First recorded in an official medical book from the Northern Song Dynasty called Taiping Huimin Heji Ju Fang （Prescriptions of the Bureau of Taiping People's Welfare Pharmacy）， Xiaoyaosan has been developed and refined over generations and is preserved to this day. It specializes in soothing the liver，resolving stagnation，fortifying the spleen，and nourishing blood. In this study，ancient traditional Chinese medicine （TCM） books and contemporary studies were reviewed to obtain information on Xiaoyaosan using bibliometrics，including its historical development，dosage，origin，processing methods，decoction dosage，and ancient and modern indications. Furthermore，a question regarding the presence of Zingiberis Rhizoma Recens and Menthae Haplocalycis Herba in Xiaoyaosan was investigated，and a table of key information on Xiaoyaosan was compiled，providing references for developing Xiaoyaosan preparations. According to the weight and measurement system of the Song dynasty，the contemporary equivalent formulation of the decocted Xiaoyaosan consists of 20.65 g of Glycyrrhizae Radix et Rhizoma and 41.3 g of Angelica Sinensis Radix，Poria，Paeoniae Radix Alba，Atractylodis Macrocephalae Rhizoma，and Bupleuri Radix. The formulation is processed to obtain a mixed powder with a particle size of 10 mesh. For each dose，8.25 g of the mixed powder is combined with 1 g of unprocessed Zingiberis Rhizoma Recens and 0.62 g of Menthae Haplocalycis Herba in 300 mL of water. The mixture is decocted until the volume reaches 210 mL，and the residue is then removed，with no specific timing required for administration. After the processing，each dose consists of approximately 0.75 g of Glycyrrhizae Radix et Rhizoma and 1.50 g of Radix Angelica Sinensis，Poria，Paeoniae Radix Alba，Atractylodis Macrocephalae Rhizoma，and Bupleuri Radix. Ancient medical literature shows that Xiaoyaosan primarily treats blood deficiency and overstrain，specifically for symptoms including heat caused by blood deficiency and fatigue，irregular menstruation，headache，eye soreness，pain in the ribs and limbs，and emaciation and bone steaming. In the Qing Dynasty，ZHANG Lu clearly proposed the pathogenesis of liver depression，and since then，the use of Xiaoyaosan in treating various syndromes associated with liver depression has been highly praised by physicians in the Qing dynasty and modern times. Xiaoyaosan has a wide application in modern clinical practices，involving digestive diseases，gynecological diseases，psychological diseases，nervous system diseases，and otorhinolaryngologic diseases. Moreover，it is most commonly used to treat depression and other diseases complicated with depression，hyperplasia of the mammary gland，etc. The key information on Xiaoyaosan and its clinical applications in ancient and modern times investigated in the study could serve as a scientific reference for in-depth research and extended clinical applications of the prescription.

Objective To establish an analytical method combining gas chromatography-tandem mass spectrometry(GC-MS)and liquid chromatography-tandem mass spectrometry(LC-MS)to detect diazepam residue in bait nest materials and fish samples,and improve the pretreatment steps of samples to make the experimental results accurate and the sample processing convenient and fast.Methods Taking diazepam as the research object,samples were extracted with methanol and dichloromethane/n-hexane as solvents according to the type,and the supernatant was taken for detection after centrifugation.Results The diazepam standard sample showed a good linear relationship in the range of 10～10 000 ng/mL.The retention times in methanol and mixed solvent were 13.54 min and 13.83 min,respectively,and the correlation coefficients were 0.998 and 0.999,respectively;The limit of detection(LOD)of using methanol as extraction solvent was 2 ppb,and limit of quantification(LOQ)was 6 ppb.The LOD of using mixed solvents was 5 ppb,and the LOQ was 15 ppb.When the sample is a bait nest material,the GC-MS spectrum was clear and standard,and the peak shape was sharp and prominent;When the sample is biological specimen,the GC-MS spectra are disturbed by matrix,while the LC-MS data is more accurate and faster.Conclusion It is more appropriate to use GC-MS to determine the content of bait nest materialsamples,and it is more accurate to LC-MS to determine the content of fish samples due to the complexity of the organism.

