Orodispersible films (oral dispersible films), a novel form of oral solid dosage forms, are widely used for patients with dysphagia and those with uncontrollable autonomic behavior. In this study, suvorexant orodispersible film was prepared by hot melt extrusion technology, and the disintegration time, mechanical properties, in vitro dissolution and pharmacokinetics were evaluated, compared with other orodispersible films and commercially available tablets Belsomra. All experiments were approved by the Committee on the Management and Use of Laboratory Animals of Academy of Military Medical Sciences (IACUC-DWZX-2024-504). The results showed that the dissolution rate of suvorexant orodispersible film was faster and the mechanical strength was better than that of other commercially available orodispersible film, which could meet the needs of storage and transportation. Differential scanning calorimetry and X-ray diffraction results showed that suvorexant was dispersed within the orodispersible film in an amorphous state. The in vitro dissolution of the film was observed to be four times faster than that of the commercial tablets, achieving complete dissolution within five minutes. Pharmacokinetic evaluations in Beagle dogs revealed that the self-formulated orodispersible film exhibited no significant differences in the area under the blood concentration-time curve when compared with Belsomra. However, the film showed a faster onset of action, with a peak time that was twice as rapid, and a maximum blood concentration that was twice as high as that of Belsomra. Leveraging hot melt extrusion technology, the suvorexant orodispersible film offers a straightforward, continuous production process with consistent quality. It serves as an excellent platform for the development of solvent-free film preparations tailored for patients with special needs.

The rheological properties of drug and carrier materials have a wide range of guiding significance for the formulation and process development of solid dispersions. In this study, the rheological properties of materials with different drug carrier ratios were systematically studied with suvorexant as the model drug and copovidone as the carrier material, which provided a sufficient basis for determining the formulation and process of solid dispersions. The optimal suvorexant-copovidone ratio obtained by oscillating temperature scanning was 1∶4. If the ratio is greater than 1∶ 4, the glass transformation temperature of the material will increase significantly, and the solubilization effect of the solid dispersion will show a downward trend. The results of oscillation temperature scanning and oscillation temperature sweep can show that when the extrusion temperature is greater than 150 ℃, the viscosity of the material is less than 10 000 Pa·s, and the melt can be extruded smoothly, and the best extrusion temperature of 160-180 ℃ can be obtained by combining the dissolution results. Finally, the dissolution of suvorexant tablets guided by rheological property studies in multiple media is similar to that of the commercially available tablets Belsomra. Therefore, rheological studies can screen and optimize the formulation and process of suvorexant solid dispersions at the mechanism level, which is of great significance to improve the success rate of R&D and shorten the R&D cycle of solid dispersions prepared by hot melt extrusion.

AIM To establish a UPLC-MS/MS method for the simultaneous content determination of Asp,Guad,Adeno,Arg,Ade,Cyti,Phe,Leu,Ile,Glu,Ser,Gln,Gly,Ala,Hyp,Thr,Pro and Lys in Asini Corii Colla.METHODS The analysis was performed on a 45℃ thermostatic Waters BEH C18column(2.1 mm×50 mm,1.7 μm),with the mobile phase comprising of acetonitrile(containing 0.1% formic acid)-water flowing at 0.35 mL/min in a gradient elution manner,and electron spray ionization source was adopted in positive ion scanning with multiple reaction monitoring mode.Subsequently,chemical pattern recognition was performed by hierarchical clustering analysis,principal component analysis and orthogonal partial least squares-discriminant analysis.RESULTS Eighteen nucleosides and free amino acids showed good linear relationships within their own ranges(r≥0.999 0),whose average recoveries were 98.0%-104.9% with the RSDs of 1.6%-4.9% .Seventeen batches of samples were clustered into two categories,two principal components demonstrated the accumulative variance contribution rate of 60.75%,Leu,Phe,Ade and Guad were potential index constituents.CONCLUSION This stable and reliable method can be used for the quality control of Asini Corii Colla.

The deubiquitinases (DUBs), as the crucial peptidohydrolases in the ubiquitin system, can reverse and strictly regulate ubiquitination and play key roles in various biological processes, including the regulation of protein stability, cell signal transduction. Ubiquitin-specific protease 28 (USP28) involves multiple cancer-related signaling pathways by enhancing the stability of various cancer-related proteins, and is closely associated with the progression of colorectal, breast cancer, lung carcinomas, and pancreatic cancer. USP28 has been considered as a promising drug target in anticancer therapy, and the development of USP28 inhibitors has made some progress. In this article, we review the structure of USP28 and its interaction with substrates, discuss the research progress of USP28 in cancers and summarize the development of USP28 inhibitors.

