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 mechanism of Danxing Zhishuang Prescription in the treatment of Parkinson's disease (PD) by combining network pharmacology with animal models.Methods:TCMSP, BATMAN database, Genecards, and OMIM databases were retrieved to obtain the active components and action targets of Danxing Zhishuang Prescription. Venny 2.1.0 was used to intersect drug targets and PD related genes, and a protein interaction network of the intersection targets was constructed using the STRING 12.0 platform. Topology analysis was performed using Cytoscape 3.10.0 software to identify the key targets of Danxing Zhishuang Prescription on PD; GO functional and KEGG pathway enrichment analysis was performed on key targets using the WeChat platform, and molecular docking was validated through AutoDockTools 1.5.7. Using a random number table method, mice were divided into a blank control group, a model group, and a Danxing Zhishuang Prescription group, with 20 mice in each group; except for the blank group, all other groups of mice were orally administered fisetin to prepare PD models; Danxing Zhishuang Prescription group was orally administered with concentrated Danxing Zhishuang Prescription at a dosage of 10.5 g/kg, while the blank group and model group were orally administered with 0.2 ml of physiological saline for 21 days; Western blot was used to detect the expressions of Akt1, Bcl-2, Bax, and α-Syn proteins.Results:359 intersection targets, 69 core targets, and 185 active components were obtained the treatment of PD with Danxing Zhishuang Prescription. The main active components included quercetin, kaempferol, phenylalanine, etc., and the key targets were AKT1, TP53, TNF, ESR1, etc. KEGG analysis revealed several key signaling pathways, such as AGE-RAGE, PI3K-Akt, fluid shear stress and atherosclerosis signaling pathways. The validation experiment results showed that compared with the model group, the expression of Bcl-2 protein was up-regulated ( P<0.01), and the expressions of Bax, Akt1, and α-Syn proteins were down-regulated in the Danxing Zhishuang Prescription group ( P<0.01). Conclusions:Danxing Zhishuang Prescription has the advantages of multi target and multi pathway treatment for PD. Its mechanism may be related to down-regulating the expressions of Bax, Akt1, and α-Syn proteins, improving brain blood supply, regulating neurotransmitter balance, inhibiting oxidative stress response, and promoting nerve regeneration.

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.

Objective : Objective Methods : The expression levels of PATL1 in pancar- cinoma，gastric cancer and normal tissues were analyzed by TCGA database．The expression level of PATL1 in 40 human gastric cancer tissues and paired adjacent tissues was evaluated by quantitative real-time PCR (RT-qPCR) . The Kaplan-Meier Plotter database was used to analyze the prognosis of PATL1 in gastric cancer patients．The gas- tric cancer cell line AGS was transfected with PATL1 interference vector，and the interference effect was evaluated by RT-qPCR. The effects of PATL1 on the proliferation and migration of AGS were detected by cell counting kit-8 ( CCK-8) ，Transwell test and scratch healing test．The effects of interference with PATL1 on the expression of cel- lular-myelocytomatosis viral oncogene ( c-Myc) and autophagy related 7 ( ATG7) proteins in gastric cancer cells were detected by Western blot assay. Results : RT-qPCR showed that the expression of PATL1 in human gastric cancer tissue was higher than that in normal gastric tissue (P＜0. 001) ，and PATL1 was correlated with the progno- sis of patients with enteric gastric cancer (P＜0. 000 1) ．After PATL1 was knocked down，the number of prolifera- ting and migrating gastric cancer cells decreased (P＜0. 05) ．Western blot test results showed that the expression level of ATG7 protein decreased after PATL1 was knocked down (P＜0. 05) ． Conclusion PATL1 may inhibit the proliferation and migration of gastric cancer cells through crosstalk with c-Myc and ATG7 .