High glucose level, bacterial infection, and persistent inflammation within the microenvironment are key factors contributing to the delay of diabetic ulcers healing, while traditional therapeutic methods generally fail to address these issues simultaneously. Here, we present a spatiotemporally responsive cascade bilayer microneedle (MN) patch for accelerating diabetic wound healing via local glucose depletion and sustained nitric oxide (NO) release for long-term antibacterial and anti-inflammatory effects. The MN patch (G/AZ-MNs) possesses a degradable tip layer loading glucose oxidase (GOx), as well as a dissolvable base layer encapsulating l-arginine (Arg)-loaded nanoparticles (NPs). After wound administration, the base part rapidly dissolved, resulting in prompt separation of the MN tip within the wound tissue, which subsequently responded to the overexpressed matrix metalloproteinase-9 (MMP-9) in diabetic lesions, leading to the responsive release of GOx. The released enzyme catalyzed glucose into gluconic acid and hydrogen peroxide (H₂O₂), which not only reduced glucose level within the diabetic wound, but also initiated the cascade reaction between H₂O₂ with the Arg that was released from NPs, thereby achieving continuous production of NO for 7 days. Our findings demonstrate that a single administration of the MN patch could effectively heal non-infected or biofilm-infected diabetic wounds with the multifunctional properties.

Purpose: The unique chromosomal rearrangements of endometrial stromal sarcoma (ESS) make it possible to distinguish high-grade ESS (HGESS) and low-grade ESS (LGESS) from the molecular perspective. Analysis of ESS at the genomic and transcriptomic levels can help us achieve accurate diagnosis of ESS and provide potential therapy options for ESS patients. Materials and Methods: A total of 36 ESS patients who conducted DNA- and/or RNA-based next-generation sequencing were retrospectively enrolled in this study. The molecular characteristics of ESS at genomic and transcriptomic levels, including mutational spectrum, fusion profiles, gene expression and pathway enrichment analysis and features about immune microenvironment were comprehensively explored. Results: TP53 and DNMT3A mutations were the most frequent mutations. The classical fusions frequently found in HGESS (ZC3H7B-BCOR and NUTM2B-YWHAE) and LGESS (JAZF1-SUZ12) were detected in our cohort. CCND1 was significantly up-regulated in HGESS, while the expression of GPER1 and PGR encoding estrogen receptor (ER) and progesterone receptor (PR) did not differ significantly between HGESS and LGESS. Actionable mutations enriched in homologous recombination repair, cell cycle, and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways were detected in 60% of HGESS patients. Genes with up-regulated expression in HGESS were significantly enriched in five immune-related pathways. Most HGESS patients (85.7%) had positive predictors of immunotherapy efficacy. Moreover, immune microenvironment analysis showed that HGESS had relatively high immune infiltration. The degree of immune infiltration in HGESS patients with ZC3H7B-BCOR fusion was relatively higher than that of those with NUTM2B-YWHAE fusion. Conclusion This study investigated the molecular characteristics of ESS patients at the genomic and transcriptomic levels and revealed the potentially high sensitivity of targeted therapy and immunotherapy in a subset of HGESS with specific molecular features, providing a basis for guiding decision-making of treatment and the design of future clinical trials on precision therapy.

Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Objective:To analyze the changing trends in maternal mortality ratios (MMRs) and the main cause-specific MMRs in China from 2010 to 2020, evaluate the association between MMRs and pregnancy healthcare and predict the MMRs for the next five years.Methods:Data on MMRs, the main cause-specific MMRs, and maternal healthcare in China from 2010 to 2020 were collected from China Health Statistical Yearbook. Estimated annual percent changes (EAPCs) were used to analyze the trends in MMRs and the main cause-specific MMRs in China. Average growth rate was used to describe the trend of perinatal healthcare indicators, and spearman rank correlation was used to analyze the correlation between MMRs and perinatal healthcare indicators. GM (1,1) model was established to predict the MMRs for the following five years. Results:(1) From 2010 to 2020, the EAPCs were－5.16%,－6.24%, and－4.28%, respectively, indicating downward trends in MMRs in the whole nation, urban and rural areas ( t=－0.98,－12.42 and－8.96, all P<0.001). (2) From 2010 to 2020, the main cause-specific MMRs in China from obstetric hemorrhage, hypertension during pregnancy, amniotic fluid embolism, and liver disease were all in downward trends ( t=－12.42,－5.44,－3.98 and－3.63, all P<0.001). Except for the MMR from hypertension during pregnancy in urban areas (average growth rate =0.51%), all main cause-specific MMRs in both urban and rural areas decreased significantly, especially the MMRs from hepatopathy in urban and rural areas (average growth rate=－10.40% and－13.96%). (3) The nation wide MMR was negatively correlated with maternal system management rate ( r s=－0.80, P=0.003), prenatal examination rate ( r s=－0.97, P<0.001), postpartum visit rate ( r s=－0.82, P=0.002) and hospital delivery rate ( r s=－0.98, P<0.001). Negative correlations were also found between the MMR and hospital delivery rate in both urban ( r s=－0.82, P=0.002) and rural areas ( r s=－0.95, P<0.001). (4) The GM (1, 1) models for forecasting MMRs in the whole nation, urban and rural areas were established with an accuracy of level 1. The MMR was predicted to show a downward trend in the following five years. The MMRs in China were 15.86/100 000 in 2021 and 15.13/100 000 in 2022 through prediction, similar to the 16.1/100 000 and 15.7/100 000 as announced by the government. Conclusions:The overall MMR in China shows a downward trend, and it dropped faster in urban areas than the rural areas. In addition, it is predicted that the MMR will continue to decline in the following five years, but the gap between urban and rural areas will remain.

