Objective To explore the pharmacokinetic changes of single dose of fentanyl in rats in a simulated high-altitude and contributing factors.Methods Thirty-six healthy female SD rats(6～8 weeks old,250±20 g)were randomly divided into high-altitude-acute-exposure group(group A),high-altitude-chronic-exposure group(group S)and control group(group C)through random number table,with 12 rats in each group.The group A and S were housed in a low-pressure chamber simulating the high altitude of 5000 m above sea level for 3 and 30 d respectively,and the group C was housed out of the chamber(at an altitude of 300 m).A single dose of fentanyl was administered through the femoral vein to 6 rats randomly selected from each group.Liquid chromatography tandem mass spectrometry(LC-MS/MS)was used to detect blood concentrations of fentanyl and WinNonlin 8.2 software was used to calculate the pharmacokinetic parameters,while blood samples were taken through the femoral artery before and in 1,2,4,8,15,30,60,120 and 180 min after administration.The remaining 6 rats were ultrasonographically assessed for portal vein internal diameter(PVD),peak flow velocity(PVV)and blood flow(PVF),and liver tissues were collected for CYP3A1 protein content assay.Results The blood drug concentrations of fentanyl in the group A and group S were significantly lower than those in the group C at 60,120,and 180 min(P=0.002,P＜0.001,P= 0.001).Compared with the group C,the clearance rate(CL)of the group A was increased by 54.06%(P=0.021),and the mean residence time(MRTlast)was shortened by 24.21%(P=0.033);CL of the group S was increased by 50.10%(P=0.041),the area under the concentration-time curve(AUC0-t,AUC0-∞)and MRTlast were reduced by 18.92%(P=0.039),27.54%(P=0.018)and 33.61%(P= 0.004),respectively.PVD and PVF in the group S increased by 10.87%(P=0.006)and 42.50%(P= 0.006)when compared with the group C.The CYP3A1 protein content in the group A was 28.74%,which was higher than that in the group C(P=0.048).Conclusion Fentanyl is cleared significantly faster after a single dose in rats in simulated high-altitude,which may be related to the increased liver blood flow and increased CYP3A1 protein expression in liver.

Objective To investigate the effect of locking plate combined with cortical screw internal fixation on ankle function and quality of life in patients with ankle fracture with tibiofibular separation.Methods A total of 120 patients with ankle fracture and distal tibiofibular separation treated in our hospital from May 2020 to December 2021 were selected and divided into control group and observation group according to random number table method,with 60 patients/group.The control group was treated with cortical screw fixation alone,and the observation group was treated with locking plate combined with cortical screw internal fixation.Before surgery and 6 months after surgery,the recovery function of the two groups was compared.X-ray,operation duration,healing time,intraoperative blood loss,postoperative complications were compared,and the living ability of the two groups of patients was evaluated.Results Before treatment,there was no difference in joint function between the two groups(P＞0.05).After treatment,the longest walking of the control group(15.89±0.85),foot alignment(15.06±0.71),pain response(29.03±4.48)and ground walking(15.65±0.59).The longest walking distance(16.19±0.87),foot alignment(15.29±0.76),pain response(31.24±4.55)and ground walking(15.96±0.68)in the observation group,which were higher than those in control group(P＜0.05).Compared with the control group,the intraoperative blood loss and healing time in the observation group were lower(P＜0.05).BI index of the two groups before treatment had no difference(P＞0.05);After treatment,BI index of observation group was higher than that of control group(P＜0.05).There was no difference in the total complication rate between the two groups(P＞0.05).Conclusion Locking plate combined with cortical screw internal fixation has a good therapeutic effect on improving ankle function,reducing intraoperative blood loss,promoting healing and improving behavioral ability in the treatment of ankle fracture combined with hypotibiofibular syndesmosis injury.

