Antibody drug conjugates (ADC) have emerged as a cutting-edge technology in anti-tumor treatment, making significant strides in recent years. ADC couple a highly active small molecule toxin payload to highly specific antibodies through a linker, enabling precise targeting of tumor cells while reducing systemic toxicity, thereby expanding the therapeutic window. However, due to the complexity of ADC molecule design, its efficacy and safety are influenced by various factors. Model-informed drug development (MIDD) is a powerful tool that utilizes various mathematical models for modeling and simulation to conduct quantitative analysis, guiding drug development and decision-making. By integrating multi-faceted data and information using mathematical models, it is possible to gain insights into the complex mechanisms, pharmacokinetics, and pharmacodynamics of ADC, providing unique perspectives for optimizing ADC development processes and clinical translation decisions. This review will introduce the basic concepts of MIDD and ADC and discuss application cases of MIDD in different stages of ADC development, aiming to provide beneficial references for the advancement of ADC.

OBJECTIVE To provide reference for optimizing or formulating unified evaluation methods for evidence and recommendation in expert consensus on off-label use of drugs. METHODS Retrieved from CNKI， Wanfang data， VIP， CBM， PubMed and Web of Science， Chinese expert consensuses on off-label use of drugs involving evaluation methods for evidence and recommendations were collected from the inception to August 1， 2024. After screening the literature and extracting relevant data， descriptive statistical analysis was conducted. RESULTS & CONCLUSIONS Among the 32 articles included， 14 articles （43.8%） used Micromedex’s Thomson grading system， only 7 articles （21.9%） considered economic factors when forming recommendations， 10 articles （31.3%） reported the conflicts of interest； only 2 articles （6.3%） involved experts in the field of evidence-based medicine methodology. There were differences in the sources of evidence， factors considered in forming recommendations， and the grading standards for evidence and recommendations among different expert consensus evidence evaluation methods. There were also differences in evidence levels and recommendation strength of the same drug off-label use in different expert consensus. It is recommended that in future consensus-building processes， greater attention should be paid to potential conflicts of interest among participants， collaboration with methodological experts should be enhanced， and efforts should be expedited to establish unified standards for evaluating evidence and recommendation methodologies.

Aim To investigate the effect and role of neuronal restriction silencing factor(REST/NRSF)in epilepsy disorder.Methods Immunohistochemistry,immunofluorescence,Western blot and qPCR tech-niques were used to detect REST/NRSF expression levels in hippocampal tissues of mice induced by kainic acid and human brain tissue.Viral injections,EEG re-cordings and behavioral methods were used to test the effects on epileptic mice after knockdown and overex-pression of REST/NRSF in the hippocampal CA1 re-gion,respectively.Results The positive rate of REST/NRSF in the lesions of epileptic patients was significantly higher compared with that in the control group.The levels of REST/NRSF protein and mRNA in the CA1 region of the hippocampus of mice in the KA model group were significantly higher.Kv7.2 and Kv7.3 potassium channel mRNA expression levels were significantly down-regulated.Significant up-regu-lation of REST/NRSF expression levels was observed in mouse hippocampus after NMDA injection.Knock-down of REST/NRSF in the CA1 region of hippocam-pus significantly elevated the expression levels of Kv7.2 and Kv7.3 potassium channel mRNAs.The fre-quency of EEG spiking and sharp-wave issuance and epileptic seizure grade were significantly lower.Over-expression of REST/NRSF in the CA1 region of hippo-campus significantly reduced the mRNA expression lev-els of Kv7.2 and Kv7.3 potassium channels.The fre-quency of EEG spiking and sharp-wave issuance was significantly higher and epileptic symptoms were exac-erbated.Conclusion REST/NRSF in mouse hipp-ocampal brain regions is involved in epileptic disease development through transcriptional regulation of Kv7.2 and Kv7.3 potassium channels.

Cardiac contractility modulation(CCM),as a new implantable electronic therapy device for treating chronic heart failure with reduced ejection fraction(HFrEF),has rapidly become a hot topic in the cardiovascular field due to its ability to enhance ventricular myocardial contractility,improve patients'symptoms and signs,cardiac function indexes and even long-term prognosis.This article reviews the mechanism and clinical studies of CCM in treating HFrEF,and based on its mechanism and signal transduction algorithm,further analyzes and prospects its efficacy in patients with heart failure with preserved ejection fraction,cardiac resynchronization therapy non-response,and HFrEF with concomitant atrial fibrillation,aiming to promote CCM to meet the needs of more diverse clinical situations in heart failure patients.

