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 revolu-tionizing 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 estab-lishing 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.

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 explore the therapeutic effect of precise disconnection of pargastric varices guided by endoscopic ultrasound in the treatment of esophagogastric variceal bleeding.Method A retrospective analysis was conducted on 20 patients with cirrhosis esophagogastric variceal bleeding treated with endoscopic ultrasound-guided precise disconnection of pargastric varices from January 1,2024 to December 31,2024.The efficacy was analyzed.Result All 20 patients successfully completed the precise disconnection of pargastric varices under the guidance of endoscopic ultrasound.The injection of tissue gel combined with the placement of spring coils(14 cases)and the injection of tissue gel alone(4 cases)successfully blocked the pargastric varices.All patients did not experience perforation,esophageal and cardia stenosis,massive bleeding,septicemia,or ectopic embolization.One patient who received tissue gel alone had slight bleeding from the pargastric varices after surgery and improved after 3 days of treatment to reduce portal vein pressure.Another one patient who received tissue gel alone had a low-grade fever and normal body temperature after 3 days of anti-infection treatment.Conclusion Precise disconnection of pargastric varices under the guidance of endoscopic ultrasound has a good therapeutic effect on esophagogastric variceal bleeding,with fewer complications such as ectopic embolization,massive bleeding,infection,and perforation.However,close follow-up observation is still needed to address the issue of pargastric varices.

The core pathological feature of Parkinson's disease(PD)is the abnormal aggregation of α-synuclein and the result ing neuronal damage.α-Synuclein exhibits toxic effects when it forms oligomers or fibrils,leading to neuronal death via multiple pathways,including mitochondrial dysfunction,impaired vesicular trafficking,dopamine auto-oxidation,and neuroinflammation.In addition,α-synuclein can propagate between cells via exosomes,endocytosis/exocytosis,tunneling nanotubes,or vagal nerve axonal transport,creating a cascade of pathological effects.Animal models of PD that recapitulate the key pathological hallmark of α-synuclein accumulation are indispensable tools for elucidating disease mechanisms and developing novel therapeutic interventions.To date,various strategies,including transgenic techniques,bacterial artificial chromosome(BAC)-mediated expression,viral vector-mediated overexpression,and gene editing,have been employed to develop α-synuclein overexpression animal models.These models have significantly advanced our exploration of the relationship between PD and α-synuclein.This systematic review considers the structure and function of α-synuclein,its mechanisms of toxicity,intercellular propagation pathways,animal models of overexpression,and potential therapeutic targets based on its pathogenic mechanisms.

The core pathological feature of Parkinson's disease(PD)is the abnormal aggregation of α-synuclein and the result ing neuronal damage.α-Synuclein exhibits toxic effects when it forms oligomers or fibrils,leading to neuronal death via multiple pathways,including mitochondrial dysfunction,impaired vesicular trafficking,dopamine auto-oxidation,and neuroinflammation.In addition,α-synuclein can propagate between cells via exosomes,endocytosis/exocytosis,tunneling nanotubes,or vagal nerve axonal transport,creating a cascade of pathological effects.Animal models of PD that recapitulate the key pathological hallmark of α-synuclein accumulation are indispensable tools for elucidating disease mechanisms and developing novel therapeutic interventions.To date,various strategies,including transgenic techniques,bacterial artificial chromosome(BAC)-mediated expression,viral vector-mediated overexpression,and gene editing,have been employed to develop α-synuclein overexpression animal models.These models have significantly advanced our exploration of the relationship between PD and α-synuclein.This systematic review considers the structure and function of α-synuclein,its mechanisms of toxicity,intercellular propagation pathways,animal models of overexpression,and potential therapeutic targets based on its pathogenic mechanisms.

