BACKGROUND:Skeletal muscle insulin resistance is the key pathological link of type 2 diabetes.The traditional Chinese medicine compound Roujishuncuiyin can effectively improve skeletal muscle insulin resistance,but its mechanism has not been clarified.OBJECTIVE:To explore the mechanism of Roujishuncuiyin on skeletal muscle insulin resistance in type 2 diabetes mice.METHODS:Forty db/db mice with type 2 diabetes mellitus were randomized into a model group,a low-dose Roujishuncuiyin group,a high-dose Roujishuncuiyin group,and a positive drug group,with 10 mice in each group.The latter three administration groups were given 157.5 mg/g and 630 mg/g Roujishuncuiyin and 200 mg/g metformin hydrochloride aqueous solution by gavage once a day,respectively.In addition,10 db/dm mice were selected as the blank control group.Mice in the model and blank control groups were given the same dose of 0.9％NaCl solution by gavage.After 12 weeks of intervention,fasting blood glucose was measured in each group of mice,and oral glucose tolerance test was performed to calculate the area under the blood glucose curve.ELISA was used to detect serum insulin level and calculate the resistance index.Mitochondrial structure of skeletal muscle tissue was observed under transmission electron microscopy.Western blot was used to detect the expression levels and phosphorylation levels of protein kinase B(AKT)and glycogen synthase kinase 3β(GSK-3β)proteins in skeletal muscle.RESULTS AND CONCLUSION:(1)Compared with the blank control group,fasting blood glucose,fasting insulin and insulin resistance index were significantly higher in the model group(P＜0.05),the area under the curve of the oral glucose tolerance test was significantly increased(P＜0.05),the expression of p-AKT and p-GSK3β proteins in tibialis anterior muscle was significantly decreased(P＜0.05),and there was a large amount of mitochondrial damage in tibialis anterior muscle and a large number of lipid droplets in the interstitium.(2)Compared with the model group,fasting blood glucose,fasting insulin,and insulin resistance index were significantly reduced in the low-and high-dose Roujishuncuiyin groups and the positive control group(P＜0.05),the area under the curve of the oral glucose tolerance test was reduced(P＜0.05),the expression of p-AKT and p-GSK3β proteins in the tibialis anterior muscle was significantly elevated(P＜0.05),and mitochondrial damage in the tibialis anterior muscle was significantly ameliorated,with decreased lipid droplets in the interstitium.(3)The above indexes were better in the high-dose Roujishuncuiyin group than the low-dose Roujishuncuiyin group(P＜0.05),while there was no significant difference between the high-dose Roujishuncuiyin group and positive control group(P＞0.05).To conclude,by upregulating the protein levels of p-AKT and p-GSK3β in skeletal muscle tissue,the traditional Chinese medicine compound Roujishuncuiyin can improve structural disorders and mitochondrial morphology in skeletal muscle tissue,reduce insulin resistance in the skeletal muscle and regulate glucose homeostasis in the body.

Objective:To investigate the characteristics of serum immunoglobulin G (IgG) N-glycans in male patients with different subtypes and severity grades of androgenetic alopecia (AGA) .Methods:A cross-sectional study was conducted on male patients diagnosed with male-pattern hair loss (MPHL) or female-pattern hair loss (FPHL) who attended the Department of Dermatology, Huashan Hospital, Fudan University between June and December 2022. Clinical data were collected, and serum IgG N-glycans were quantitatively analyzed using ultra-performance liquid chromatography (UPLC) . The content of serum IgG N-glycan structures was compared between patients with different AGA subtypes and among patients with different severity grades of MPHL or FPHL, while derived traits were compared between patients with different AGA subtypes. Point-biserial correlation analysis was conducted to assess associations between serum IgG N-glycans and hair loss severity.Results:A total of 85 male patients with AGA were included, comprising 44 MPHL patients and 41 FPHL patients. No significant differences were observed between the two subgroups in terms of age, age at onset, or serum levels of testosterone, sex hormone-binding globulin, uric acid, and 25-hydroxyvitamin D (all P > 0.05) . UPLC showed 23 serum IgG glycans and 5 derived glycan traits (afucosylation, fucosylation, bisecting GlcNAc, terminal galactosylation, and terminal sialylation) . Compared with the MPHL patients, the FPHL patients exhibited significantly increased levels of N-glycans GP5, GP11, GP17, and GP20 (all P < 0.05) , significantly elevated levels of afucosylated IgG N-glycans ( P = 0.047) , but significantly reduced core fucosylated IgG N-glycans ( P = 0.047) . No significant differences in serum IgG N-glycan composition were observed among patients with varying severity grades of MPHL (all P > 0.05) . In the FPHL patients, the levels of N-glycans GP10 ( r = 0.32, P = 0.039) and GP22 ( r = -0.32, P = 0.045) were significantly positively and negatively correlated with hair loss severity respectively; receiver operating characteristic curve analysis showed that both GP10 and GP22 had moderate diagnostic value for predicting hair loss severity, with the area under the curve values being 0.69 (95% CI: 0.52 - 0.86) and 0.71 (95% CI: 0.55 - 0.86) , respectively. Conclusion:Serum IgG N-glycan profiles differed among male patients with different AGA subtypes, and N-glycans GP10 and GP22 may serve as potential biomarkers for early assessment of hair loss severity in male FPHL patients.

