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.

ObjectiveTo clarify the differences in the efficacy and mechanism of different processed products of Atractylodes chinensis rhizoma by the pharmacodynamics and metabolomics studies of raw， bran-fried and rice water-processed products on rats with spleen deficiency. MethodSixty male SD rats were randomly divided into blank group， model group， raw product group（3.75 g·kg^-1）， bran-fried product group（3.75 g·kg^-1）， rice water-processed product group（3.75 g·kg^-1） and Shenling Baizhusan group（6.7 g·kg^-1）， with 10 rats in each group. The method of excessive fatigue+improper diet was used to establish a spleen deficiency model in rats. After the end of modeling， except for the blank and model groups， each dosing group was given the corresponding drug suspension， the immune organ coefficients of each group of rats were examined， the levels of interleukin-6（IL-6）， tumor necrosis factor-α（TNF-α）， immunoglobulin G（IgG）， amylase（AMS）， motilin（MTL）， gastrin（GAS）， Na⁺-K⁺-adenosine triphosphatase（ATPase）， aquaporin 2（AQP2）， AQP3 and AQP8 in rats were measured by enzyme-linked immunosorbent assay（ELISA）. Ultra high performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry（UPLC-Q-TOF-MS） combined with orthogonal partial least squares-discriminant analysis（OPLS-DA） were used to search for biomarkers in the plasma samples of spleen-deficient rats by using two criteria［P<0.05 and variable importance in the projection（VIP） value>1］， and to compare the different modulatory effects of the three decoction pieces on the splenic-deficient biomarkers， and metabolic pathway analysis was conducted through the Kyoto Encyclopedia of Genes and Genomes（KEGG） database. ResultCompared with the blank group， the thymus index and spleen index of rats in the model group were significantly decreased（P<0.05）， the levels of IL-6， TNF-α， IgG and AQP2 were significantly increased（P<0.05）， the levels of AMS， GAS， MTL， AQP3， AQP8 and Na⁺-K⁺-ATPase were significantly decreased（P<0.05）. Compared with the model group， raw products， bran-fried products and rice water-processed products all increased thymus index and spleen index（P<0.05）， decreased IL-6， TNF-α， IgG and AQP2 levels（P<0.05）， and increased AMS， GAS， MTL， AQP3， AQP8 and Na⁺-K⁺-ATPase levels to different degrees. A total of 176 differential metabolites were screened in the model group compared with the blank group， of which 75， 72 and 84 biomarkers were called back by the raw products， bran-fried products and rice water-processed products， respectively（P<0.05， P<0.01）. Raw products of A. chinensis rhizoma mainly affected glycine， serine and threonine metabolism. Bran-fried products mainly affected alanine， aspartate and glutamate metabolism， D-arginine and D-ornithine metabolism. Rice water-processed products mainly affected glycine， serine and threonine metabolism， alanine， aspartate and glutamate metabolism， citrate cycle， thiamine metabolism， D-arginine and D-ornithine metabolism. ConclusionRaw products， bran-fried products and rice water-processed products of A. chinensis rhizoma all have good spleen strengthening effects， among which the effects of bran-fried products and rice water-processed products were stronger. Meanwhile， raw products has the strongest dryness， followed by bran-fried products， and the weakest dryness of rice water-processed products. The three decoction pieces are able to significantly modulate metabolic abnormalities in spleen-deficient rats， and the mechanism may be related to amino acid metabolism such as glycine， serine and threonine metabolism as well as alanine， aspartate and glutamate metabolism.

Renal fibrosis, especially tubulointerstitial fibrosis, is the most common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Several adaptive reactions occur in renal tubular epithelial cells after chronic injury, such as changes in glycolipid metabolism, unfolded protein response, autophagy and senescence, epithelial-to-mesenchymal transition and G2/M cell cycle arrest. Maladaptive repair mechanisms can induce tubulointerstitial fibrosis. This article will discuss the molecular mechanism of these adaptive responses of renal tubular epithelial cells driving renal tubulointerstitial fibrosis, and provide a basis for exploring new drug targets for renal tubulointerstitial fibrosis.