Objective To evaluate the predictors of biochemical recurrence after laparoscopic radical prostatectomy.Methods The study cohort consisted of 416 consecutive prostatecancer patients who underwent radical prostatectomy in Zhongshan Hospital,Fudan University between Jan 2016 and Jun 2018.No patient received adjuvant therapy until documented biochemical recurrence.Biochemical recurrence-free survival(BCRFS)was estimated using the Kaplan-Meier method.Univariable and multivariable Cox proportional hazards regression models were utilized to determine variables predictive of biochemical recurrence.Results The median follow-up period was 174 weeks(inter quartile range 133-209 weeks).The overall biochemical recurrence rate was 21.39%(88/416).The time to biochemical recurrence was(51.11±47.71)weeks.Until the end of follow-up,the biochemical recurrence rates were 10%(1/10),6.12%(3/49),16.41%(43/262)and 43.16%(41/95)for low-risk,medium-risk,high-risk and locally advanced prostate cancer,respectively.On multivariable analysis,tumor invasion of the seminal vesicles(HR:2.119,95%CI:1.154-3.891,P=0.016);Seminal vesicle invasion(HR:1.824,95%CI:1.034-3.220,P=0.038),Gleason score≥8(HR:2.746,95%CI:1.268-5.943,P=0.010),prostate-specific antigen(PSA)=10-20 ng/mL(HR:4.240,95%CI:2.550-7.050,P<0.001);PSA>20 ng/mL(HR:6.341,95%CI:3.296-12.202,P<0.001)were the main predictors of biochemical recurrence.Conclusion Laparoscopic radical prostatectomy provides effective control of biochemical recurrence during the mid-term follow-up period.Tumor invasion of the seminal vesicles,seminal vesicle invasion,GS≥8,PSA=10-20 ng/mL,PSA>20 ng/mL were important predictors of biochemical recurrence after radical prostatectomy.

Objective: To investigate the incidence and treatment of perioperative anemia in patients with gastrointestinal neoplasms in Hubei Province. Methods: The clinicopathological data of 7 474 patients with gastrointestinal neoplasms in 62 hospitals in 15 cities (state) of Hubei Province in 2019 were collected in the form of network database. There were 4 749 males and 2 725 females. The median age of the patients was 62 years (range: 17 to 96 years). The hemoglobin value of the first time in hospital and the first day after operation was used as the criterion of preoperative anemia and postoperative anemia. Anemia was defined as male hemoglobin <120 g/L and female hemoglobin <110.0 g/L, mild anemia as 90 to normal, moderate anemia as 60 to <90 g/L, severe anemia as <60 g/L. The t test and χ² test were used for inter-group comparison. Results: The overall incidence of preoperative anemia was 38.60%(2 885/7 474), and the incidences of mild anemia, moderate anemia and severe anemia were 25.09%(1 875/7 474), 11.37%(850/7 474) and 2.14%(160/7 474), respectively. The overall incidence of postoperative anemia was 61.40%(4 589/7 474). The incidence of mild anemia, moderate anemia and severe anemia were 48.73%(3 642/7 474), 12.20%(912/7 474) and 0.47%(35/7 474), respectively. The proportion of preoperative anemia patients receiving treatment was 26.86% (775/2 885), and the proportion of postoperative anemia patients receiving treatment was 14.93% (685/4 589). The proportions of preoperative anemia patients in grade ⅢA, grade ⅢB, and grade ⅡA hospitals receiving treatment were 26.12% (649/2 485), 32.32% (85/263), and 29.93% (41/137), and the proportions of postoperative anemia patients receiving treatment were 14.61% (592/4 052), 22.05% (73/331), and 9.71% (20/206). The proportion of intraoperative blood transfusion (16.74% (483/2 885) vs. 3.05% (140/4 589), χ²=434.555, P<0.01) and the incidence of postoperative complications (17.78% (513/2 885) vs. 14.08% (646/4 589), χ²=18.553, P<0.01) in the preoperative anemia group were higher than those in the non-anemia group, and the postoperative hospital stay in the preoperative anemia group was longer than that in the non-anemia group ((14.1±7.3) days vs. (13.3±6.2) days, t=5.202, P<0.01). Conclusions: The incidence of perioperative anemia in patients with gastrointestinal neoplasms is high. Preoperative anemia can increase the demand for intraoperative blood transfusion and affect the short-term prognosis of patients. At present, the concept of standardized treatment of perioperative anemia among gastrointestinal surgeons in Hubei Province needs to be improved.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anemia/epidemiology* ; Blood Transfusion ; Female ; Gastrointestinal Neoplasms/surgery* ; Humans ; Length of Stay ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; Young Adult