Objective:To explore the mediating effect of self-esteem between psychological resilience and social avoidance and distress in colorectal cancer patients.Methods:Totally 210 colorectal cancer patients who visited the outpatient clinic for follow-up at Shanxi Province Cancer Hospital from February to July 2023 were selected by convenience sampling. Data were collected using a general information questionnaire, the Connor-Davidson Resilience Scale (CD-RISC), the Self-Esteem Scale (SES), and the Social Avoidance and Distress Scale (SADS). A total of 210 questionnaires were distributed, with 205 valid responses.Results:The results showed that the total SADS score of colorectal cancer patients was (13.41±6.51), the total SES score was (23.14±5.68), and the total CD-RISC score was (57.27±13.33). Mediating effect analysis indicated that self-esteem partially mediated the relationship between psychological resilience and social avoidance and distress, accounting for 37.08% of the total effect.Conclusions:Colorectal cancer patients exhibit moderate to high levels of social avoidance and distress. Psychological resilience can directly affect patients' social avoidance and distress and can also have an indirect effect through self-esteem. Healthcare providers should implement intervention measures to enhance psychological resilience and self-esteem in colorectal cancer patients, thereby reducing social avoidance and distress and facilitating their reintegration into society.

Objective:To investigate the impact of syringin on lung tissue injury in acute respiratory distress syndrome(ARDS)rats by regulating miR-124-3p/mitogen-activated protein kinase 14(MAPK14)axis.Methods:ARDS rat model was established by intratracheal instillation of LPS(1 mg/kg,500 μl),and the successfully modeled rats were divided into ARDS group,syringin-L group(syringin 17.5 mg/kg),syringin-M group(syringin 35 mg/kg),syringin-H group(syringin 70 mg/kg),miR NC group(syringin 70 mg/kg+miR NC)and miR-124-3p inhibitor group(syringin 70 mg/kg+miR-124-3p inhibitor),with 12 rats in each group.Another 12 rats were instilled with 500 μl of normal saline in the trachea as a control group.Each administration group was injected with corre-sponding dose of syringin by intraperitoneal injection,miR NC group and miR-124-3p inhibitor group were administered with miR NC and miR-124-3p inhibitor by tail vein injection respectively,and control group and ARDS group were injected with corresponding dose of normal saline,for 3 consecutive days.RT-qPCR was applied to detect expressions of miR-124-3p and MAPK14 mRNA in lung tissue;HE staining was applied to observe lung histopathology;a blood gas analyzer was used to detect PaO2 and FiO2 in rat arterial blood,and to calculate PaO2/FiO2;ELISA was applied to detect levels of IL-1β,IL-18 and TNF-α in rat bronchoalveolar lavage fluid;Western blot was applied to detect expressions of MAPK14 and high mobility group box protein(HMGB1);dual-luciferase reporter gene assay was applied to analyze the relationship between miR-124-3p and MAPK14.Results:Compared with control group,expression of miR-124-3p in ARDS group was decreased(P<0.05),and the lung tissue structure was unclear,pulmonary interstitial congestive edema,inflammatory cell infiltration,and obvious lung tissue damage were observed,arterial blood PaO2,PaO2/FiO2 were decreased(P<0.05),the lung injury score and expression of MAPK14 mRNA in lung tissue,W/D value,levels of IL-1β,IL-18 and TNF-α in bron-choalveolar lavage fluid,and protein expressions of MAPK14 and HMGB1 were greatly increased(P<0.05);compared with ARDS group,expression of miR-124-3p in syringin-L group,syringin-M group and syringin-H group were greatly increased,the lung tissue damage was alleviated,arterial blood PaO2,PaO2/FiO2 were increased,the lung injury score and expression of MAPK14 mRNA in lung tissue,W/D value,levels of IL-1β,IL-18 and TNF-α in bronchoalveolar lavage fluid,and protein expressions of MAPK14 and HMGB1 were greatly decreased(P<0.05);down-regulation of miR-124-3p could increase MAPK14 expression,and attenuate the inflammatory inhibitory and lung-protective effects of syringin on ARDS rats.Conclusion:Syringin can alleviate lung injury in ARDS rats by regulating the miR-124-3p/MAPK14 axis.

The objective of this study was to determine the frequency and resistance patterns of ESBL-producing E.coli in lambs with diarrhea in the Kashi area,Xinjiang.The findings may provide guidance for the prevention and control of clinical E.coli disease.We collected 385 samples of perianal feces from lambs with diarrhea in the Kashgar area.From these samples,we isolated 371 strains of E.coli.We then used the double-paper-sheet synergistic method to screen for ESBL-producing E.coli.Additionally,we conducted analyses to identify drug-resistance genes,analyze drug resistance,and study the phylo-typing of the screened strains.Of 371 E.coli strains,204 were identified as ESBL-producing strains.The prevalence rates of blaCTX-M,blaCTX-M-1G,blaCTX-M-9G,and bla TEM resistance genes was 67.65％,69.12％,30.39％,and 63.73％,respectively.All ESBL-pro-ducing strains were resistant to multiple drugs,with resistance rates ranging from 90.69％to 100％for eight specific drugs:ampicillin,cefotaxime,gentamicin,enrofloxacin,azithromy-cin,tetracycline,chloramphenicol,methotrexate,and amitrazine.The phylogenetic subgroups of the strains were distributed primarily in groups A and D.Among group A strains,41.11％exhibited resistance to ten drugs,whereas among group D strains,40％exhibited resistance to 11 drugs.ESBL-pro-ducing strains of Escherichia coli are the main pathogens cau-sing diarrhea in lambs in the Kashgar region;group A is the main group,and all groups are multi-drug resistant.