Objective To study the association between mean platelet volume(MPV),platelet distribution width(PDW)and procalcitonin(PCT)and cardiac function in patients with pulmonary hypertension(PH)and their diagnostic value on heart failure.Methods 103 patients with PH(PH group)in the 3rd People's Hospital of Chengdu from October 2021 to October 2022 and 103 healthy subjects with physical examination(control group)were selected as study subjects.Fasting peripheral venous blood was collected on the 1st day of admission and MPV,PDW and PCT were detected.The left ventricular ejection fraction(LVEF)was measured and the cardiac function was evaluated by New York Heart Association(NYHA)grading criteria.The patients with PH were divided into failure group and non-failure group according to the diagnosis results of heart failure.The relations of MPV,PDW and PCT with cardiac function in patients with PH and the diagnostic value on heart failure were analyzed.Results The levels of MPV,PDW,and PCT were all higher in the experimental group compared to the control group,while the LVEF was lower,and these differences were statistically significant(P<0.05);as the NYHA classification increased,the levels of MPV,PDW,and PCT showed an increasing trend,while LVEF showed a decreasing trend,and the differences between the groups were statistically significant(P<0.05);in the heart failure group n = 65,the levels of MPV,PDW,and PCT were higher compared to the non-heart failure group n = 38,while LVEF was lower,and these differences were statistically significant(P<0.05).The levels of MPV,PDW,and PCT werr signifi-cantly positively correlated with NYHA functional classification and LVEF(P<0.05).The levels of MPV,PDW,and PCT had good reference value for the diagnosis of heart failure in PH patients,with AUC values of 0.816,0.897,and 0.825 respectively,and the combined diagnostic AUC is 0.952,which wass statistically different from the application of the three indicators alone(P<0.05).Conclusion RDW,PDW and PCT are closely related to cardiac function in patients with PH,and can provide reference information for diagnosis and treatment of heart failure in patients with PH.