Objective To explore the therapeutic effect of precise disconnection of pargastric varices guided by endoscopic ultrasound in the treatment of esophagogastric variceal bleeding.Method A retrospective analysis was conducted on 20 patients with cirrhosis esophagogastric variceal bleeding treated with endoscopic ultrasound-guided precise disconnection of pargastric varices from January 1,2024 to December 31,2024.The efficacy was analyzed.Result All 20 patients successfully completed the precise disconnection of pargastric varices under the guidance of endoscopic ultrasound.The injection of tissue gel combined with the placement of spring coils(14 cases)and the injection of tissue gel alone(4 cases)successfully blocked the pargastric varices.All patients did not experience perforation,esophageal and cardia stenosis,massive bleeding,septicemia,or ectopic embolization.One patient who received tissue gel alone had slight bleeding from the pargastric varices after surgery and improved after 3 days of treatment to reduce portal vein pressure.Another one patient who received tissue gel alone had a low-grade fever and normal body temperature after 3 days of anti-infection treatment.Conclusion Precise disconnection of pargastric varices under the guidance of endoscopic ultrasound has a good therapeutic effect on esophagogastric variceal bleeding,with fewer complications such as ectopic embolization,massive bleeding,infection,and perforation.However,close follow-up observation is still needed to address the issue of pargastric varices.

Objective To investigate the importance of echoendoscope in identifying common bile duct lesions associated with portal hypertension in liver cirrhosis.Methods From November 2022 to January 2023,a group of 37 individuals suffering from liver cirrhosis,portal hypertension,esophageal,and gastric varices underwent echoendoscope analysis to assess the common bile duct wall's thickness,its width,and to examine its cavity's dimensions.Result The common bile duct's wall exhibited roughness with 97.3%(36/37),with an average thickness of 0.19 cm,a width of 0.47 cm,and flocculent deposits constituting 73.0%(27/37).The typical bile duct exhibited curvature in 13.5%(5/37).None of the patients experienced bleeding either during or following the echoendoscope examination.Conclusion The use of echoendoscope distinctly reveals cirrhosis-induced common bile duct and portal hypertension;a majority of cirrhosis and portal hypertension sufferers exhibit inflammation in the common bile duct;this technique is deemed safe for assessing esophageal and gastric varices in cirrhosis patients.

Objective:To investigate the effect of the distance of the circumferential resection margin (CRM) on postoperative recurrence after laparoscopic radical resection of colon cancer.Methods:The clinical data of 83 patients who underwent laparoscopic radical resection of colon cancer in Yiwu Central Hospital from January 2020 to January 2022 were retrospectively included. They were divided into recurrent group (16 cases) and non-recurrent group (67 cases) according to the recurrence within 1 year after operation. The clinical data, postoperative CRM distance and laboratory indicators of the two groups were collected to analyze the influence of CRM distance on postoperative recurrence after laparoscopic radical resection of colon cancer.Results:The proportion of patients treated with postoperative chemotherapy, and postoperative CRM distance in the recurrent group were lower than those in the non-recurrent group: 9/16 vs. 83.58 % (56/67), (0.85 ± 0.23) mm vs. (1.64 ± 0.76) mm. The levels of CEA and CA19-9 at admission were higher than those in the non-recurrent group: (156.74 ± 11.58) μg/L vs. (149.96 ± 10.26) μg/L, (15.63 ± 2.77) kU/L vs. (14.04 ± 2.35) kU/L, and the differences were statistically significant ( P<0.05). Point binary correlation analysis showed that there was a negative correlation between CRM distance and postoperative recurrence after laparoscopic radical resection of colon cancer ( r = - 0.412, P<0.01). Multivariate Logistic regression analysis showed that the long distance of CRM was the protective factor of recurrence after laparoscopic radical resection of colon cancer ( OR<1, P<0.05). The results of the receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of the CRM distance to predict the recurrence after laparoscopic radical resection of colon cancer was 0.833>0.7, and the predictive value was good. When the optimal threshold was 1.080 mm, the ideal sensitivity and specificity could be obtained 87.50% and 81.00%. Conclusions:The shorter the CRM distance after laparoscopic radical resection of colon cancer, the higher the risk of recurrence. The CRM distance can be used as a predictor of recurrence after laparoscopic radical resection of colon cancer.

