Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

Objective:To describe demographic,clinical and physiological characteristics,treatment between first-episode major depressive disorder(MDD)and relapse MDD,and to explore characteristics of relapse MDD.Methods:Totally 858 patients who met the diagnostic criteria for depression of the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5),were included by using the Mini International Neuropsychiatric Interview(MINI),Clinician-Rated Dimensions of Psychosis Symptom Severity,and Hamilton Depression Scale etc.Among them,529(58.6％)were first-episode depression and 329(36.0％)were relapsed.The differences of demographic characteristics,clinical and physiological characteristics,treatment were compared byx2test and Kruskal-Wallis rank sum test.Multivariate logistic regression was used to explore the characteristics of MDD recur-rence.Results:Compared to first-episode MDD,relapse MDD had more comorbidity(OR=2.11,95％CI:1.00-4.44),more days out of role(OR=1.26,95％CI:1.01-1.56),more history of using psychiatric drug more than one month(OR=1.41,95％CI:1.02-1.97)and electroconvulsive therapy(OR=3.23,95％CI:1.42-7.36),and higher waist-hip ratio(OR=33.88,95％CI:2.88-399.32).Conclusion:Relapse MDD has positive as-sociation with comorbidity of mental disorders,out of role,and higher waist-hip ratio.

Objective:To explore the effects of applying peer-assisted learning (PAL) combined with modular teaching in physiology education, and to explore a more suitable mode for physiology teaching and learning.Methods:We selected a total of 89 undergraduate medical students of grade 2022 from a university offering physiology courses from February 28 to June 30, 2022. They were assigned using a random number table into experimental class (44 students) and control class (45 students). The experimental class adopted PAL with modular teaching, while the control class adopted the online and offline hybrid teaching method. The two classes were compared for teaching effects in terms of the completion rate of task points, final assessment scores, and questionnaire results. SPSS 19.0 was used to perform the independent samples t-test and the chi-square test. Results:The final exam scores for the objective questions of the experimental class and the control class were (43.04±3.25) and (40.24±8.64), respectively; the scores for the subjective items were (44.49±2.80) and (39.21±5.71), respectively; and the total scores were (87.53±4.24) and (79.40±12.08), respectively, all with significant differences between the two classes. There were significant differences in students' learning autonomy, micro-video preview rate, problem discussion participation rate, unit self-test participation rate, and after-class homework completion rate. The questionnaire survey showed that students in the experimental class believed that this teaching model was helpful for improving students' comprehensive qualities.Conclusions:PAL combined with modular teaching can effectively improve physiology teaching effects and students' learning autonomy and comprehensive abilities.

Objective We are entering a time when more and more digital images are being introduced to the operating room to enhance surgical outcomes .At the Surgical Simulation Research Lab of the University of Alberta, we developed a technology to superimpose a 3-dimentional (3D) breast model on top of the surgical site to guide a breast reconstruction procedure .Methods The breast models were created from the patient's magnetic resonance images .Our technician modified the breast model by taking data from pre-surgical scanning or from the healthy side of the breast .In the simulated environment , motion sensors were placed on the chest of the patient to capture the movements of the patient during the procedure, which were used to adjust the orientation of the 3D model to ensure a perfect mapping of the surgical site.Results Visual guidance was successfully displayed on top of the surgical site .Motion tracking captured movements of the simulated patient and was used for adjusting the 3D model in a short period of time.Conclusions Feasibility test on this innovative technology is reported in this short paper . We expect the same technology can be applied to other reconstruction surgical procedures in the future .

Objective We are entering a time when more and more digital images are being introduced to the operating room to enhance surgical outcomes .At the Surgical Simulation Research Lab of the University of Alberta, we developed a technology to superimpose a 3-dimentional (3D) breast model on top of the surgical site to guide a breast reconstruction procedure .Methods The breast models were created from the patient's magnetic resonance images .Our technician modified the breast model by taking data from pre-surgical scanning or from the healthy side of the breast .In the simulated environment , motion sensors were placed on the chest of the patient to capture the movements of the patient during the procedure, which were used to adjust the orientation of the 3D model to ensure a perfect mapping of the surgical site.Results Visual guidance was successfully displayed on top of the surgical site .Motion tracking captured movements of the simulated patient and was used for adjusting the 3D model in a short period of time.Conclusions Feasibility test on this innovative technology is reported in this short paper . We expect the same technology can be applied to other reconstruction surgical procedures in the future .

OBJECTIVE: To observe the effects of Spleen- strengthening decoction on GLP- 1 in patients with type II diabetes. METHODS: A randomized double- blind placebo- controlled test was conducted, and through observations for 8 wks, the changes of the two patient groups in plasma glucose, HbA1c, plasma GLP- 1 and Glucagon as well as TCM symptom score were measured for comparison. RESULTS: Before administration of Spleen- strengthening decoction, the two groups showed no significant difference in all of the indexes. After administration, the treatment group recorded lower indexes in fasting plasma glucose, HbA1c and plasma Glucagon, but higher index in fasting plasma GLP- 1, with no significant difference seen in other indexes. CONCLUSIONS: Spleen- strengthening decoction can improve glucose metabolism through heightening fasting plasma GLP- 1, and lowering both Glucagon and fasting plasma glucose.