Antibody-drug conjugates (ADCs) represent a promising class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Despite their therapeutic potential, the use of ADCs faces significant challenges, including off/on-target toxicity and resistance development. This review examines the current landscape of ADC development, focusing on the critical aspects of target selection and antibody engineering. We discuss strategies to increase ADC efficacy and safety, including multitarget approaches, pH-dependent antibodies, and masked peptide technologies. The importance of comprehensive antigen expression profiling in both tumor and normal tissues is emphasized, highlighting the role of advanced technologies, such as single-cell sequencing and artificial intelligence, in optimizing target selection. Furthermore, we explore combination therapies and innovations in linker‒payload chemistry, which may provide approaches for expanding the therapeutic window of ADCs. These advances pave the way for the development of more precise and effective cancer treatments, potentially extending ADC applications beyond oncology.
Humans ; Immunoconjugates/adverse effects* ; Neoplasms/immunology* ; Animals ; Antibodies, Monoclonal/therapeutic use* ; Antineoplastic Agents/therapeutic use*

Radiation-induced thrombocytopenia (RIT) faces a perplexing challenge in the clinical treatment of cancer patients, and current therapeutic approaches are inadequate in the clinical settings. In this research, oxymatrine, a new molecule capable of healing RIT was screened out, and the underlying regulatory mechanism associated with magakaryocyte (MK) differentiation and thrombopoiesis was demonstrated. The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro. The ability to induce thrombopoiesis was subsequently demonstrated in Tg (cd41:enhanced green fluorescent protein (eGFP)) zebrafish and RIT model mice. In addition, we carried out network pharmacological prediction, drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) analyses to explore the potential targets of oxymatrine. Moreover, the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blot (WB), and immunofluorescence. Oxymatrine markedly promoted MK differentiation and maturation in vitro. Moreover, oxymatrine induced thrombopoiesis in Tg (cd41:eGFP) zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice. Mechanistically, oxymatrine directly binds to toll-like receptor 2 (TLR2) and further regulates the downstream pathway stimulator of interferon genes (STING)/nuclear factor-kappaB (NF-κB), which can be blocked by C29 and C-176, which are specific inhibitors of TLR2 and STING, respectively. Taken together, we demonstrated that oxymatrine, a novel TLR2 agonist, plays a critical role in accelerating MK differentiation and thrombopoiesis via the STING/NF-κB axis, suggesting that oxymatrine is a promising candidate for RIT therapy.

AIM To investigate the effects of Zuogui Jiangtang Tongmai Recipe on necroptosis pathway in a rat model of type 2 diabetes mellitus(T2DM)complicated with cerebral infarction(CI).METHODS The SD rats were randomly divided into the sham operation group,the model group,the metformin group(0.045 g/kg),and the low,medium and high dose Zuogui Jiangtang Tongmai Recipe groups(6.5,13,26 g/kg),with 9 rats in each group.In contrast to rats of the sham operation group,rats of the other groups were given 4 weeks feeding of high-sugar and high-fat diet combined with intraperitoneal injection of streptozotocin to establish a T2DM rat model with one week stable blood glucose,followed by gavage of corresponding drugs 3 days before the establishment of the middle cerebral artery occlusion(MCAO)model.After 7 days of administration,the rats had their CI injury assessed by mNSS method and TTC staining;their level of blood glucose detected by blood glucose meter;their levels of glycated serum protein,serum TNF-α and IL-1β detected by ELISA;their cerebral mRNA expressions of FADD,RIPK1,RIPK3 and MLKL detected by RT-qPCR;and their cerebral protein expressions of FADD,p-RIPK1,p-RIPK3 and p-MLKL detected by Western blot.RESULTS Compared with the sham operation group,the model group displayed increased levels of blood glucose value,glycosylated serum protein,neurological function score,cerebral infarction volume,cerebral FADD,RIPK1,RIPK3 and MLKL mRNA expressions,cerebral FADD,p-RIPK1,p-RIPK3 and p-MLKL protein expressions,serum TNF-α and IL-1β levels(P＜0.01);and more disordered and morphologically diverse neurons with smaller nucleus.Compared with the model group,the groups intervened with medium or high dose Zuogui Jiangtang Tongmai Recipe,or metformin shared improvement in terms of the aforementioned indices(P＜0.05,P＜0.01);and more neurons with regular morphology neat arrangement,and reduced cell gap.CONCLUSION Zuogui Jiangtang Tongmai Recipe can improve the neurological dysfunction of the rat model of T2DM complicated with CI,which may associate with the inhibited activation of necroptosis signaling pathway.

Objective To screen biomarkers for forensic identification of acute myocardial infarction (AMI) by non-targeted metabolomic studies on changes of urine metabolites in rats with AMI.Methods The rat models of the sham surgery group,AMI group and hyperlipidemia+acute myocardial infarction (HAMI) group were established.Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the changes of urine metabolic spectrometry in AMI rats.Principal compo-nent analysis,partial least squares-discriminant analysis,and orthogonal partial least squares-discriminant analysis were used to screen differential metabolites.The MetaboAnalyst database was used to analyze the metabolic pathway enrichment and access the predictive ability of differential metabolites.Results A total of 40 and 61 differential metabolites associated with AMI and HAMI were screened,respec-tively.Among them,22 metabolites were common in both rat models.These small metabolites were mainly concentrated in the niacin and nicotinamide metabolic pathways.Within the 95% confidence in-terval,the area under the curve (AUC) values of receiver operator characteristic curve for N8-acetyl-spermidine,3-methylhistamine,and thymine were greater than 0.95.Conclusion N8-acetylspermidine,3-methylhistamine,and thymine can be used as potential biomarkers for AMI diagnosis,and abnormal metabolism in niacin and nicotinamide may be the main causes of AMI.This study can provide reference for the mechanism and causes of AMI identification.