BACKGROUND: The onset and clinical presentation of systemic lupus erythematosus (SLE) are sex-related. Few studies have investigated the distinctions in clinical characteristics and treatment preferences in male and female SLE patients in the initial cohort. This study aimed to improve the understanding of Chinese SLE patients by characterizing the different sexes of SLE patients in the inception cohort. METHODS: Based on the initial patient cohort established by the Chinese SLE Treatment and Research Group, a total of 8713 patients (795 men and 7918 women) with newly diagnosed SLE were enrolled between April 2009 and March 2021. Of these, 2900 patients (347 men and 2553 women) were eligible for lupus nephritis (LN). A cross-sectional analysis of the baseline demographic characteristics, clinical manifestations, laboratory parameters, organ damage, initial treatment regimens, and renal pathology classification was performed according to sex. RESULTS: In the SLE group, as compared to female patients, male patients had a later age of onset (male vs. female: 37.0 ± 15.8 years vs. 35.1 ± 13.7 years, P  = 0.006) and a higher SLE International Collaborative Clinic/American College of Rheumatology damage index score (male vs. female: 0.47 ± 1.13 vs. 0.34 ± 0.81, P  = 0.015), LN (male vs. female: 43.6% vs. 32.2%, P < 0.001), fever (male vs. female: 18.0% vs. 14.6%, P  = 0.010), thrombocytopenia (male vs. female: 21.4% vs. 18.5%, P  = 0.050), serositis (male vs. female: 14.7% vs. 11.7%, P  = 0.013), renal damage (male vs. female: 11.1% vs. 7.4%, P < 0.001), and treatment with cyclophosphamide (CYC) (P < 0.001). The frequency of leukopenia (male vs. female: 20.5% vs. 25.4%, P  = 0.002) and arthritis (male vs. female: 22.0% vs. 29.9%, P < 0.001) was less in male patients with SLE. In LN, no differences were observed in disease duration, SLE Disease Activity Index score, renal biopsy pathological typing, or 24-h urine protein quantification among the sexes. In comparisons with female patients with LN, male patients had later onset ages (P  = 0.026), high serum creatinine (P < 0.001), higher end-stage renal failure rates (P  = 0.002), musculoskeletal damage (P  = 0.023), cardiovascular impairment (P  = 0.009), and CYC use (P  = 0.001); while leukopenia (P  = 0.017), arthritis (P  = 0.014), and mycophenolate usage (P  = 0.013) rates were lower. CONCLUSIONS Male SLE patients had more severe organ damage and a higher LN incidence compared with female SLE patients; therefore, they may require more aggressive initial treatment compared to female patients.
Humans ; Female ; Male ; Cross-Sectional Studies ; Sex Characteristics ; East Asian People ; Severity of Illness Index ; Lupus Erythematosus, Systemic/diagnosis* ; Lupus Nephritis/pathology* ; Registries ; Cyclophosphamide/therapeutic use* ; Thrombocytopenia ; Leukopenia/drug therapy* ; Arthritis

The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

Objective:To explore CT imaging features related to disease-free survival (DFS) for gastric cancer (GC) patients with no clinical lymph node metastasis (cN0).Methods:From January 2005 to December 2018, 298 patients with GC were collected retrospectively in Peking University People′s Hospital. All the patients performed CT scanning before operation, and cT1-4N0M0 was defined by CT images. The clinical tumor stage (cT), extramural vessel invasion (EMVI), tumor morphological type, location and size were defined and recorded based on preoperative contrast-enhanced CT images. According to the pathological results, the patients were divided into pT1-2, pT3-4, pN0, and pN1-3 subgroups, with 148, 150, 135, and 163 cases, respectively. Progressive events and corresponding time were recorded during follow-up. DFS was defined as the time from radical operation to progressive events; if no progressive events occurred, DFS was defined as the time from radical operation to the last follow-up. The Kaplan-Meier curve and log-rank test were used to analyze the differences in cumulative DFS among patients with different CT imaging features, and Cox survival analysis was used to explore the independent CT imaging risk factors affecting DFS of cN0 patients. The log-rank test was used to test the effect of independent risk factors on cumulative DFS in different subgroups.Results:The follow-up time of enrolled patients was 36.0 (14.9, 59.3) months. The 3-year cumulative DFS rates of cT3-4 and cT1-2 GC patients were 61.2% and 85.6%, respectively, and the difference of DFS was statistically significant (χ 2=22.72, P<0.001). The 3-year cumulative DFS rate of EMVI-positive patients was 46.3%, which was lower than that of EMVI-negative patients (77.1%), and the difference was statistically significant (χ 2=21.34, P<0.001). There was no significant difference in 3-year cumulative DFS between different tumor locations and morphological types (χ 2=1.75, 1.73, P=0.189, 0.196). The difference in 3-year cumulative DFS between the tumor maximal diameter ≥3.4 cm and <3.4 cm groups was statistically significant (χ 2=17.58, P<0.001). On Cox survival analysis, cT (HR=5.203, P=0.001) and EMVI (HR=1.971, P=0.025) were independent risk factors for 3-year DFS in patients with cN0 GC. The results of subgroup analysis showed that the effect of EMVI on the 3-year DFS in pN0, pN1-3, pT1-2 and pT3-4 subgroups was statistically significant ( P<0.05). The effect of cT on the 3-year DFS was statistically significant in pN0, pN1-3, and pT1-2 subgroups ( P<0.05), but not in pT3-4 group (χ 2=2.58, P=0.108). Conclusion:cT and EMVI defined on preoperative CT examination are independently prognostic factors of 3-year DFS for patients with cN0 GC.