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 discuss the effect of acupuncture on the differentiation and apoptosis of quadriceps muscle satellite cells in model rats with knee osteoarthritis(KOA),and to clarify its related mechanism.Methods:A total of 40 SPF-grade rats were selected and randomly divided into control group,model group,celecoxib group,and acupuncture group,with 10 rats in each group.The rats in control group only underwent joint cavity incision followed by suturing,while the rats in model group,celecoxib group,and acupuncture group were used to replicate the KOA models.The maximum circumference of the femoral segment of the affected limb,rat body mass,and quadriceps wet weight of the rats in various groups were measured;the quadriceps wet weight maintenance rate and quadriceps wet weight/body mass ratio of the rats in various groups were calculated.HE staining was used to observe the pathomorphology of articular cartilage and quadriceps muscle tissue of the rats in various groups;terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick end labeling(TUNEL)method was used to detect the apoptosis indexes in articular cartilage and quadriceps muscle tissue of the rats in various groups;immunofluorescence method was used to detect the protein expression levels of interleukin-6(IL-6),Janus kinase(JAK),and signal transducer and activator of transcription 3(STAT3)in quadriceps muscle tissue of the rats in various groups;Western blotting method was used to detect the expression levels of IL-6/JAK/STAT3 signaling pathway proteins,and muscle satellite cells,and apoptosis-related proteins in quadriceps muscle tissue of the rats in various groups.Results:Compared with control group,the affected hind limb circumference,quadriceps wet weight,wet weight maintenance rate,and wet weight/body mass ratio of the rats in model group were significantly decreased(P<0.05);compared with model group,the affected hind limb circumference,quadriceps wet weight,wet weight maintenance rate,and wet weight/body mass ratio of the rats in celecoxib group and acupuncture group were significantly increased(P<0.05);compared with celecoxib group,the affected hind limb circumference,quadriceps wet weight,wet weight maintenance rate,and wet weight/body mass ratio of the rats in acupuncture group were significantly increased(P<0.05).The HE staining results showed that the knee articular cartilage of the rats in control group remained intact,chondrocytes were aggregated and horizontally arranged with smooth edges,and quadriceps muscle cells were long cylindrical,orderly arranged,and regular in shape;in model group,the knee articular cartilage was thinner with rough edges,reduced number of cartilage layers,and disordered arrangement,and the quadriceps muscle fibers were disorganized,with some muscle fiber dissolution and muscle cell membrane damage,accompanied by muscle fiber fragments and a large amount of inflammatory exudate;in celecoxib group,the morphology of knee articular cartilage was generally normal,occasionally with irregular cartilage arrangement and reduced thickness,sporadically visible necrotic chondrocytes,quadriceps muscle fibers and sarcolemma were relatively intact,new muscle fibers appeared,some muscle fiber edges were blurred,accompanied by a small amount of cell debris and mild inflammatory infiltration;in acupuncture group,the knee articular cartilage structure remained intact with smooth edges,occasionally rough edges,and chondrocytes were aggregated and orderly arranged.The TUNEL assay results showed that compared with control group,the apoptosis indexes in articular cartilage and quadriceps muscle tissue of the rats in model group were significantly increased(P<0.05);compared with model group,the apoptosis indexes in articular cartilage and quadriceps muscle tissue of the rats in celecoxib group and acupuncture group were significantly decreased(P<0.05);compared with celecoxib group,the apoptosis index in articular cartilage and quadriceps muscle tissue of the rats in acupuncture group were significantly decreased(P<0.05).The immunofluorescence assay results showed that compared with control group,the expression levels of IL-6,JAK,and STAT3 proteins in quadriceps muscle tissue of the rats in model group were significantly decreased(P<0.05);compared with model group,the expression levels of IL-6,JAK,and STAT3 proteins in quadriceps muscle tissue of the rats in celecoxib group and acupuncture group were significantly increased(P<0.05);compared with celecoxib group,the expression levels of IL-6,JAK,and STAT3 proteins in quadriceps muscle tissue of the rats in acupuncture group were significantly increased(P<0.05).The Western blotting results showed that compared with control group,the expression levels of IL-6,JAK,STAT3,paired box transcription factor 7(Pax7),Desmin,Myosin,and Myogenin proteins in quadriceps muscle tissue of the rats in model group were significantly decreased(P<0.05);compared with model group,the expression levels of IL-6,JAK,STAT3,Pax7,Desmin,Myosin,and Myogenin proteins in quadriceps muscle tissue of the rats in celecoxib group and acupuncture group were significantly increased(P<0.05);compared with celecoxib group,the expression levels of IL-6,JAK,STAT3,Pax7,Desmin,Myosin,and Myogenin proteins in quadriceps muscle tissue of the rats in acupuncture group were significantly increased(P<0.05).Compared with control group,the expression levels of B-cell lymphoma 2(Bcl-2),B-cell lymphoma-xl(Bcl-xl),and myeloid cell leukemia 1(MCL1)proteins in quadriceps muscle tissue in model group were significantly decreased(P<0.05),and the expression levels of Bcl-2-associated X protein(Bax)and cysteinyl aspartate specific proteinase-3(Caspase-3)proteins were significantly increased(P<0.05);compared with model group,the expression levels of Bcl-2,Bcl-xl,and MCL1 proteins in quadriceps muscle tissue of the rats in celecoxib group and acupuncture group were significantly increased(P<0.05),and the expression levels of Bax and Caspase-3 proteins were significantly decreased(P<0.05);compared with celecoxib group,the expression levels of Bcl-2,Bcl-xl,and MCL1 proteins in quadriceps muscle tissue of the rats in acupuncture group were significantly increased(P<0.05),and the expression levels of Bax and Caspase-3 proteins were significantly decreased(P<0.05).Conclusion:Acupuncture can promote the differentiation of quadriceps muscle satellite cells and inhibit muscle cell apoptosis in the model rats with KOA,and the mechanism may be related to the up-regulation of expressions of IL-6,JAK,and STAT3 proteins in the quadriceps muscle tissue.

