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 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.

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 : 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 .

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.

Chronic hepatitis B(CHB)is an infectious disease caused by persistent infection with the hepatitis B virus(HBV)and is highly prevalent worldwide.Non-alcoholic fatty liver disease(NAFLD)is a group of liver diseases related to metabolic abnormalities,excluding those caused by alcohol consumption or other liver injury factors.In recent years,with improvement of living standards and changes in lifestyle,the incidence of NAFLD has been increasing substantially,becoming the most common type of liver diseases in China and Western countries,and the second leading cause of liver transplantation in the West.The rising prevalence of NAFLD has also led to an increase in the incidence of NAFLD in patients with chronic HBV infection.However,there is considerable controversy both domestically and internationally regarding the relationship between these two diseases,including the disease progression,pathogenesis,impact on antiviral treatment efficacy,and prognosis of these concomitant CHB and NAFLD patients.Currently,both domestic and international guidelines lack detailed descriptions of diagnostic and treatment strategies for these conditions.This article summarizes the recent research progress in concomitant CHB and NAFLD,including epidemiology,diagnostic criteria,the impact of NAFLD on the virology of HBV infection,potential mechanisms of NAFLD-induced negative regulation of HBV,the effect of NAFLD on antiviral therapy effiicacy,and prognosis.This article aims to gain a deeper understanding of the diseases themselves and provide new insights for basic and clinical research as well as diagnostic and treatment approaches.

Objective:To explore the effects of mechanical factors on the morphology of the growth plate and proximal femur development, in order to provide a mechanical basis for the mechanism of Cam lesions in femoral acetabular impingement (FAI).Methods:Using CT scan data of hip joint from adolescents, we constructed three-dimensional finite element models of normal and extended proximal femoral epiphyseal growth plates. Dynamic mechanics and position data from daily activities (walk, stand on one and two feet, go upstairs and downstairs, sit and stand up, squat and stand up) and basketball layup drills were collected from five healthy volunteers using the Vicon system. The mean values of femoral head mechanical loads and positions at peak values, movement onset, and termination were selected for finite element analysis to observe the distribution of equivalent stress, normal stress, and shear stress on the two growth plate models under different activity modes.Results:Successful construction of three-dimensional finite element models for normal and extended proximal femoral epiphyseal growth plates was achieved. Mechanical load values and spatial positions of the femoral head during daily activities and layup movements were obtained. In daily activities, peak equivalent stress values for normal and extended growth plates ranged from 1.6 to 11.0 MPa; compressive stress ranged from 1.7 to 12.0 MPa; tensile stress ranged from 0.5 to 10.0 MPa; and shear force ranged from 0.4 to 7.1 MPa. The compressive stress during walking, standing on one or both feet, going up and down stairs, sitting and standing, and squatting was concentrated in the central and lateral areas; tensile stress was concentrated in the central and medial areas; shear force was concentrated in the medial area and the anterior and posterior edges of the growth plate. During a layup, the compressive stress in the center, outer upper side, and medial edge of the growth plate of the normal model was notably concentrated, with peaks fluctuating between 5.5-19.0 MPa, 5.7-11.0 MPa, and 5.4-7.3 MPa respectively; tensile stress and shear force were concentrated at the inner and outer edges as well as in the central area, with peaks fluctuating between 3.0-24.0 MPa and 3.0-26.0 MPa respectively, these values were significantly different from those observed during daily activities. For the elongated growth plate, compressive stress was concentrated at the central and lateral edges with peaks fluctuating between 17.0-41.0 MPa and 17.0-38.0 MPa respectively; simulated shear stress and tensile stress showed significant concentration at peaks fluctuating between 4.9-34.0 MPa, also significantly different from those observed during daily activities.Conclusion:The difference in mechanical distribution between daily activities, basketball layup training, as well as between normal and extended growth plates may be the mechanical initiating factor in the development of extended growth plates and the formation of Cam lesions, it may be the mechanical initiating factor for the development of extended growth plates and the collision of Cam lesions in FAI.

Humans ; Mass Vaccination ; COVID-19 Vaccines/therapeutic use* ; COVID-19/prevention & control* ; Immunity, Herd ; Vaccination

‍ ObjectiveTo investigate the protective effect of safranal against sepsis-related liver injury （SRLI） induced by lipopolysaccharide （LPS） in mice and its mechanism. MethodsA total of 32 experimental male C57BL/6 mice were divided into control group， single drug group， model group， and treatment group using the simple random method， with 8 mice in each group. The mice in the single drug group and the treatment group were intraperitoneally injected with safranal （60 mg/kg） for 7 days of pretreatment， and the mice in the model group and the treatment group were intraperitoneally injected with LPS （10 mg/kg） to induce acute liver injury. The activities of serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were measured； HE staining was used to observe liver tissue sections； immunohistochemistry was used to analyze the expression of the downstream protein heme oxygenase-1 （HO-1） in the signal pathway； TUNEL was used to analyze the apoptosis of hepatocytes； Western blot was used to measure the expression of total proteins （nuclear factor erythroid 2-related factor 2 ［Nrf-2］ and HO-1） in liver tissue. The human liver cell line L02 was pretreated with safranal （100 μmol/L）， followed by induction of acute hepatocellular injury with LPS （100 ng/mL）， and DCFH-DA fluorescent labeling was used to detect reactive oxygen species （ROS）. ResultsAfter safranal pretreatment， the treatment group had significantly lower levels of ALT and AST than the model group （both P<0.001）， with a relatively intact pseudolobular structure and a smaller necrotic area in the liver. Compared with the model group， the treatment group had significant increases in the expression levels of Nrf2 and HO-1 in liver tissue after safranal+LPS treatment （both P<0.001）， and immunohistochemistry showed that safranal pretreatment increased the number of HO-1-positive cells. In the cell model of LPS-induced acute liver injury， the treatment group had a significant reduction in the production of ROS compared with the model group. ConclusionSafranal can exert a protective effect against SRLI induced by LPS in mice through the Nrf2/HO-1 pathway.