This study was designed to investigate the effect of Sijunzi decoction(SJZD)on the expression of inflammatory factors and autophagic proteins in the hippocampus of senescence-accelerated mouse prone 8(SAMP8)mice and its mechanism.SAMR1 mice were used as control group,and 32 SAMP8 mice were divided into model group,donepezil group,SJZD low and SJZD high dose treatment groups.Y-maze experiment was performed to detect changes in mouse memory function;the expression of NF-κB was detected by immunohistochemistry;the levels of TNF-α,IL-1β,IL-6 were detected by ELISA;the expression of A[3,caspse-1,beclin-1 and LC3-Ⅱproteins in hippocampal tissue were detected by Western blotting.Compared with the control group,the model group mice showed a decrease in total number of entries and alternations,an elevation in the levels of TNF-α,IL-1β,IL-6,Aβ protein and caspse-1 protein,and downregulation in the expression of beclin-1 and LC3-Ⅱ proteins.Both donepezil and SJZD(low-dose group and high-dose group)can reverse these changes in model mice.In conclusion,the mechanism of SJZD in treating Alzheimer's disease may relate to the correction of central hippocampal inflammatory factors and autophagy dysfunction.

Objective:To seek a correlation between short-chain fatty acids (SCFAs) and skill in the activities of daily living (ADL) after an ischemic stroke.Methods:Ninety ischemic stroke survivors were assessed using the Barthel Index (BI). Fecal samples were collected and analyzed for the concentration of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid using gas chromatography. Spearman correlation analysis was conducted to identify SCFAs that correlated with the total BI score. Linear regressions were evaluated to explore the correlation between the total BI score and SCFAs.Results:The concentrations of propionic and butyric acids in the feces were found to correlate significantly with the total BI scores. Data including propionic acid and butyric acid levels, age, gender, body mass index, disease duration, any history of hypertension or diabetes, and other SCFAs were included in the regression models. Propionic and butyric acid levels were found to be potentially useful predictors of total BI scores.Conclusions:The concentration of propionic and butyric acids in the feces after an ischemic stroke can predict the survivor′s total BI score. Those concentrations could therefore be useful for predicting ADL ability.

Pan-immune inflammation value (PIV) is a comprehensive immune inflammatory biomarker based on complete blood cell counts, which has been proven to predict treatment response and survival outcomes for different types of tumors. However, the predictive value of the PIV varies in different strategies for tumor treatment. This paper aims to systematically review the latest progress of PIV in predicting survival outcomes and tumor prognosis for immunotherapy, radiotherapy, targeted therapy, endocrine therapy, surgical treatment and neoadjuvant therapy, and analyze its existing challenges and issues, as well as look forward to its future development direction and application prospects.

Objective To investigate the expression and clinical significance of microRNA-148a-3p (miR-148a-3p) in lung adenocarcinoma and analyze the effect and mechanism of miR-148a-3p on radiotherapy sensitivity of lung adenocarcinoma cells by targeting the protein core 1β13-galactosyltransferase 1(C1GALT1). Methods Seventy-six patients' tumor tissues from lung adenocarcinoma tissue microarrays and lung adenocarcinoma A549 cell line were selected for the study. The miR-148a-3p in situ hybridizations (ISH) and C1GALT1 immunohistochemical staining were performed on the tissue microarrays to analyze the correlations of miR-148a-3p expression with clinical pathology, prognosis and C1GALT1 expression in the tumor tissues of the 76 patients with lung adenocarcinoma. A549 cells were transfected with miR-148a-3p overexpression plasmid by using cell transfection technique; the clone formation assay was used to detect the sensitivity of the transfected cells for radiotherapy after receiving 2 Gy radiotherapy; the protein expression level of cellular C1GALT1 was detected by western blot; the targeted regulatory relationship between miR-148a-3p and C1GALT1 was verified by dual-luciferase reporter gene experiment; the mechanism of miR-148a-3p regulating the sensitivity of A549 cells to radiotherapy was analyzed by co-transfection technique. Results Low expression of miR-148a-3p in 76 cases of lung adenocarcinoma tissues was significantly associated with lymph node metastasis (P=0.012); the prognosis of patients with high expression of miR-148a-3p was significantly better than that of patients with low expression of miR-148a-3p (P=0.005); there was a significant negative correlation between the expression of miR-148a-3p and C1GALT1 in lung adenocarcinoma tissues (P=0.023). Multivariate analysis showed that low expression of miR-148a-3p, T staging and lymph node metastasis were the independent risk factors for prognosis. Clone formation experiment showed that the number of clone formation in the miR-148a-3p overexpression group was significantly lower than that in the control group (P < 0.001); western blot result showed that overexpression of miR-148a-3p was able to significantly down-regulate the level of C1GALT1 protein in cells (P < 0.001). Dual luciferase reporter gene experiment showed that miR-148a-3p was able to regulate the expression of C1GALT1 by binding to the 3'UTR of C1GALT1. Functional rescue experiment showed that C1GALT1 could partially offset the radiosensitization effect of miR-148a-3p. Conclusion Low expression of miR-148a-3p in lung adenocarcinoma is significantly associated with lymph node metastasis, high expression of C1GALT1 and poor prognosis, and miR-148a-3p can enhance the radiosensitivity of lung adenocarcinoma cells by negatively regulating the expression of C1GALT1.