Nucleic acid-based molecular diagnostic methods are considered the gold standard for detecting infectious pathogens.However,when applied to portable or on-site rapid diagnostics,they still face various limitations and challenges,such as poor specificity,cumbersome operation,and portability difficulties.The CRISPR(Clustered regularly interspaced short palindromic repeats)/CRISPR-associated protein(Cas)-fluorescence detection method holds the potential to significantly enhance the specificity and signal-to-noise ratio of nucleic acid detection.In this study,we developed a portable grayscale reader detection system based on loop-mediated isothermal amplification(LAMP)-CRISPR/Cas.On one hand,in the presence of CRISPR RNA(crRNA),the CRISPR/Cas12a system was employed to achieve precise fluorescent detection of self-designed LAMP amplification reactions for influenza A and influenza B viruses.This further validated the high selectivity and versatility of the CRISPR/Cas system.On the other hand,the accompanying independently developed portable grayscale reader allowed for low-cost collection of fluorescence signals and high-reliability visual interpretation.At the end of the detection process,it directly provided positive or negative results.Practical sample analyses using this detection system have verified its reliability and utility,demonstrating that this system can achieve highly sensitive and highly specific portable analysis of influenza viruses.

ObjectiveTo analyze the research status and trends in low-level occupational benzene exposure. Methods Articles on low-level occupational benzene exposure from Chinese and English journals from January 1st, 2000, to December 31th, 2022 were retrieved using the Web of Science and the China National Knowledge Infrastructure, and a bibliometric analysis was conducted. Results A total of 327 articles were included in the analysis, comprising 216 English articles and 111 Chinese articles. i) The number of articles published in English fluctuates greatly over the years, without a trend of continuous growth or decline. Authors from 359 research institutions in 45 countries and regions have published relevant English articles in 97 kinds of journals, involving 281 grants from 226 foundations. The top three countries in terms of articles amount were the United States, Italy, and China, with 81, 46, and 43 papers, respectively. The English articles mainly focused on mechanistic research at the genetic level, such as hematotoxicity, oxidative stress, and DNA damage. ii) The number of Chinese articles increased gradually after 2012, with the growth peak in 2017. Authors from 127 research institutions in 26 provinces, autonomous regions, and municipalities published Chinese articles in 51 kinds of journals, involving 154 grants from 78 foundations. Chinese articles tended to focus on benzene-induced hematotoxicity and occupational health damage. Conclusion Most studies on low-level occupational benzene exposure were conducted in China, the United States and Italy, focused on hematotoxicity. Monitoring international research topics and hotspots of the field has certain reference value for related research in China.

Objective:To test the hypothesis that Pertussis toxin (PTX) can promote the occurrence of interstitial lung disease (ILD) in experimental autoimmune myositis (EAM) model and clarify the potential pathogenic mechanism.Methods:EAM mice model were induced by Skeletal muscle thomogenate with or without PTX, and the relationship between ILD phenotypes and neutrophil extracellular traps (NETs) infiltration was analyzed by histopathological and serological studies in EAM with PTX group and EAM without PTX group. Healthy mice were given PTX alone intraperitoneally to clarify whether NETs formation could be induced in vivo, and neutrophils separated from healthy human blood were intervened with PTX to induce NETs formation in vitro. The data was tested for normality using Shapiro-Wilk. Statistical methods and were analyzed using t-test or ANOVA, and multiple comparisons between different groups were tested using Tukey test. Results:Compared with EAM without PTX group, lung tissues in EAM with PTX group had multiple pathological changes similar to polymyositis/dermatomyositis-related ILD. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the main pathological types. The pulmonary interstitial lesions were accompanied by significant infiltration of NETs; and serum NETs markers levels were obviously elevated in EAM with PTX group, compared with the control group [ n=5, (87±10) ng/ml], cfDNA levels were statistically significantly elevated in both the EAM without PTX group [ n=4, (115±27) ng/ml] and the EAM with PTX group [ n=7, (150±50) ng/ml] ( F=4.24, P=0.038); Cit-H3-DNA levels were elevated in the EAM without PTX group ( n=4, 0.24±0.09), and in the EAM EAM with PTX group ( n=6, 0.33±0.11) compared with the control group ( n=4, 0.13±0.02) ( F=6.21, P=0.016). After PTX intervention, serum cfDNA levels were higher in the PTX group [ n=3, (100±40) ng/ml] than in the control group [ n=3, (45±12) ng/ml, t=2.27, P=0.086]; PTX also induced neutrophils to form NETs in vitro. Conclusion:PTX may promote the development of ILD in EAM mice model by inducing the formation of NETs, indicating that EAM mice can serve as a model for targeting NETs to study the pathogenesis ILD.