Schisandra Chinensis Fructus (SCF) is the fruit of Schisandra chinensis (Turcz.) Baill., a perennial vine. It was first recorded in Shen Nong's herbal classic and has a long application history. Studies have shown that SCF has anti-inflammatory, protective liver, antioxidant, antibacterial and other pharmacological effects. Ancient prescriptions are commonly used in the treatment of chronic diarrhea and other intestinal diseases and diabetes. Modern clinical phar?macology features of SCF polysaccharide (SCFP) in diabetes, liver diseases, enteritis and other aspects have achieved excellent results. Gut is an important digestive organ of human body, but intestinal diseases are varied, including Crohn's disease, ulcerative colitis, intestinal flora imbalance, etc.. It is a chronic and non-specific inflammatory disease. The disease is persisted for a long time and the incidence rate is expected to rise. Most of the symptoms are recurrent diarrhea, bloody stool and abdominal pain. It is considered by the World Health Organization as a refractory disease. At present, there is little possibility of complete cure, which is closely related to complex environmental factors, eating hab?its and heredity. In recent years, clinical studies have found that SCFP has a variety of pharmacological effects on intes?tinal protection.①Reduce inflammatory factors:intestinal mucositis is a common adverse reaction in patients with chemo?therapy. The development of mucositis is related to pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, Interferon-γ(IFN-γ). SCFP can significantly reduce IL-6 TNF-α, IL-1β, and IL-8, as well as the accumulation of T cells in the process of resisting apoptosis, reduce the inflammatory reaction and protect the dam?age to villi and crypts, improve the symptoms of small intestinal mucositis caused by weight loss and diarrhea. ② Pro?mote immunoglobulin A secretion: intestinal mucosal immunity is the first line of defense of the body's immune system. Its main antibody is secretory immunoglobulin A, which can destroy and phagocytize microorganisms, bacteria and viruses. SCFP can improve intestinal immunity by increasing the number and activity of T lymphocytes, promoting the secre?tion of secretory immunoglobulin A, and affecting the activity of a variety of cytokines. ③ Regulation of intestinal flora:the flora in the intestine has the functions of auxiliary nutrient absorption, biological antagonism and immune regulation, and can form a natural barrier for the host's intestine. When the human intestinal flora is disordered, probiotics will be greatly reduced, harmful bacteria will proliferate and destroy the intestinal environment. Under these conditions, the intake of SCFP significantly increased the number of beneficial bacteria such as bifidobacteria and lactobacillus, and sig?nificantly decreased the number of conditional pathogens such as enterococcus and escherichia coli, indicating that SCFP can indeed regulate the intestinal disorder caused by lincomycin hydrochloride to a certain extent. This may be because beneficial bacteria in the intestine metabolize polysaccharides produce short chain fatty acids such as lactic acid and acetic acid, which reduces the pH value in the intestine and inhibits the growth of enterococcus and Escherichia coli. In conclusion, SCFP can treat and protect intestinal diseases to a certain extent, which provides a favorable basis for the treatment of intestinal diseases.

BACKGROUND: The current deep learning diagnosis of breast masses is mainly reflected by the diagnosis of benign and malignant lesions. In China, breast masses are divided into four categories according to the treatment method: inflammatory masses, adenosis, benign tumors, and malignant tumors. These categorizations are important for guiding clinical treatment. In this study, we aimed to develop a convolutional neural network (CNN) for classification of these four breast mass types using ultrasound (US) images. METHODS: Taking breast biopsy or pathological examinations as the reference standard, CNNs were used to establish models for the four-way classification of 3623 breast cancer patients from 13 centers. The patients were randomly divided into training and test groups (n = 1810 vs. n = 1813). Separate models were created for two-dimensional (2D) images only, 2D and color Doppler flow imaging (2D-CDFI), and 2D-CDFI and pulsed wave Doppler (2D-CDFI-PW) images. The performance of these three models was compared using sensitivity, specificity, area under receiver operating characteristic curve (AUC), positive (PPV) and negative predictive values (NPV), positive (LR+) and negative likelihood ratios (LR-), and the performance of the 2D model was further compared between masses of different sizes with above statistical indicators, between images from different hospitals with AUC, and with the performance of 37 radiologists. RESULTS: The accuracies of the 2D, 2D-CDFI, and 2D-CDFI-PW models on the test set were 87.9%, 89.2%, and 88.7%, respectively. The AUCs for classification of benign tumors, malignant tumors, inflammatory masses, and adenosis were 0.90, 0.91, 0.90, and 0.89, respectively (95% confidence intervals [CIs], 0.87-0.91, 0.89-0.92, 0.87-0.91, and 0.86-0.90). The 2D-CDFI model showed better accuracy (89.2%) on the test set than the 2D (87.9%) and 2D-CDFI-PW (88.7%) models. The 2D model showed accuracy of 81.7% on breast masses ≤1 cm and 82.3% on breast masses >1 cm; there was a significant difference between the two groups (P < 0.001). The accuracy of the CNN classifications for the test set (89.2%) was significantly higher than that of all the radiologists (30%). CONCLUSIONS: The CNN may have high accuracy for classification of US images of breast masses and perform significantly better than human radiologists. TRIAL REGISTRATION Chictr.org, ChiCTR1900021375; http://www.chictr.org.cn/showproj.aspx?proj=33139.
Area Under Curve ; Breast/diagnostic imaging* ; Breast Neoplasms/diagnostic imaging* ; China ; Deep Learning ; Humans ; ROC Curve ; Sensitivity and Specificity