Objective To investigate the correlation between pre-treatment pan-immune inflammation value (PIV) and clinicopathological features in esophageal squamous cell carcinoma (ESCC) patients with postoperative adjuvant radiotherapy and evaluate its value in prognosis assessment combined with T stage. Methods A retrospective analysis was conducted on data of 85 ESCC patients with postoperative adjuvant radiotherapy in the Department of Radiation Oncology of the Affiliated Hospital of Yangzhou University from January 2019 to January 2023. The receiver operating characteristic (ROC) curve was drew to obtain the optimal cut-off value of PIV and other immune-inflammatory biomarkers. The area under the curve (AUC) and clinical applicability of PIV and other immune-inflammatory biomarkers were compared based on the ROC curve and decision curve analysis (DCA). According to the optimal cut-off value, patients were divided into high PIV group and low PIV group, and the correlation between PIV level and clinicopathological features of ESCC was evaluated. Kaplan-Meier method was used for survival analysis, the Cox proportional hazards model was used for multivariate analysis, and a risk stratification model combining PIV and T stage was established by recursive partitioning analysis (RPA). Results The optimal cut-off value of pre-treatment PIV was determined as 187.22 based on the ROC curve. The AUC of PIV was 0.679, which was greater than 0.640, 0.583, 0.656 and 0.644 of the other four immune-inflammatory biomarkers such as the systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR). The 85 patients were divided into low PIV group (< 187.22, n=48) and high PIV group (≥187.22, n=37). The level of PIV was significantly correlated with tumor diameter (P < 0.05). The 3-year overall survival (OS) (75.6% versus 30.6%, P < 0.001) and 3-year disease-free survival (DFS) (56.1% versus 21.0%, P < 0.001) were significantly higher in the low PIV group than the high PIV group. Tumor diameter, T stage and PIV were independent factors affecting OS in ESCC patients (P < 0.05), and T stage and PIV were independent factors affecting DFS in ESCC patients (P < 0.05). A new staging system with three risk groups was established by the RPA stratification model based on T stage and PIV, which further improved the predictive value of prognosis compared with T stage or PIV alone. Conclusion Pre-treatment PIV is helpful in predicting the prognosis of ESCC patients with postoperative adjuvant radiotherapy, and the combination of PIV and T stage can improve the predictive value.