Objective:To observe the therapeutic effect of vibrating the abdomen on anorexia model rats,as well as its effects on cholecystokinin octapeptide(CCK-8)and motilin(MTL)in the peripheral blood. Methods:Forty young rats were randomly divided into a normal group(n=10)and a modeling group(n=30).Rats in the normal group were fed common feed.The anorexia model was established by the etiological simulation method in the modeling group,and these rats were further randomly divided into a drug group,a vibrating abdomen group,and a model group 3 weeks after the anorexia model was induced,with 10 rats in each group.The drug group was given Jian Wei Xiao Shi Pian by intragastric administration at a dose of 0.72 g/(kg·bw)(0.72 g drug was dissolved in 10 mL purified water).The normal group and the model group were given purified water once a day in the morning.The vibrating abdomen group was treated with vibrating the abdomen once a day for 21 times.The body mass,food intake,serum CCK-8,MTL,gastrin(GAS),neurotensin(NT)levels,and the intestinal propulsion rate of rats in each group were measured. Results:Compared with the model group,the body mass,food intake,serum MTL and GAS levels,and the small intestine propulsion rate increased significantly,and the serum CCK-8 and NT levels,the gastric residual rate decreased significantly in the vibrating abdomen group and the drug group(P<0.05).There were no significant differences between the vibrating abdomen group and the drug group(P>0.05). Conclusion:Vibrating the abdomen increases the food intake and body mass of anorexia model rats,reduces the residue of gastric contents,improves the small intestine propulsion rate,and therefore has a good therapeutic effect on anorexia.The mechanism may be related to inhibiting the secretion of CCK-8 and NT in plasma and promoting the release of MTL and GAS in serum.

The aim of this study was to investigate and evaluate the antitumor effects of a novel poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor, YHP-836, in combination with temozolomide (TMZ) for the treatment of glioblastoma (GBM). The cytotoxicity of YHP-836 was tested alone or in combination with TMZ using MTT assay. Immunoblotting and flow cytometry were also employed to assess the combination activity of YHP-836 and TMZ in multiply GBM cell lines. Further, the antitumor activity of YHP-836 and TMZ was evaluated using subcutaneous and orthotopic mice xenograft tumor models. All procedures were approved by the Ethics Committee for Animal Experiments of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and conducted under the Guidelines for Animal Experiments of Peking Union Medical College. The approval number is 00009138. It was demonstrated that the combination of YHP-836 and TMZ increased the cytotoxicity against GBM cells and upregulated histone H2AX phosphorylation (γH2AX) expression levels compared to TMZ treatment alone. The combination also led to the S-phase cell cycle arrest. Moreover, YHP-836 significantly enhanced TMZ antitumor effects without significantly increasing chemotherapy drug toxicity in vivo, whereas YHP-836 alone showed limited therapeutic efficacy against GBM. In conclusion, the novel PARP1/2 inhibitor, YHP-836, sensitizes TMZ and provides a basis for further investigation into its mechanism of action. These findings suggest that YHP-836 may be a potential candidate for combination therapy with TMZ in patients with TMZ resistance.

Objective To analyze the characteristics and influencing factors of healthcare-associated bloodstream infection(HA-BSI)of carbapenem-resistant Enterobacterales(CRE).Methods Retrospective nested case-control study was adopted.Fifty-six patients with CRE HA-BSI in a tertiary general hospital from January 2020 to Decem-ber 2022 were selected as the CRE group.With a 1:1 ratio,56 patients with carbapenem-sensitive Enterobacterales(CSE)BSI during the same period was selected as the CSE group.Distribution of infection strains and departments was analyzed,and the relevant factors for CRE BSI were analyzed by univariate and multivariate logistic regression analyses.Results The distribution of CRE BSI was mainly in intensive care unit(ICU,n=23,41.07％)and de-partment of hematology(n=17,30.36％).The main infection strains were Klebsiella pneumoniae(n=32,57.14％)and Escherichia coli(n=16,28.57％).Univariate analysis showed that malignant tumor,hospitalization history within 60 days,stay in ICU for＞48 hours before infection,mechanical ventilation,indwelling central venous cathe-ter,combined use of at least two kinds of antimicrobial agents,and duration of antimicrobial use ≥10 days were all related to CRE BSI(all P＜0.05).Multivariate logistic regression analysis found that stay in ICU＞48 hours before infection and duration of antimicrobial use ≥10 days before infection were independent risk factors for CRE HA-BSI(P＜0.05).Conclusion Clinical departments,especially ICU,should pay attention to the epidemiological history of patients,identify patients with high-risk factors for CRE BSI as early as possible,use antimicrobial agents ratio-nally and standardize invasive procedure,so as to reduce the occurrence of CRE HA-BSI.