BACKGROUND: Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. METHODS: This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70-120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion. RESULTS: The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2 (13.5-14.9) g/L and 14.3 (13.5-15.0) g/L, respectively. Over weeks 24-36 and 36-52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon. CONCLUSIONS: Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings. REGISTRATION Chinese Clinical Trial Registry ( www.chictr.org.cn ) ChiCTR2100046322; CDE ( www.chinadrugtrials.org.cn ) CTR20201568.
Humans ; Male ; Female ; Anemia/etiology* ; Middle Aged ; Renal Insufficiency, Chronic/complications* ; Glycine/adverse effects* ; Isoquinolines/adverse effects* ; Aged ; Prospective Studies ; Adult ; Hemoglobins/metabolism* ; Treatment Outcome ; China ; Registries ; East Asian People

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

Objective:To explore the association between the variability of triglyceride glucose index (TyG) and the risk of type 2 diabetes mellitus(T2DM).Methods:This study was a retrospective cohort study. A total of 22 929 community-dwelling elderly (aged≥60 years) who received annual health check-ups in Kunshan city of Suzhou Municipality during 2014 to 2021 were enrolled in the study. Fasting triglycerides and blood glucose were measured during annual physical check-ups and the TyG was calculated, the standard deviation of TyG measurements in three consecutive physical check-ups was used as the indicatior of TyG long-term variability. According to the quartile of TyG long-term variability, the study subjects were divided into four groups, namely Q 1 (0-0.14), Q 2 (>0.14-0.22), Q 3 (>0.22-0.33), Q 4 (>0.33-1.90). The outcome variable was the occurrence of T2DM. The relationship between TyG variability and T2DM incidence was analyzed by multivariate Cox regression. Results:In the study cohort 11 518 (50.2%) were females and the mean age was (67.42±5.35) years. By the end of follow-up, 2 934 cases of new T2DM were diagnosed, with an oveall incidence rate of 12.8%. After adjusting for multiple confounders and average TyG, long-term variability of TyG was significantly associated with T2DM risk ( HR=1.83, 95% CI: 1.51-2.20). The risk of T2DM in Q 4 group was significantly higher than that in Q 1 group ( HR=1.33, 95% CI: 1.19-1.47). Kaplan-Meier survival curve showed that long-term variability of TyG was significantly correlated with the cumulative risk of T2DM incidence ( P<0.001). Conclusions:TyG variability is an independent risk factor for T2DM, suggesting that attention should be paid not only to specific time-point TyG levels but also to TyG fluctuation for early identification of T2DM risk.

The cochlear auditory epithelium contains two types of sound receptors, inner hair cells (IHCs) and outer hair cells (OHCs). Mouse models for labelling juvenile and adult IHCs or OHCs exist; however, labelling for embryonic and perinatal IHCs or OHCs are lacking. Here, we generated a new knock-in Fgf8^P2A-3×GFP/+ (Fgf8^GFP/+) strain, in which the expression of a series of three GFP fragments is controlled by endogenous Fgf8 cis-regulatory elements. After confirming that GFP expression accurately reflects the expression of Fgf8, we successfully obtained both embryonic and neonatal IHCs with high purity, highlighting the power of Fgf8^GFP/+. Furthermore, our fate-mapping analysis revealed, unexpectedly, that IHCs are also derived from inner ear progenitors expressing Insm1, which is currently regarded as an OHC marker. Thus, besides serving as a highly favorable tool for sorting early IHCs, Fgf8^GFP/+ will facilitate the isolation of pure early OHCs by excluding IHCs from the entire hair cell pool.
Animals ; Mice ; Hair Cells, Auditory, Inner ; Cochlea/metabolism* ; Hair Cells, Auditory, Outer/metabolism* ; Disease Models, Animal ; Fibroblast Growth Factor 8/metabolism*