Objective To investigate the predictive value of serum neuron-specific enolase (NSE), prognostic nutritional index (PNI) score, hepatic encephalopathy (HE) grading, and the integrated model for end-stage liver disease (iMELD) score in assessing the short-term (90-day) prognosis of patients with cirrhosis complicated by overt hepatic encephalopathy (HE). Methods A retrospective analysis was conducted on clinical data from 470 patients with cirrhosis and overt HE, and they were divided into survival group (n=359) and mortality group (n=111) based on their survival status 90 days after admission. The PNI and iMELD scores were calculated using patient demographics, blood routine tests, coagulation function, liver and renal function electrolyte levels, and serum NSE levels within 24 hours of admission, along with HE grading. Receiver operating characteristic (ROC) curves, multivariate Logistic regression analysis, and Kaplan-Meier survival curves were employed to evaluate influencing factors of short-term prognosis of patients with cirrhosis and overt HE. Results The mortality group exhibited significantly higher serum NSE levels, HE grades, and iMELD scores, while demonstrated lower PNI score compared to the survival group (P < 0.05). Multivariate Logistic regression analysis identified serum NSE, PNI score, HE grade, and iMELD score as independent predictors of short-term prognosis. The areas under the curve (AUCs) for serum NSE, PNI score, HE grade, and iMELD score in predicting short-term prognosis were 0.727, 0.717, 0.721, and 0.728, respectively, with cut-off values of 12.23 ng/mL, 34.05 ng/mL, and 39.26 points for serum NSE, PNI score, and iMELD score. A combined prediction model of four factors demonstrated the highest predictive performance, with an AUC of 0.919 and a cut-off value of 0.23. Kaplan-Meier survival analysis revealed that patients with combined score of serum NSE, PNI score, HE grade, and iMELD cut-off value < 0.23 had a significantly higher 90-day survival rate compared to those with cut-off value≥0.23 (Log-Rank=265.567, P < 0.001). Conclusion Serum NSE, PNI score, HE grade, and iMELD score exhibit good value in predicting the short-term prognosis of patients with cirrhosis and overt HE, with an even higher predictive value when used in combination.

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex (TRiC) contains eight paralogous subunits (CCT1-8), and assists the folding of as many as 10% of cytosolic proteome. TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma, and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma. Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.

ObjectiveTo study the expression changes of Lon protein and mitochondrial dynamics-related protein in the hippocampus of SAMP8 mice and provide a theoretical basis for the treatment of Alzheimer's disease by invigorating the spleen and supplementing Qi. MethodEight 3-month-old SAMR1 mice were used as the normal group， and 32 3-month-old SAPM8 mice were divided into model group， western medicine group （0.013 g·kg^-1）， low-dose Si Junziwan group （3.24 g·kg^-1）， and high-dose Si Junziwan group （12.56 g·kg^-1）， with 8 mice in each group. The western medicine group was gavaged with donepezil， and the Si Junziwan low- and high-dose groups were gavaged with Si Junziwan for 30 days. The positioning navigation experiment of the water maze was started on the 25^th day， and the space exploration experiment of the water maze was started on the 30^th day. On the 30^th day， the protein expression of mitofusin 2 （MFN2） was detected by immunohistochemistry， the expression of adenosine 5'-monophosphate （AMP）-activated protein kinase （AMPK） was detected by enzyme-linked immunosorbent assay （ELISA）， the content of ATP was detected by colorimetry， the microstructure of neuron mitochondria was detected by electron microscope， and the expressions of Aβ protein， Lon protein， dynamin-related protein 1 （DRP1） protein， and MFN1 protein were detected by Western blot. ResultAs compared with the normal group， the latency escape period increased， the number of crossings decreased， the expression of AMPK increased， and the content of ATP decreased in the model group. The expressions of Aβ protein and DRP1 protein increased （P<0.01）， whereas the expressions of Lon protein， MFN1 protein decreased in the model group （P<0.05，P<0.01）， and MFN2 protein decreased. The vacuolation of mitochondria increased and the cristae broke in the model group. As compared with model group， the time of the latent escape period decreased （P<0.01）， and the number of crossings increased in the low-dose and high-dose Si Junziwan groups （P<0.05）. The expression of AMPK （P<0.01） decreased， the content of ATP increased （P<0.01）， the expression of Aβ and DRP1 protein decreased （P<0.05， P<0.01）， and the expression of MFN1 protein was up-regulated （P<0.05） in high-dose Si Junziwan groups. The vacuolation was more obvious in the low-dose Si Junziwan group， whereas the vacuolation was restored and the ridge was clear in the high-dose Si Junziwan group. ConclusionSi Junziwan treats Alzheimer's disease by up-regulating the protein expression of Lon， correcting the disorder of mitochondrial division and fusion protein， and changing the memory function of SAMP8 mice.