Objective To evaluate myocardial microvascular lesions in patients with type 2 diabetes mellitus(T2DM)by 2D-speckle tracking echocardiography(2D-STE)and myocardial contrast echocar-diography(MCE).Methods A total of 45 T2DM patients admitted to the Endocrine Department of The First Affiliated Hospital of Air Force Military Medical University from August to November 2022 were enrolled in this study.All the patients were divided into two groups:simple T2DM group(n=22)and T2DM with microvascular complication group(MIC,n=23).In addition,24 healthy subjects were included as normal control(NC)group.2D-STE obtained the global longitudinal strain(GLS)and global circumferential strain(GCS);MCE obtained the average acoustic intensity(A),perfusion slope(b)of left ventricular segment,then myocardial blood flow(Aβ)was calculated and compared between groups.Results Compared with NC group,GLS,GCS,β and Aβ were lower in T2DM and MIC group(P＜0.05).Among the parameters of 2D-STE and MCE,GLS and Aβ have high diagnostic performance(P＜0.05)and GCS and β have medium diagnostic performance(P＜0.05).ROC curve analysis showed that the early warning values of myocardial microcirculation disorders were-17.63%(GLS),-21.55%(GCS),0.845 s-1(β),7.045 dB/s(Aβ)in patients with T2DM.Conclusion The mechanical strain and perfusion of myocar-dium in T2DM patients have already decreased even no lesion was shown in the peripheral micro-vessels.2D-STE combined with MCE can assess the changes of myocardial elasticity and microcirculation in T2DM in real time,which is helpful for early clinical diagnosis of diabetes cardiomyopathy and intervention guidance.

[Objective] To evaluate the effects of preoperative ureteroscopy (URS) on the prognosis of patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). [Methods] Data of 712 UTUC patients who received RNU in West China Hospital during May 2003 and Jun.2019 were retrospectively analyzed. Patients were divided into URS group (n=187) and non-URS group (n=525) according to whether URS was performed before RNU. Kaplan-Meier curves were used to analyze the overall survival (OS), cancer-specific survival (CSS), and intravesical recurrence-free survival (IVRFS). Cox proportional risk model was used for risk assessment. Subgroup analysis and interaction test were used to further verify the results. [Results] Significant differences were observed between the two groups in terms of body mass index (BMI), diabetes mellitus, surgical method, hydronephrosis, tumor location, tumor grade, lymph node metastasis, lymphovascular invasion and tumor diameter (P<0.05). Kaplan-Meier survival analysis showed that IVRFS was significantly lower in the URS group than in the non-URS group (P<0.001), and the difference was more pronounced in renal pelvis carcinoma (P<0.001); there were no differences in OS and CSS between the two groups (P>0.05). Cox multivariate regression showed that URS was an independent risk factor for intravesical recurrence (HR=2.12, 95%CI: 1.34-3.36, P<0.001). [Conclusion] Preoperative URS can increase the recurrence rate of UTUC, but it has no effect on the OS and CSS.