Discoidin domain receptor 1 (DDR1) is overexpressed in various tumors, such as triple-negative breast cancer (TNBC), and is rarely expressed in normal tissues. These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate (ADC) for targeted therapy. Here, we investigated the preparation and preclinical efficacy of DDR1-DX8951, an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly (GGFG) linker. The anti-DDR1 monoclonal antibody was coupled to DX8951 (i.e., DDR1-DX8951), producing the targeted therapy ADC. The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models. DDR1-DX8951 can specifically target DDR1, be quickly internalized by TNBC cells, and reduce the viability of TNBC cells in vitro. The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models. Importantly, our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment (TME) of TNBC. Taken together, this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.

Discoidin domain receptor 1(DDR1)is overexpressed in various tumors,such as triple-negative breast cancer(TNBC),and is rarely expressed in normal tissues.These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate(ADC)for targeted therapy.Here,we investigated the preparation and preclinical efficacy of DDR1-DX8951,an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly(GGFG)linker.The anti-DDR1 monoclonal antibody was coupled to DX8951(i.e.,DDR1-DX8951),producing the targeted ther-apy ADC.The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models.DDR1-DX8951 can specifically target DDR1,be quickly internal-ized by TNBC cells,and reduce the viability of TNBC cells in vitro.The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models.Importantly,our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvi-ronment(TME)of TNBC.Taken together,this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.

OBJECTIVE: To explore the impact of age on the genetic variant spectrum and prognosis of patients with previously untreated Diffuse large B-cell lymphoma (DLBCL). METHODS: A retrospective analysis was conducted on the clinical data and follow-up information of 254 previously untreated DLBCL patients from 14 hospitals in the Jiangsu Cooperative Lymphoma Group (JCLG) enrolled from July 2018 and July 2023. Following extraction of DNA from tumor tissue samples, next-generation sequencing (NGS) technique was employed to analyze the genetic variant spectrum of the DLBCL patients, with an evaluation of the relationship between age and genetic variants as well as prognosis. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Nantong University (Ethics No.: 2023-K048-01). RESULTS: The median age of the 254 DLBCL patients was 62 years old, with 55% of patients aged 60 years or above. Clinical evaluation showed that younger (< 60 years) patients had higher complete response (CR) (70% vs. 59%), and objective response rate (ORR) (88% vs. 79%) than older patients, though the difference between the two groups was not statistically. Survival analysis indicated that both the five-year overall survival (OS) (82.7% vs. 71.7%, P = 0.006) and progression-free survival (PFS) (70.6% vs. 50.2%, P < 0.05) rates were significantly higher in younger patients. NGS showed that 99.6% of the patients harbored genetic variants, with PIM1, KMT2D, TP53, MYD88, and CD79B being the most common genes. Age significantly affected the variant frequency of certain genes, with MYC variants serving an adverse prognostic factor for OS in younger patients (P = 0.002), while TP53 (P = 0.024) and BCL2 (P = 0.002) variants significantly impacted OS in older patients. Prognostic analysis identified age ≥ 60 years (HR = 3.439, 95%CI: 1.318~9.874), presence of B symptoms (HR = 2.871, 95%CI = 1.133~7.307), and elevated lactate dehydrogenase (HR = 3.528, 95%CI = 1.231~10.66) as independent adverse prognostic factors. CONCLUSION Age, genetic variants, and clinical factors may significantly affect the prognosis of the DLBCL patients. Younger patients have better survival compared to older patients. Variants of the MYC, BCL2, and TP53 genes are closely associated with poor prognosis.
Humans ; Lymphoma, Large B-Cell, Diffuse/diagnosis* ; Middle Aged ; Female ; Male ; Retrospective Studies ; Aged ; Prognosis ; Adult ; Aged, 80 and over ; High-Throughput Nucleotide Sequencing ; Young Adult ; Adolescent ; Genetic Variation

After 50 years of clinical development， endoscopic retrograde cholangiopancreatography （ERCP） has become the preferred method for the clinical diagnosis and treatment of cholangio-pancreatic duct diseases； however， the major postoperative complications of ERCP， such as pancreatitis， hemorrhage， and perforation， are still a difficult issue faced by clinicians， and postoperative perforation is associated with an extremely high risk of death. Therefore， it is very important to explore the risk factors for perforation after ERCP， make a definite diagnosis of perforation in a timely manner， and formulate precise prevention and treatment measures. By reviewing a large number of articles， this article summarizes the influencing factors for perforation after ERCP and related diagnosis and treatment measures.