Objective:To measure the retinal structural and functional parameters of adult Macaca fascicularis, and explore the similarity of the retinal structural and functional parameters between non-human primates and normal human retinas.Methods:Six eyes of 3 5-year-old adult Macaca fascicularis were examined by in vivo detection including color fundus photography, retinal optical coherence tomography (OCT) and electroretinogram (ERG) to determine the thickness of the inner/outer retina at the fovea and 1 000/2 000 μm away from the nasal, temporal, superior and inferior regions of the fovea, the thickness of the retinal nerve fiber layer (RNFL), the area of optic disc, the area of optic cup, the area ratio of cup to disc and the biological parameters of flash ERG.Differences in the above parameters between left and right eyes were analyzed.The similarity of parameters between Macaca fascicularis and human was compared with reference to published literature.The use and care of animals complied with the Regulation on the Management of Experimental Animals.The study protocol was approved by the Institutional Animal Care and Use Committee of Hubei Topgene Biotechnology (NO.IACUC-2019-012). Results:The foveal thickness, optic disc area, cup-disc area ratio, and average RNFL thickness in normal adult Macaca fascicularis were (252.31±4.79)μm, (1.89±0.05)mm 2, 0.14±0.01, and (103.53±0.58)μm, respectively.The b-wave amplitude of dark-adapted 0.01 ERG was (66.75±7.29)μV.The a- and b-wave amplitudes of dark-adapted 3.0 ERG response were (57.15±15.01) and (122.10±25.51)μV, respectively.The a- and b-wave amplitudes, the amplitude of oscillation potentials, and the latency of dark-adapted 10.0 ERG response were (72.98±20.14)μV, (131.67±13.78)μV, (49.98±10.08)μV, and (30.02±5.76)ms, respectively.The a- and b-wave amplitudes of light-adapted 3.0 ERG were (9.16±2.75) and (40.43±5.57)μV, respectively.The latency and the amplitude of the light-adapted 30 Hz flicker was (26.61±1.19)ms and (24.72±5.10)μV, respectively.There was no significant difference in the parameters between left and right eyes (all at P>0.05). The retinal thickness in central fovea, mean RNFL thickness, waveform and amplitude of ERG of Macaca fascicularis were similar to normal human. Conclusions:The structure and function of the retina of adult Macaca fascicularis are similar to those of normal humans.As a laboratory animal for preclinical drug research, in vivo studies of Macaca fascicularis can refer to normal human retinal parameters.

Objective:To determine the accuracy of injury severity score(ISS)in the assessment of patients with severe trauma by the consistency analysis of the patients'ISS with severe trauma scored by three clinicians,and to guide the allocation of medical resource.Methods:Through retrospective analysis of 100 patients with serious or severe trauma admitted to Peking University People's Hospital since Sep-tember 2020 to December 2021(ISS ≥ 16 points),we conducted a consistency analysis of ISS within dif-ferent evaluators.The general information(gender,age),vital signs,physical examination,imaging,laboratory examination and other associated data of the patients after admission were retrospectively diag-nosed by 3 clinicians specializing in trauma surgery and ISS was determined.SPSS 22.0 software was used for statistical analysis,descriptive reports were made on the observed values of each set of data,and Fleiss kappa test was used for consistency analysis of the credibility of the ISS within three clinicians.Results:Through the consistency analysis of the ISS in 100 patients with severe trauma scored by 3 eva-luators,the total Fleiss kappa value was 0.581,and the overall consistency was medium.Consistency analysis of the different scores was conducted according to the calculation rules of ISS.Among the patients with single-site severe trauma,abbreviated injury scale(AIS)was 4 or 5 points,ISS was 16 or 25 points,and Fleiss kappa value was 0.756 and 0.712 within the three evaluators,showing a relatively high consistency.AIS of each part was more than 4 points,and total ISS was more than 41 points in the severe trauma patients,Fleiss kappa values are higher than 0.8 within the 3 evaluators,showing a high consistency.Conclusion:According to the consistency analysis of severe trauma patients ISS within the three evaluators,when the severe trauma patients with ISS≥16 points are treated or transported,there is a certain accuracy error when the score is used for inter-department communication or inter-hospital trans-portation,and the consistency of different evaluators for the same injury is moderate.It may lead to mis-judgment of the severity of trauma and misallocation of medical resources.However,for trauma patients with single or multiple site AIS ≥ 4 points,ISS is highly consistent among different evaluators,which can accurately indicate the severity of the patient's condition.

Objective:To explore the standardization of totally implantable venous power port of nursing process in CT enhancement and application effect of contrast medium injection, so as to provide a safer and more efficient way for contrast medium injection in CT enhanced examination for patients with malignant tumors.Methods:A non-randomized prospective study was conducted, 358 patients with malignant tumors were selected in Sun Yat-sen Memorial Hospital, Sun Yat-sen University who underwent CT enhanced examination from August 1, 2022 to July 31, 2023, 179 patients who had been implanted totally implantable venous power port were selected as the experimental group, and the standardized nursing procedure was given. The other 179 patients were the control group, using radiology routine high-pressure intravenous indwelling needle as the contrast medium access, with routine peripheral venous nursing process. The incidence of contrast medium extravasation during CT enhanced examination was observed and compared between the two groups.Results:All the patients were included. There were 85 males and 94 females, aged (55.50±11.72) years old in the control group. There were 83 males and 96 females, aged (54.50±12.24) years old in the experimental group. The incidence of contrast medium extravasation was 0 in the experimental group and 3.35%(6/179) in the control group. The difference between the two groups was statistically significant (Fisher exact probability, P<0.05). Conclusions:The application of standardized nursing procedure of totally implantable venous power port to the injection of contrast medium in CT enhanced examination of malignant tumor patients, can significantly reduce the incidence of contrast medium extravasation.

