 12th months of intervention,the number of acute exacerbations in the the smoking cessation failure group and smoking cessation success group was less than that in the smoking group(P＜0.05).At the 9th and 12th months of intervention,the number of acute exacerbation in the smoking cessation success group was less than that in the smoking cessation failure group(P＜0.05).The results of Pearson correlation analysis showed that smoking cessation was negatively correlated with the number of acute exacerbation in smokers with COPD(P＜0.05),and this negative correlation gradually in-creased with the extension of smoking cessation duration.Conclusion Smoking cessation can im-prove HRCT phenotypes and effectively reduce the number of acute exacerbation in smokers with COPD.

Objective:To investigate the influencing factors of major adverse cardiovascular events (MACE) in maintenance hemodialysis (MHD) patients, and to construct and verify the nomogram.Methods:The clinical data of 240 patients with MHD admitted to the First Affiliated Hospital of Hebei North University from July 2022 to October 2023 were retrospectively analyzed. According to whether the patients had MACE, they were divided into two groups, namely the occurrence group (with MACE, n=55) and the non-occurrence group (without MACE, n=185). After comparing the clinical data of the two groups, The independent risk factors of MHD patients with MACE were screened by binary logistic regression analysis, and the risk nomogram prediction model was constructed according to the risk factors, and the prediction efficiency of the model was analyzed by Bootstrap method. Results:There were significant differences in age, dialysis age, hyperlipidemia, hyperuricemia and hemodialysis flux between the two groups (all P<0.05). Binary logistic regression model analysis showed that dialysis age >12 months, combined with hyperlipidemia, combined with hyperuricemia, and low throughput hemodialysis were independent risk factors for MHD patients with MACE (all P<0.05). The neomorph risk prediction model was constructed based on independent risk factors. The area under the curve (AUC) of the prediction model was 0.842(95% CI: 0.789-0.896), the specificity was 69.1%, the sensitivity was 89.7%, the cutoff value was 13.128, and the Yoden index was 0.588, suggesting that the accuracy of the model was good. Conclusions:Dialysis age >12 months, combined with hyperlipidemia, combined with hyperuricemia and low throughput hemodialysis are independent risk factors for MACE in MHD patients. Intervention and control of risk factors can reduce the incidence of MACE.

Objective:To construct and validate a predictive model for postoperative pulmonary complications (PPCs) in patients undergoing robot-assisted laparoscopic urological surgery.Methods:This retrospective study included the medical records of 932 patients who underwent robot-assisted laparoscopic urological surgery at the First Affiliated Hospital of Zhejiang University School of Medicine from January 2020 to February 2022. The patients were divided into a training group ( n=559) and a validation group ( n=373) at a 6∶4 ratio. Logistic regression analysis was used to determine the independent risk factors for PPCs, and a nomogram prediction model was constructed based on these factors. The performance of the model was evaluated using the receiver operating characteristic curve and calibration curve, and the clinical benefit was assessed using the clinical decision curve analysis. Results:The independent risk factors for PPCs included advanced age (>60 yr), smoking history, respiratory tract infection within 1 month, preoperative low SpO 2 (<96%), and prolonged length of postoperative hospital stay ( P<0.05), and the body mass index (18.5-<28.0 kg/m 2) was a protective factor. The nomogram prediction model developed based on the aforementioned 6 influencing factors had an area under the receiver operating characteristic curve of 0.81 (95% confidence interval 0.76-0.86) in training group and 0.80 (95% confidence interval 0.75-0.86) in validation group. The calibration curve indicated a good consistency between the predicted and actual occurrence curves, and the clinical decision curve analysis showed good accuracy and net benefit of the prediction model. Conclusions:The predictive model for PPCs is successfully constructed based on age, low body mass index, smoking history, history of respiratory tract infection within 1 month, preoperative low SpO 2 and prolonged length of postoperative hospital stay and has good predictive performance in patients undergoing robot-assisted laparoscopic urological surgery.