ObjectiveTo investigate the influence of empagliflozin combined with donafenib or lenvatinib on the pharmacokinetic parameters of each drug， and to provide a reference for combined medication in clinical practice. MethodsA total of 48 healthy male Sprague-Dawley rats were divided into 8 groups： empagliflozin group 1 and 2， donafenib group， lenvatinib group， donafenib pretreatment+empagliflozin group， lenvatinib pretreatment + empagliflozin group， empagliflozin pretreatment+donafenib group， and empagliflozin pretreatment+lenvatinib group， with 6 rats in each group. The doses of empagliflozin， donafenib， and lenvatinib were 2.5 mg/kg， 40 mg/kg， and 1.2 mg/kg， respectively. The rats in the empagliflozin group， donafenib group， and lenvatinib group were given a blank solvent by gavage for 7 consecutive days， followed by a single dose of empagliflozin， donafenib， or lenvatinib on day 7 after the administration of the blank solvent； the rats in the pretreatment groups were given the pretreatment drug by gavage for 7 consecutive days， followed by a single dose of drug combination on day 7 after administration of the pretreatment drug. Blood samples were collected at different time points， and plasma was separated to measure the concentration of each drug. A validated ultra-performance liquid chromatography-tandem mass spectrometry method was used to measure the plasma concentrations of donafenib， lenvatinib， and empagliflozin， and a non-compartmental model was used to calculate the main pharmacokinetic parameters of each drug （area under the plasma concentration-time curve ［AUC］， time to peak ［T_max］， peak concentration ［C_max］， and half-life time ［t_1/2］）. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. ResultsCompared with the empagliflozin group， the donafenib pretreatment+empagliflozin group had significant increases in the AUC_0-t and AUC_0-∞ of empagliflozin （P=0.011 and 0.008）， while the lenvatinib pretreatment+empagliflozin group had no significant change in the AUC of empagliflozin， with a slightly shorter T_max （P=0.019）. Compared with the donafenib group， the empagliflozin pretreatment+donafenib group had significant increases in the AUC_0-t and AUC_0-∞ of donafenib （P=0.027 and 0.025）， as well as a significant increase in C_max （P=0.015） and significant reductions in CLz/F and Vz/F （P=0.005 and 0.004）； compared with the lenvatinib group， the empagliflozin pretreatment+lenvatinib group had a reduction in the t_1/2 of lenvatinib by approximately 5 hours （P=0.002）， with a trend of reduction in AUC_0-t （P0.05）. ConclusionEmpagliflozin combined with donafenib may alter the pharmacokinetic parameters of both drugs， leading to a significant increase in the exposure levels of both drugs， and efficacy and adverse reactions should be monitored during co-administration. There are no significant changes in the exposure levels of empagliflozin and lenvatinib during co-administration.

Objective: To investigate the spatio-temporal clustering characteristics of influenza in Ningxia Hui Autonomous Region from 2014 to 2023, so as to provide the basis for strengthening influenza prevention and control. Methods: Data pertaining to influenza cases reported in Ningxia Hui Autonomous Region from 2014 to 2023 were retrieved from the Infectious Disease Surveillance System of the Chinese Disease Prevention and Control Information System, including age, sex, current residence, onset date, and reporting date. The seasonal incidence of influenza was analyzed using seasonal index. The spatio-temporal clustering characteristics of influenza were identified using spatial autocorrelation analysis and spatio-temporal scan analysis. Results: A total of 20 377 influenza cases were reported in Ningxia Hui Autonomous Region from 2014 to 2023, with a male-to-female ratio of 1.15∶1. The majority were children under 15 years, with 10 950 cases accounting for 53.74%. Influenza was highly prevalent in January, February, March, and December, with seasonal indices of 219.06%, 111.00%, 246.65%, and 366.24%, respectively. The average annual reported incidence was 29.55/100 000, among which Pengyang County, Jinfeng District, Dawukou District, Xiji County, and Litong District had higher average annual reported incidence, at 63.99/100 000, 55.71/100 000, 55.70/100 000, 49.49/100 000, and 49.04/100 000, respectively. Spatial autocorrelation analysis showed that in 2023, there was spatial clustering of influenza cases in Ningxia Hui Autonomous Region (Moran's I=0.333, P<0.05), with a high-high cluster in Jingyuan County, while in other years, the distribution of influenza cases was random (all P>0.05). Spatio-temporal scan analysis showed that from 2014 to 2023, there were four space-time clusters in Ningxia Hui Autonomous Region, including one type Ⅰ cluster in Hongsibao District of Wuzhong City, with the clustering period from January 20 to 26, 2014; and three type Ⅱ clusters, mainly in January, February, March and December, covering one area in Shizuishan City, five areas in Guyuan City, one area in Zhongwei City, three areas in Wuzhong City, and four areas in Yinchuan City. Conclusions From 2014 to 2023, children under 15 years were the primary population affected by influenza in Ningxia Hui Autonomous Region, with distinct spatio-temporal distribution characteristics. The peak incidence occurred during the winter and spring seasons, and the main clustering areas were in the southern regions.