Purpose: This study aims to explore whether neoadjuvant chemotherapy with immunotherapy (NACI) leads to different tumor shrinkage patterns, based on magnetic resonance imaging (MRI), compared to neoadjuvant chemotherapy (NAC) alone in patients with triple-negative breast cancer (TNBC). Additionally, the study investigates the relationship between tumor shrinkage patterns and treatment efficacy was investigated. Methods: This retrospective study included patients with TNBC patients receiving NAC or NACI from January 2019 until July 2021 at our center. Pre- and post-treatment MRI results were obtained for each patient, and tumor shrinkage patterns were classified into three categories as follows: 1) concentric shrinkage (CS); 2) diffuse decrease; and 3) no change.Tumor shrinkage patterns were compared between the NAC and NACI groups, and the relevance of the patterns to treatment efficacy was assessed. Results: Of the 99 patients, 65 received NAC and 34 received NACI. The CS pattern was observed in 53% and 20% of patients in the NAC and NACI groups, respectively. Diffuse decrease pattern was observed in 36% and 68% of patients in the NAC and NACI groups. The association between the treatment regimens (NAC and NACI) and tumor shrinkage patterns was statistically significant (p = 0.004). The postoperative pathological complete response (pCR) rate was 45% and 82% in the NAC and NACI groups (p < 0.001), respectively. In the NACI group, 17% of patients with the CS pattern and 56% of those with the diffuse decrease pattern achieved pCR (p = 0.903). All tumor shrinkage patterns were associated with achieved a high pCR rate in the NACI group. Conclusion Our study demonstrates that the diffuse decrease pattern of tumor shrinkage is more common following NACI than that following NAC. Furthermore, our findings suggest that all tumor shrinkage patterns are associated with a high pCR rate in patients with TNBC treated with NACI.

Objective　To compare pain in patients with young-onset (YOPD) and late-onset (LOPD) Parkinson’s disease and analyze influencing factors.Methods　Seventy participants who visiting outpatient and inpatient of the neurology department of the Provincial Hospital Affiliated to Anhui Medical University from October 2018 to July 2020 were selected and divided into YOPD and LOPD group according to age and Hoehn-Yahr (H-Y) Scale.General data were collected.The king’s Parkinson’s disease pain scale (KPPS)，part 3 of the Unified Parkinson’s disease rating scale (UPDRS-Ⅲ).The hamilton rating scale for depression (HAMD） were used to assess the item of pain,motor function and prevalence of depression.And further analyses of their effects on pain were made.Results　Compared with LOPD patients,YOPD patients had lower mean age,HAMA score and prevalence of hypertension and constipation,longer mean duration of disease,higher mean HAMD score,MMSE score,KPPS score and incidence of pain (P<0.05).Compared with LOPD patients with pain,YOPD patients with pain had higher prevalence of pain occurring in the waist,lower prevalence of pain occurring in the legs (P<0.05).YOPD patients with pain had higher mean UPDRS-Ⅲ score,HAMD score,HAMA score and dyskinesia stage than those without pain (P<0.05).LOPD patients with pain had higher mean HAMD score,HAMA score and dyskinesia stage than those without pain (P<0.05).Conclusion　Patients with YOPD have a higher incidence of PD pain and more severe pain than those with LOPD.The more severe the emotional disorders and motor symptoms are,the more likely they will suffer from pain.Clinicians should standardize the treatment of pain according to the type and location of pain in PD patients,so as to improve the quality of life of patients.

Objective To investigate the effect of fenofibrate on glucolipid metabolism and insulin sensitivity in lipoprotein lipase heterozygous knockout ( LPL+/-) mice, and to explore its mechanism. Methods LPL+/- mice and wild type ( WT) C57 mice were selected and divided into 3 groups ( n=6 each group):LPL+/-( FB) group, LPL+/-(W)group,andWTgroup.MiceinLPL+/-(FB)groupweregavagedwithfenofibrate(50mg·kg-1·d-1)for8 weeks. Mice in LPL+/-( W) and WT groups were orally fed with the same volume water as that in LPL+/-( FB) group for 8 weeks. Body weight was observed. Plasma triglyceride ( TG ) and free fatty acid ( FFA ) were measured. Intraperitoneal glucose tolerance test in 3 groups of mice were performed. The glucose area under the curve ( AUCG) and homeostasis model assessment for insulin resistance index ( HOMA-IR) were calculated. Insulin-stimulated Ser473 Akt phosphorylation in liver and skeletal muscle was measured by Western blot. Reactive oxygen species ( ROS) levels in liver and skeletal muscle were determined by dihydroethidium staining method and superoxide dismutase ( SOD) and catalase ( CAT) mRNA expression levels were detected by real-time PCR. Results Compared with LPL+/-( W) mice, body weight of LPL+/-( FB) mice was lowered, plasma TG and FFA levels were decreased by about 46.0％and 76.5％respectively, and fasting insulin level and HOMA-IR were decreased while there were no significant differences in fasting glucose level and AUCG between two groups. Insulin-stimulated Ser473 Akt phosphorylation levels in liver and skeletal muscle of LPL+/-mice were enhanced by fenofibrate. ROS level in skeletal muscle of LPL+/-( FB) mice was lower than that in LPL+/-( W) mice while there was no significant difference in ROS of liver between two groups. Fenofibrate significantly increased SOD and CAT mRNA expressions in skeletal muscle of LPL+/-mice, but not in liver. Conclusion Fenofibrate reduces body weight, ameliorates lipid metabolism, and improves insulin sensitivity in LPL+/- mice, with reduced oxidative stress.