Objective:By analyzing the genetic risk of triglyceride-glucose index(Tyg)and insulin resistance(IR)for cardiovascular disease(CVD), to elucidate the extent to which the contribution of Tyg to the risk of CVD development is influenced by IR genetic risk.Methods:In this study, we selected data from a cohort of elderly people in the Kunshan community, screened 7, 385 individuals with both clinical and genomic data, and calculated the polygenic risk score of insulin resistance(IRPRS)for each participant based on publicly available IR genome-wide association data, and assessed the effect of genetic risk and Tyg level on the risk of developing CVD using a multivariate Cox proportional risk model.Calculating interactions to assess the effects of genetic risk and Tyg levels on the risk of developing CVD, the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD were assessed using a multivariate Cox proportional risk model, and subgroup analyses were performed for gender to assess the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD by gender.Results:In the univariate Cox model, Q3 and IRPRS with the highest TYG levels were significantly associated with the risk of CVD, respectively( HR=1.59, 95% CI: 1.33-1.89; P<0.001; HR=1.61, 95% CI: 1.18-2.20; P=0.003).After adjusting for multiple confounders, the Q3 Group with the highest TYG level was still significantly associated with the risk of CVD( HR=1.28, 95% CI: 1.05-1.57; P=0.014), the Association of TYG with the risk of CVD did not change significantly( HR=1.29, 95% CI: 1.05-1.57; P=0.014).We conducted a subgroup analysis by sex and found that among older men, 13, the highest levels of TYG and IRPRS were significantly associated with CVD risk, respectively( HR=1.70, 95% CI: 1.31.2.20; P<0.001; HR=1.98, 95% CI: 1.24-3.15; P=0.004).After adding IRPRS to the model, the Association of TYG with the risk of CVD remained unchanged( HR=1.69, 95% CI: 1.31-2.19; P<0.001).After adjusting for various confounders, Tyg remained significantly associated with the risk of CVD( HR=1.39, 95% CI: 1.04-1.88; P=0.028), the results showed that TYG remained significantly associated with the risk of CVD( HR=1.41, 95% CI: 1.05-1.90; P=0.023), and the association did not decrease.No Association of IRPRS with CVD risk was found in older women. Conclusions:IRPRS and TYG are the risk factors of CVD, and diet, exercise, drugs and other external factors on TYG are the main risk factors of CVD.For individuals with high genetic factors, the risk of CVD can still be reduced by lifestyle adjustments such as diet, exercise and drug intervention.

Objective:To investigate the influencing factors of major adverse cardiovascular events (MACE) in maintenance hemodialysis (MHD) patients, and to construct and verify the nomogram.Methods:The clinical data of 240 patients with MHD admitted to the First Affiliated Hospital of Hebei North University from July 2022 to October 2023 were retrospectively analyzed. According to whether the patients had MACE, they were divided into two groups, namely the occurrence group (with MACE, n=55) and the non-occurrence group (without MACE, n=185). After comparing the clinical data of the two groups, The independent risk factors of MHD patients with MACE were screened by binary logistic regression analysis, and the risk nomogram prediction model was constructed according to the risk factors, and the prediction efficiency of the model was analyzed by Bootstrap method. Results:There were significant differences in age, dialysis age, hyperlipidemia, hyperuricemia and hemodialysis flux between the two groups (all P<0.05). Binary logistic regression model analysis showed that dialysis age >12 months, combined with hyperlipidemia, combined with hyperuricemia, and low throughput hemodialysis were independent risk factors for MHD patients with MACE (all P<0.05). The neomorph risk prediction model was constructed based on independent risk factors. The area under the curve (AUC) of the prediction model was 0.842(95% CI: 0.789-0.896), the specificity was 69.1%, the sensitivity was 89.7%, the cutoff value was 13.128, and the Yoden index was 0.588, suggesting that the accuracy of the model was good. Conclusions:Dialysis age >12 months, combined with hyperlipidemia, combined with hyperuricemia and low throughput hemodialysis are independent risk factors for MACE in MHD patients. Intervention and control of risk factors can reduce the incidence of MACE.

Objective:To accurately ascertain the whole genome sequencing and the composition of open reading frames (ORFs) of non-replicating Tiantan strain of vaccinia virus (NTV) using next-generation long-read sequencing technology.Methods:NTV, obtained from our laboratory stock, was amplified and purified on chicken embryo fibroblast cells(CEFs), and the full-length genomic nucleic acid of NTV was extracted. The PacBio HiFi sequencing platform was utilized for de novo assembly to obtain the complete genomic sequence of NTV. Using a homology annotation strategy, we identified its ORF composition and compared it with known non-replicating vaccinia virus strains. Results:The total length of NTV′s genome was 171 729 bp, with a GC content of 33%. Its unique inverted terminal repeat (ITR) region comprised hairpin structures, two tandem repeat regions, and three non-repeat regions. NTV contained 166 ORFs, with major differences observed in the ITR and its surrounding regions when compared to MVA-BN and NYVAC. These three strains shared a common set of 138 ORFs. NTV encoded six unique ORFs related to virus evasion of host antiviral response.Conclusions:This study accurately determines the whole genome sequencing and ORFs composition of NTV, and reveals its similarities and differences with other replication-deficient vaccinia virus strains, which pave a way for the development and application of the next generation of monkeypox vaccines and novel viral vectors.