Objective:To investigate the efficacy of endoscopic retrograde cholangiopancreatography in the treatment of Child-Pugh C cirrhosis complicated by obstructive jaundice and its effects on liver function and infection indexes.Methods:The clinical data of 86 patients with Child-Pugh C cirrhosis complicated by obstructive jaundice who received treatment in the Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, from June 2017 to June 2022 were retrospectively analyzed. These patients were divided into an observation group ( n = 56) and a control group ( n = 30) according to different treatment methods. Patients in the observation group underwent endoscopic retrograde cholangiopancreatography and those in the control group received conservative drug treatment. After 14 days of treatment, clinical efficacy was compared between the two groups. The changes in liver function [alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl transpeptide (GGT)] and infection indicators [white blood cell count (WBC), procalcitonin (PCT), and C-reactive protein (CRP)] were compared between the two groups before and after treatment. The incidence of postoperative complications was compared between the two groups. At 6 months after treatment, the prognosis was compared between the two groups. Results:The total response rate in the observation group was 98.21% (55/56), which was significantly higher than 60.00% (18/30) in the control group ( Z = 23.43, P < 0.001). Before treatment, serum ALT, AST, GGT levels in the control group were (294.53 ± 45.19) U/L, (286.62 ± 17.15) U/L, and (304.53 ± 12.34) U/L, respectively, and they were (96.25 ± 16.7) U/L, (113.25 ± 8.56) U/L, (122.25 ± 9.24) U/L after 14 days of treatment. Before treatment, serum ALT, AST, and GGT levels in the observation group were (352.36 ± 70.23) U/L, (303.31 ± 12.12) U/L, and (368.36 ± 10.23) U/L, respectively, and they were (108.65 ± 12.38) U/L, (95.65 ± 6.54) U/L, and (85.66 ± 7.28) U/L, respectively, after 14 days of treatment. After treatment, serum ALT, AST, and GGT levels in each group were significantly decreased compared with those before treatment (observation group t = 22.54, 49.54, 64.76; control group t = 25.57, 112.83, 168.48, all P < 0.05). After treatment, the amplitude of decrease in serum ALT, AST, and GGT levels in the observation group were significantly greater than those in the control group ( t = 2.27, 3.18, 4.61, all P < 0.05). After treatment, PCT, CRP, and WBC in each group were significantly decreased compared with those before treatment (observation group: t = 11.68, 11.46, 5.42, control group: t = 20.39, 18.69, 19.02, all P < 0.05). After treatment, the amplitude of decrease in serum PCT, CRP, and WBC in the observation group were significantly greater than those in the control group ( t = 5.14, 1.67, and 2.11, all P < 0.05). Within 14 days after treatment, there were two cases of acute pancreatitis, one case of hyperamylasemia, and one case of transient biliary bleeding in the observation group. There was one case of acute pancreatitis in the control group. The incidence of complications in the observation group was slightly, but not significantly, higher than that in the control group ( P > 0.05). After treatment, 12 patients (40.00%) in the control group experienced worsening jaundice, and additional endoscopic retrograde cholangiopancreatography salvage treatment was given. After treatment, total bilirubin level decreased by > 50%, reaching the standard of significant efficacy. At 6 months after treatment, stent obstruction occurred in two patients, which was effectively treated by replacement. There were no deaths in each group during the follow-up period. Conclusion:Implantation of a nasobiliary duct or a biliary duct stent during endoscopic retrograde cholangiopancreatography is more effective at treating yelloxemia in patients with Child-Pugh C cirrhosis complicated by obstructive jaundice than medication. The former method can effectively relieve obstructive jaundice, smooth drainage, improve liver function, reduce infection, and be relatively safe.

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.