Objective:To explore the relationship between ABCB1 or ABCG2 gene polymorphisms and therapeutic effects of gefitinib in non-small cell lung cancer (NSCLC) patients, and establish a prediction model of efficacy.Methods:A total of 176 NSCLC patients with epidermal growth factor receptor (EGFR) -sensitive mutation treated with gefitinib admitted to Department of Pulmonary Disease of Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine of Hebei Province from December 2018 to December 2020 were employed as subjects, and all patients were detected ABCB1 and ABCG2 gene polymorphisms. Patients were divided into remission group and non-remission group according to curative effect after 3 months of gefitinib treatment. The clinical data, ABCB1 and ABCG2 gene polymorphisms, levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125) were compared between the two groups. The related factors of failure to remission after treatment were analyzed by multivariate logistic regression analysis. Combined with ABCB1 and ABCG2 gene polymorphisms, the prediction model for gefitinib efficacy was constructed and the nomogram was drawn.Results:During the follow-up period, 5 patients were lost to follow-up and 7 patients withdrew from the trial due to intolerable adverse effects, finally 108 patients were employed as remission group, and 56 patients were employed as non-remission group. The numbers of GG, GT and TT at ABCB1 rs2032582 in the remission group were 49, 50 and 9, and those in the non-remission group were 12, 35 and 9, with a statistically significant difference ( χ2=9.56, P=0.008). The numbers of GG, GA and AA at ABCG2 rs2231137 in the remission group were 13, 72 and 23, and those in the non-remission group were 11, 42 and 3, with a statistically significant difference ( χ2=7.74, P=0.021). Before treatment, the levels of serum CEA in the remission group and the non-remission group were (34.28±5.11) ng/ml and (37.88±7.05) ng/ml, with a statistically significant difference ( t=3.74, P<0.001). The levels of CA125 of the two groups were (27.24±6.50) U/ml and (33.31±6.09) U/ml, with a statistically significant difference ( t=-5.79, P<0.001). Multivariate logistic regression analysis showed that TT at rs2032582 of ABCB1 gene ( OR=12.99, 95% CI: 3.17-53.23, P<0.001), GG at rs2231137 of ABCG2 gene ( OR=7.75, 95% CI: 1.36-44.07, P=0.021) and GA ( OR=6.94, 95% CI: 1.47-32.84, P=0.015), CA125 ( OR=1.18, 95% CI: 1.10-1.28, P<0.001) were independent risk factors of failure to remission in NSCLC patients with EGFR sensitive mutation after treatment. The consistency index (C-index) of nomogram for predicting failure to remission was 0.92 (95% CI: 0.86-0.94) . Conclusion:ABCB1 rs2032582 and ABCG2 rs2231137 polymorphisms are related to therapeutic effects of gefitinib in the NSCLC patients, the nomogram based on the two genes combined with serum CA125 can predict efficacy of gefitinib.

OBJECTIVE：To s tudy the intestinal absorption differences of 6 kinds of active constituents of Polygonum orientale （kaempferol，isokaempferol，vitexin，protocatechuic acid ，kaempferol-3-O-β-D-glucoside and quercetin ）in normal and myocardial ischemia（MI）model rats. METHODS ：UPLC-MS/MS method was adopted to determine the contents of 6 active components in the intestinal circulatory perfusion fluid. Totally male SD 80 rats were divided into normal group and model group ，with 40 rats in each group. Model group was given isoproterenol hydrochloride （50 mg/kg） subcutaneously to induce MI model；normal group was given constant volume of normalsaline， once a day ， for consecutive 2 days. 24 h after successful molding ，normal group and model group received in-situ intestinal circulatory perfusion experiment. The effects of different concentration s of P. orientale extract（5.0，10.0， 20.0 mg/mL），different intestinal segments （duodenum，jejunum，ileum，colon），P-glycoprotein（P-gp）inhibitors（verapamil） and bile on the intestinal absorption of each constituent were explored. RESULTS ：The linear ranges of concentrations of kaempferol， isokaempferol， vitexin， protocatechuic acid ， kaempferol-3-O-β-D-glucoside and quercetin were 3.15-50.40， 3.21-51.31，1.63-52.43，1.60-50.94，1.31-20.97，8.07-129.25 µg/mL（r＞0.999）. The lower limits of quantification were 7.86， 8.45，6.52，4.00，3.28，16.14 ng/mL，respectively. RSDs of precision ，matrix effect and stability tests were all lower than 11％； the accuracy were 85.64％-107.65％，which were in line with the requirements of biological sample quantification analysis. Except for there was no statistical significance in the absorption of kaempferol absorption in duodenum of model group at different concentrations，absorption of other five constituents in duodenum of normal and model rats increased with the increase of the concentration of active constituents ，and absorption of medium- and/or high- concentration active constituents （except quercetin ）in model group was significantly lower than normal group （P＜0.05）. In normal group ，the absorption of kaempferol was more in jejunum，ileum and colon ，isokaempferol was more in ileum ，vitexin and protocatechuic acid were more in jejunum and ileum ， kaempferin-3-O- β-D-glucoside was more in duodenum ，jejunum and colon ，quercetin was more in colon ；in the model group ，the absorption of Polygonum orientale in jejunum and colon was more ，the absorption of isokaempferol in 4 intestinal segments was little different ，vitexin was mainly absorbed in ileum ，protocatechuic acid and kaempferol- 3-O-β-D-glucoside was mainly absorbed in jejunum ，quercetin was mainly absorbed in duodenum and ileum ；in the same intestine ，the absorption of constituents in the model group was less than normal group. After adding verapamil ，absorption of all constituents in the normal group increased ，but the difference was not statistically significant （P＞0.05）；absorption of kaempferol ，isokaempferol，vitexin，protocatechuic acid and kaempferol- 3-O-β-D-glucoside were all increased significantly in model group （P＜0.05），while there was no statistical significance in the increase of quercetin （P＞0.05）. After the bile flowed into the duodenum ，absorption of protocatechuic acid was increased significantly in normal group （P＜0.05）；absorption of other active constituents were increased significantly in model group，except for isokaempferol and quercetin （P＜0.05）. CONCLUSIONS ：Six active constituents of P. orientale were absorbed in the whole intestine of normal and MI model rats ，and the absorption of above constituents may be enhanced more significantly by P-gp inhibitor and bile under pathological condition.