Myeloid neoplasms (MNs) belong to a group of hematological malignancies characterized by the abnormal biological functions of hematopoietic stem progenitor cells. The abnormal immune and hematopoietic microenvironment of patients with MN interact with malignant clonal hematopoietic stem cells, promoting the occurrence and development of their diseases. MN large granular lymphocyte proliferation (MN-LGLP) is a special and rare clinical phenomenon in this type of disease. Currently, research on this disease in domestic and international cohorts is limited. This study analyzes the clinical and laboratory characteristics of this type of patient and explores the impact of LGLP on the clinical characteristics and survival of patients with MN. Patients with MN-LGLP are prone to neutropenia and splenomegaly. The presence of LGLP is not a risk factor affecting the survival of patients with MN-LGLP. STAG, ASXL1, and TET2 are the most common accompanying gene mutations in MN-LGLP, and patients with MN-LGLP and STAG2 mutations have poor prognoses.

Objective:To analyze the incidence of stillbirth and the associated factors in pregnancy among pregnant residents in Wuhan.Methods:A previous birth cohort was retrospectively reviewed. The cohort was based on Wuhan Maternal and Child Information System, and the perinatal information of pregnant residents in Wuhan from January 1, 2011, to September 30, 2017 and information of selected cases was collected, including socio-demographic characteristics, pregnant history, and healthcare information during pregnancy and labor. Data on stillbirth, including fetal death in uterus and in labor, were selected for this study. Chi-square test was adopted for comparing the differences in pregnancy-related factors between live birth and stillbirth, and binary logistic regressions for exploring the influencing factors associated with the occurrence of stillbirth. Results:A total of 509 057 deliveries in Wuhan were included in this study, including 505 839 live births and 3 218 stillbirths (3 155 after exclusion of fetal death in labor), with an overall incidence of stillbirth of 6.32‰(3 218/509 057), and an annual incidence between 4.90‰ to 8.11‰. Statistically significant differences were found between the live birth and stillbirth group in the following items: maternal age [<25 years old: 19.28% (97 544/505 839) vs 19.36% (623/3 218); 25-30 years old: 48.45% (245 077/505 839) vs 45.15% (1 453/3 218); 30-35 years old: 26.09% (131 952/505 839) vs 26.29% (846/3 218); >35 years old: 6.18% (31 266/505 839) vs 9.20% (296/3 218)], educational background [middle school or below: 22.90% (115 833/505 839) vs 22.03% (709/3 218); high school: 36.37% (183 978/505 839) vs 38.72% (1 246/3 218); college or above: 40.73% (206 028/505 839) vs 39.25% (1 263/3 218)], occupation [brainworker or professionals: 33.51% (169 514/505 839) vs 31.54% (1 015/3 218); manual or freelance worker: 66.38% (335 763/505 839) vs 68.34% (2 199/3 218)], residential area [urban area: 70.00% (354 365/505 839) vs 76.32% (2 456/3 218); rural area: 30.00% (151 474/505 839) vs 23.68%(762/3 218)], and time of conception [spring (March to May): 24.27% (122 746/505 839) vs 24.08% (775/3 218); summer (June to August): 24.09% (121 867/505 839) vs 23.87% (768/3 218); fall (September to November): 26.69% (135 012/505 839) vs 25.08% (807/3 218); winter (December to next February): 24.95% (126 214/505 839) vs 26.97% (868/3 218)] (all P<0.05), but no significant difference was found in fetal gender ( P>0.05). Besides, gravidity [once: 49.32% (249 484/505 839) vs 47.02% (1 513/3 218); over twice: 50.68% (256 355/505 839) vs 52.98% (1 705/3 218)], parity [once: 73.60% (372 316/505 839) vs 77.07% (2 480/3 218); over twice: 26.40% (133 523/505 839) vs 22.93% (738/3 218)], history of stillbirth [0.33% (842/256 355) vs 0.65% (11/1 705)], hypertensive disorders in pregnancy [3.25% (16 464/505 839) vs 5.59% (180/3 218)], first trimester vaginal bleeding [2.02% (10 251/505 839) vs 2.61% (84/3 218)], placenta previa [0.98% (4 963/505 491) vs 2.64% (53/2 009)], and oligohydramnios [2.52% (12 764/505 839) vs 1.90% (61/3 218)] differed significantly between the two groups (all P<0.05). However, no significant difference was found between the two groups in terms of the proportion of women with gestational diabetes mellitus and previous spontaneous abortion (both P>0.05). After exclusion of fetal death in labor from the 3 218 stillbirths, the same results were achieved. Binary logistic regression analysis showed that women who were over 30 years old (30-35 years old: OR=1.42, 95% CI: 1.30-1.56; >35 years old: OR=2.59, 95% CI: 2.25-2.98), with a high school degree or below (middle school or below: OR=1.37, 95% CI: 1.21-1.55; high school: OR=1.28, 95% CI: 1.16-1.42), manual or freelance worker ( OR=1.18, 95% CI: 1.07-1.31), in the urban area ( OR=1.43, 95% CI:1.31-1.57), and gravidity ≥ 2 times ( OR=1.32, 95% CI: 1.21-1.43), primiparity ( OR=1.76, 95% CI: 1.58-1.96), gestational hypertension ( OR=2.80, 95% CI: 2.40-3.27), vaginal bleeding in the first trimester ( OR=1.35, 95% CI: 1.08-1.68), placenta previa ( OR=10.86, 95% CI: 8.84-13.35) and history of stillbirth ( OR=2.27, 95% CI: 1.30-3.98) were all risk factors of stillbirth. Conclusion:Pregnant women who were over 30 years old, less educated, manual worker or freelance or with a history of adverse pregnancy, vaginal bleeding in the first trimester, hypertension in pregnancy, and placenta previa are at higher risk of stillbirth