This study was designed to predict the Q-markers of Citri Reticulatae Pericarpium volatile oil and conduct quantitative analysis by GC-MS. The common components of Citri Reticulatae Pericarpium volatile oil were detected by GC-MS. The network pharmacology approaches were utilized for constructing the component-target network and protein-protein interaction(PPI) network, followed by the GO and KEGG pathway enrichment analysis to clarify the pharmacological effects of common components. Molecular docking was conducted to observe the biological activities of common components, thus identifying the Q-markers of Citri Reticulatae Pericarpium volatile oil. The obtained Q-markers were subjected to quantitative analysis by GC-MS. The GC-MS analysis of 19 batches of Citri Reticulatae Pericarpium volatile oil revealed three common components, namely, D-limonene, γ-terpinene, and myrcene. The common components were analyzed based on network pharmacology, and the results showed that Citri Reticulatae Pericarpium volatile oil mainly acted on the core targets GABRA1, GABRA6, GABRA5, GABRA3, and GABRA2 through D-limonene and γ-terpinene, with five important pathways such as nicotine addiction and GABAergic synapse involved. The core targets were mainly distributed in olfactory region, cerebral cortex, cerebellum, basal ganglia, hippocampus, and amygdala to exert the pharmacological effects. As revealed by molecular docking, D-limonene and γ-terpinene exhibited good biological activities, so they were identified as the Q-markers of Citri Reticulatae Pericarpium volatile oil. The results of quantitative analysis showed that the volume fraction of D-limonene was within the range of 0.77-1.03 μL·mL~(-1), and that of γ-terpinene within the range of 0.04-0.13 μL·mL~(-1). The prediction of D-limonene and γ-terpinene as the Q-markers of Citri Reticulatae Pericarpium volatile oil has laid an experimental foundation for the establishment of the quality evaluation standard for Citri Reticulatae Pericarpium volatile oil.
Citrus ; Drugs, Chinese Herbal/pharmacology* ; Gas Chromatography-Mass Spectrometry ; Molecular Docking Simulation ; Network Pharmacology ; Oils, Volatile/pharmacology*

OBJECTIVE: To investigate the clinical characteristics of the patients with chronic myeloid leukemia (CML) discontinued tyrosine kinase inhibitors (TKI) therapy and the outcome of the patients. METHODS: 35 cases of CML patients experienced initiative discontinuation of TKI therapy in our hospital from June 1st 2015 to December 31th 2019 were retrospectively analyzed. The TFR of the patients and the factors affecting it were analyzed. RESULTS: The median duration of TKI administration was 72 (range 35-173) months in the 35 patients. Among these patients, 8 had experienced TKI dose reduction or suspension. All the enrolled patients have achieved at least MMR. The median time for these patients achieving MMR was 15 (range 3-75) months after administration of TKI, and for MMR maintenance before TKI suspension was 55 (range 13-164) months. After TKI withdrawal the median follow up time was 20.3 (range 3-57.9) months, 22 out of 35 patients kept TFR, among them, 2 （5.71%） patients restarted TKI after 12 month suspension, and maintained MMR during suspension. 13 （37.1%）patients lost MMR, among them, 9 patients restarted TKI treatment, and 5 of them achieved MR4.0 after the median duration of 3(2-5) month. No patients were found to have disease progression. The estimated TFR rate was 57.8% and 51.8% at 12 and 24 months after discontinuation, respectively. Other clinical characteristic related to relapse were also analyzed, including the cumulative TKI administration duration, cumulative MMR duration, time to achieve MMR, median age at diagnosis, risk stratification by Sokal score, TKI dose reduction and discontinuation history, and second-generation TKI administration before stopping TKI, however, no statistical difference was found. CONCLUSION TKI discontinuation is practical for CML patients in our center.
Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Protein Kinase Inhibitors ; Recurrence ; Retrospective Studies ; Treatment Outcome