Objective: To study the effect of plumbagin on epithelial-mesenchymal transition (EMT) and underlying mechanisms in human tongue squamous cell carcinoma (TSCC) cells. Methods: Methyl thiazolyl tetrazolium assay was apllied to examine the proliferation inhibition effect and half maximal inhibitory concentration (IC₅₀) of plumbagin (0.1, 1.0, 5.0, 10.0, 20.0 μmol/L) in 12, 24, 48 h in TSCC cells. Transwell assay was used to count the number of transmembrane cells and scratch test was performed to examine cells mobility. The flow cytometry was applied to measure intracellular reactive oxygen species (ROS) level in control group, plumbagin group (1.0 μmol/L, 24 h) and glutathione (GSH)+plumbagin group. The expression of E-cadherin, vimentin, Slug, p38 mitogen activated protein kinases (p38MAPK) and phospho-p38MAPK (p-p38MAPK) proteins were determined by Western blotting. The expression of E-cadherin, vimentin and Slug were detected by Western blotting in control group, plumbagin group, activator combined group (p38MAPK activator+plumbagin) and inhibitor combined group (p38MAPK inhibitor+plumbagin). Results: After the treatment of plumbagin for 12, 24, and 48 h, the IC₅₀ of TSCC cells were 10.3, 3.1, 1.5 μmol/L. After treated by 1.0 μmol/L plumbagin for 24 h, the number of transmembrane cells were significantly reduced ([50±13], P<0.05) in comparison to control group (204±6), as well as the cells mobility ([18.2±2.3]%, P<0.05) in comparison to control group ([49.3±1.2]%). Compared to control group (2.32±0.52), the ROS level was increased in plumbagin group (902.20±10.69), while compared to plumbagin group, the ROS level was reduced in GSH combined group (2.18±0.15). In comparison to control group, the expression of E-cadherin was up-regulated (P<0.05), and vimentin, Slug, p-p38MAPK/p38MAPK were down-regulated in plumbagin group (P<0.05). In comparison to plumbagin group, the expression of E-cadherin was down-regulated (P<0.05), and vimentin, Slug, p-p38MAPK/p38MAPK were up-regulated in GSH combined group (P<0.05). Treatment of cells with p38MAPK activator could decrease the expression of E-cadherin significantly (P<0.05) and increase the expression of vimentin (P<0.05) and Slug (P<0.05) in comparison to plumbagin group. Treatment of cells with p38MAPK inhibitor could increase the expression of E-cadherin significantly (P<0.05) and decrease the expression of vimentin (P<0.05) and Slug (P<0.05) in comparison to plumbagin group. Conclusions Plumbagin inhibits EMT via ROS/p38MAPK-mediated pathway in human TSCC cells.

Objective To investigate the application effect of nursing risk management among severe burn patients in intensive care unit ( ICU). Methods To select patients who were treated by nursing risk management intervention before was as control group, and the patients after nursing risk management intervention were chosen as observation group. We comparatively analyzed the knowledge control of nursing risk management before and after the intervention, adverse events of the patients, BICU hospitalization time, and the nursing work quality. Results The knowledge related severe burn acquired the average score of (78. 3 ± 10. 8) before intervention and (87. 6 ±11. 3) after intervention (t =2. 524,P <0. 05). During the treatment in the observation group, there were 14 cases pressure ulcer, 2 cases nosocomial infection, and 22 cases wound sepsis, all which were lower than those of the control group (χ2 =5. 340,5. 273,9. 877,respectively;P <0. 05). Conclusions The implementation of the nursing risk management can effectively improve the nurses′ risk consciousness and coping capacity, and it has great significance in reducing the occurrence of nursing adverse events and nursing disputes, so it is worth of popularization and application.