Objective To investigate the sustained release of BSA from chitosan-OREC/BSA films coated mats in vitro.Methods The negatively charged cellulose acetate (CA) fibrous mats were modified with multilayers of the positively charged chitosan or chitosan-OREC intercalated composites and the negatively charged bovine serum albumin (BSA) via electrostatic layer-by-layer (LBL) self-assembly technique.The adsorption and rinsing steps were repeated until the desired number of deposition bilayers was obtained.The in vitro BSA encapsulation and release experiments demonstrated that OREC could affect the degree of protein loading capacity and release ficiency of the LBL films coating.Results In the pH-gradient release assay,only a small amount of BSA was released from the mats in 1 h.As the time increased,the release rate of BSA of all the samples gradually went up to the maximum data within 8 h.For the samples with identical number of bilayers and record time,obvious increasing of the release amount could be seen in pH 7.4,in comparison with pH 1.2.Besides,doubling bilayers film-coated mats generally.Meanwhile,it was slightly distinguishable between 5 and 5.5 as well as 10 and 10.5 bilayers (t=0.651～ 1.324,P＞0.05).Interestingly,it could be seen that protein release of the chitosan-OREC/BSA films coated mats remarkably increased compared with that of chitosan/BSA films coated mats(t=2.264～ 2.305,P＜0.05).Conclusion The release of protein in the initial time could be controlled by adjusting the number of deposition bilayers,the outmost layer and the composition of coating bilayers.

Objective To explore the normal values for two-dimension solid state high resolution anorectal manometry (HRAM) in healthy adult volunteers.Methods The healthy adult volunteers were recruited by advertisement and underwent solid state HRAM in the left lateral position.Anorectal pressures and rectal sensation were recorded and analyzed.Results (1) A total of 126 Chinese healthy adult volunteers (male:50 cases (39.7％);age:(37.5 ± 14.2) years old) were recruited in this study.(2)Mean anal resting pressure (MERP) was (71.8 ± 17.3) mmHg (1 mmHg =0.133 kPa).Maximum anal resting pressure (MARP) was (79.3 ± 17.8) mmHg,Maximum anal squeeze pressure (MSP) was (178.7 ± 52.8) mmHg.Anal high pressure zone (HPZ) length was (3.4 ± 0.6) cm.During simulated evacuation,residual anal pressure (RAP) was (63.8 ±20.5) mmHg,and anal relaxation rate (ARR) was (37.0 ± 11.5) ％.Rectal threshold volume for first sensation (FST),desire to defecate (DDT),urgency to defecate (UDT) and maximum discomfort (MDT) was (47.4 ±10.0) ml,(84.5 ±18.2) ml,(125.8 ± 28.5) ml,and (175.5 ±36.1) ml,respectively.(3) Compared with female subjects,male subjects had higher MSP [(211.0 ± 50.7) mmHg vs (157.5 ± 42.5) mmHg],RAP [(71.6 ± 18.1) mmHg vs (58.8 ± 20.5) mmHg]and rectal MDT[(187.0 ±36.4) mmHg vs (168.0 ±34.1)mmHg],but lower ARR [(32.1 ±8.0)％ vs (40.2 ±12.3)％],all P＜0.01.(4) MERP,MARP,MSP and rectal MDT were higher in young group (≤ 40 years old),all P ＜ 0.05.Conclusions These observations provide normal values for two-dimension solid state HRAM,which have significant difference between genders and different age groups.

[Summary] In newly diagnosed diabetic patients, fasting plasma glucose, HbA1C , and plasma lipid profiles were measured to analyze the association between HbA1C and plasma lipid profiles. HbA1C might affect plasma lipid profiles in newly diagnosed diabetic patients. Higher HbA1C was associated with the worse plasma lipid profiles and more severe insulin resistance.