The cdc73(cell division cycle 73)gene encodes the RNA polymerase Ⅱ cofactor Cdc73 in fis-sion yeast(Schizosaccharomyces Pombe),and is involved in G2 checkpoint activation and regulates the cell cycle.However,whether Cdc73 regulates cell mitotic dynamics is unknown.In this study,fluores-cent protein labeling and live cell imaging techniques were used to investigate the effects of cdc73 deletion on sexual reproduction and the dynamics of microtubules,actin,mitochondria,and histones during mito-sis.The results showed that in sexual reproduction,cdc73 deletion resulted in a 14.23％increase in the length of ascospores and a 64.08％decrease in the number of cells producing four spores.Analysis of the live cell imaging results revealed that,in mitosis,the elongation length of microtubules in anaphase was shortened by 11.21％,and the elongation time was reduced by 17.39％;the formation and contraction rates of actin rings decreased by 33.33％and 26.09％,respectively,and the formation and contraction times were prolonged by 58.00％and 40.38％,respectively.Meanwhile,the expression levels of actin ring,mitochondrion,and histones also increased.This study revealed the cdc73 deletion inhibits spindle elongation and delays actin ring formation and contraction in mitosis,which provides some scientific basis for further exploring the involvement of Cdc73 in regulating microtubule and actin dynamics in cell divi-sion.

Cardiac arrest most commonly occurs outside of the hospital, known as out-of-hospital cardiac arrest (OHCA), and is an important global health problem. Approximately 40% of cardiac arrest has no clear cause. Hereditary arrhythmias and cardiomyopathies factors contribute to cardiac arrest. The identification of genetic factors for cardiac arrest after its occurrence is of great value not only for the individual, but also for relatives who may be at risk for the disease in their family. In the United States, there are over 350?000 cases of OHCA and over 200?000 cases of in-hospital cardiac arrest (IHCA) each year, and in Western Europe, cardiac arrest accounts for 15%-20% of all adult natural deaths and 50% of all cardiovascular deaths. In order to reduce the burden caused by cardiac arrest within society, it is essential to further understand its etiological factors, such as incidence in different regions, risk factors, and populations at higher risk. For each individual, cardiac arrest is the result of a complex interaction of genetic and acquired factors. Understanding the complex interplay of pathogenic factors in cardiac arrest and the development of individualized prevention and treatment approaches requires the collection of clinical data from cardiac arrest populations and multimodal analysis in order to identify epidemiological features and risk factors for cardiac arrest. Recently, cardiac arrest-related data are being collected and integrated in Europe in different regions and populations. As a result of the commitment to the creation of large datasets of clinical information on cardiac arrest populations, the knowledge of the pathology of cardiac arrest pathogenesis as well as risk factors is steadily increasing. This article reviews the epidemiologic data of cardiac arrest in recent years and the associated risk factors, thus providing ideas for developing better strategies for the prevention and treatment of cardiac arrest.

AIM To rapidly screen xanthine oxidase(XOD)inhibitors from Smilax glabra Roxb.by enzyme-immobilized magnetic microspheres and LC-MS/MS,and to confirm the anti-uric acid constituents from S.glabra Roxb.METHODS The immobilized xanthine oxidase was prepared by covalent coupling with carboxyl magnetic beads as a carrier.The xanthine oxidase inhibitors in S.glabra were screened by the specific adsorption of immobilized enzyme.LC-MS/MS and standard substances were used for analysis and comparison,and the inhibitory activity and inhibition type of the screened and identified components were investigated.RESULTS The successful synthesis of immobilized xanthine oxidase was characterized by scanning electron microscopy and infrared spectroscopy.The enzyme loading was 70.50 μg/mg and the relative activity was 79.44%.Thirteen active compounds were screened from the extract of S.glabra,and eleven compounds were identified.The enzyme activity test showed that the inhibitory activites of engeletin and isoengeletin were the strongest,which was close to the positive control allopurinol.The IC50 value and inhibition type were 32.25 μg/mL,mixed inhibition,35.12 μg/mL,competitive inhibition.CONCLUSION The method is simple,rapid,accurate and suitable for directly screened active ingredients which can inhibit XOD from complex extract of traditional Chinese medicines.