Objective:To establish the reference values and neurological intervention cutoffs for cerebral ventricular size in neonates born at 33 +0-41 +6 weeks of gestation and to investigate the influential factors and reliability of the related indices. Methods:This study prospectively recruited 1 370 1-to 7-day neonates born or hospitalized at the Hunan Provincial Maternal and Child Health Care Hospital from February to August 2021. All the neonates, who were born between 33 +0 and 41 +6 weeks of gestation, were subjected to ultrasound scanning to obtain the indices, including ventricular index (VI), anterior horn width (AHW), thalamo-occipital distance (TOD), and ventricular height (VH). The reference value and neurological intervention cutoff for each index were set. Quantile regression was used to estimate the correlation between each index and continuous covariates [gestational age at birth (GA) and birth weight (BW)]. Mann-Whitney U test was used to analyze the differences in the medians of indices in different categorical covariates groups (males/females, left/right lateral ventricles, vaginal delivery/cesarean section, and singleton/multiple births). Intraclass correlation coefficient (ICC) calculated by a two-way mixed effect model and absolute agreement was used to access intra-rater reliability; ICC via a two-way random effect model and absolute agreement was utilized to rate inter-rater reliability (pool reliability: ICC below 0.50; moderate reliability: ICC between 0.50 and 0.75; good reliability: ICC between 0.75 and 0.90; excellent reliability: ICC exceeding 0.90). Results:The upper limits of reference values for AHW, TOD, VI, and VH in 555 (40.5%) preterm neonates were 2.7-3.5 mm, 20.9-22.5 mm, 12.6-13.7 mm, and 3.8-4.9 mm, and in 815 (59.5%) term newborns were 3.4-4.3 mm, 18.6-21.3 mm, 14.2-14.7 mm, and 3.4-3.8 mm, respectively. The cutoff of neurosurgical intervention for each index was the upper limit of reference value plus 4 mm. AHW median was positively correlated with GA [partial regression coefficient (PRC): 0.12, P<0.05], while TOD and VH medians were negatively correlated with GA (PRC:－0.31 and－0.06, both P<0.05). VI, AHW, and TOD medians were positively associated with BW (PRC: 0.46, 0.23, and 0.97, all P<0.05). The medians of VH, AHW, and TOD in the left cerebral ventricular exceeded those in the right cerebral ventricular, respectively (VH: 2.0 vs 1.8 mm, U=836 071.50; AHW: 1.8 vs 1.7 mm, U=874 141.50; TOD: 13.6 vs 12.5 mm, U=738 409.00, all P<0.05). The medians of AHW and VI in male neonates were greater than those in female newborns, respectively (AHW: 1.8 vs 1.7 mm, U=834 124.00; VI: 11.1 vs 10.8 mm, U=884 156.50, both P<0.05). The neonates delivered vaginally had greater AHW median, but smaller TOD median than those delivered by cesarean section (AHW: 2.0 vs 1.6 mm, U=685 546.00, P<0.001; TOD: 13.1 vs 12.9 mm, U=850 797.00, P=0.010). The AHW median in singleton newborns exceeded that in multiple births (1.9 vs 1.4 mm, U=356 999.00, P<0.001). The lower limits of 95% confidence intervals for intra-rater and inter-rater ICCs exceeded 0.75 and 0.50, respectively. Conclusion:Reference values and surgical intervention thresholds for VI, AHW, TOD, VH of newborns with a gestational age of 33 +0-41 +6 weeks were preliminarily established, and the reliability of these indicators were verified.