Objective To observe the therapeutic effect and mechanism of acupuncture at Zusanli-Zhongwan combined matching points on rats with exercise-induced stress gastric ulcer.Methods Forty male SD rats were randomly divided into blank group,model group,acupuncture group and Omeprazole group,with 10 rats in each group.Except for the blank group,the rats in the other groups were used to construct the model of exercise stress gastric ulcer by daily exhaustive swimming.After successful modeling,the acupuncture group was intervened by acupuncture at Zusanli(ST36)and Zhongwan(RN12),once a day,10 minutes each time.Rats in the Omeprazole group were given Omeprazole Enteric-Coated Tablets distilled water suspension by gavage two hours before daily swimming.After continuous 7-day intervention,the overall state and behavior of rats were observed,the gastric mucosal injury index was calculated by Guth method,the pathological morphology of gastric mucosa was observed by hematoxylin-eosin(HE)staining,the contents of superoxide dismutase(SOD),glutathione peroxidase(GSH-PX)and malondialdehyde(MDA)in serum were correspondingly determined by WST-1 method,colorimetry and TBA method,respectively,enzyme-linked immunosorbent assay(ELISA)was used to detect the contents of gastrin(GAS),somatostatin(SS),tumor necrosis factor-α(TNF-α),interleukin-1 β(IL-1β),interleukin-6(IL-6)and interleukin-10(IL-10)in serum,the expression levels of epidermal growth factor receptor(EGFR),matrix metalloproteinase 3(MMP3),nuclear factor erythroid-related factor 2(NRF2),heme oxygenase 1(HO-1)and mitochondrial SOD2,TNF-α,IL-1β,IL-6 and IL-10 mRNA in gastric mucosa were detected by real-time fluorescence quantitative polymerase chain reaction(qPCR).Results Compared with the blank group,the body mass of rats in the model group was increased slowly,the activity distance and activity in the open field test were decreased,the gastric mucosal ulcer index was increased significantly,the gastric mucosal function indexes involving GAS level was increased and SS level was decreased in serum,the mRNA expression level of EGFR in gastric mucosa was decreased and the mRNA expression level of MMP3 in gastric mucosa was increased.The serum levels of antioxidant substances SOD and GSH-PX were decreased significantly,and the serum level of oxidation product MDA was increased significantly.The mRNA expression levels of antioxidant genes NRF2,HO-1 and SOD2 in gastric mucosa were significantly decreased.The serum contents and the gastric mucosa mRNA levels of inflammatory factors TNF-α,IL-1α,IL-6 were significantly increased,while the serum content and the gastric mucosa mRNA level of IL-10 were significantly decreased.The differences were statistically significant(P＜0.05 or P＜0.01 or P＜0.001).HE staining showed obvious gastric mucosal injury.Compared with the model group,the above indexes in the acupuncture group and the Omeprazole group were significantly improved(P＜0.05 or P＜0.01 or P＜0.001).HE staining showed that the gastric mucosal injury was significantly reduced.Conclusion Acupuncture at Zusanli-Zhongwan combined matching points can reduce the local oxidative stress and inflammatory response in rats with exercise-induced stress gastric ulcer,reduce gastric mucosal injury,improve the emotional state of rats,and maintain the overall vitality of rats.

The Piezo protein is a non-selective mechanosensitive cation channel that exhibits sensitivity to mechanical stimuli such as pressure and shear stress. It converts mechanical signals into bioelectric activity within cells, thus triggering specific biological responses. In the digestive system, Piezo protein plays a crucial role in maintaining normal physiological activities, including digestion, absorption, metabolic regulation, and immune modulation. However, dysregulation in Piezo protein expression may lead to the occurrence of several pathological conditions, including visceral hypersensitivity, impairment of intestinal mucosal barrier function, and immune inflammation.Therefore, conducting a comprehensive review of the physiological functions and pathological roles of Piezo protein in the digestive system is of paramount importance. In this review, we systematically summarize the structural and dynamic characteristics of Piezo protein, its expression patterns, and physiological functions in the digestive system. We particularly focus on elucidating the mechanisms of action of Piezo protein in digestive system tumor diseases, inflammatory diseases, fibrotic diseases, and functional disorders. Through the integration of the latest research findings, we have observed that Piezo protein plays a crucial role in the pathogenesis of various digestive system diseases. There exist intricate interactions between Piezo protein and multiple phenotypes of digestive system tumors such as proliferation, apoptosis, and metastasis. In inflammatory diseases, Piezo protein promotes intestinal immune responses and pancreatic trypsinogen activation, contributing to the development of ulcerative colitis, Crohn’s disease, and pancreatitis. Additionally, Piezo1, through pathways involving co-action with the TRPV4 ion channel, facilitates neutrophil recruitment and suppresses HIF-1α ubiquitination, thereby mediating organ fibrosis in organs like the liver and pancreas. Moreover, Piezo protein regulation by gut microbiota or factors like age and gender can result in increased or decreased visceral sensitivity, and alterations in intestinal mucosal barrier structure and permeability, which are closely associated with functional disorders like irritable bowel sydrome (IBS) and functional consitipaction (FC). A thorough exploration of Piezo protein as a potential therapeutic target in digestive system diseases can provide a scientific basis and theoretical support for future clinical diagnosis and treatment strategies.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Objective:To assess the ultrasonographic features and potential diseases of fetal abnormal sylvian fissure(SF), and to explore the value of whole-genome sequencing (WGS) in prenatal detection.Methods:A total of 28 fetuses with a sonographic diagnosis of abnormal SF in Shenzhen Maternal and Child Health Hospital Affiliated to Southern Medical University between October 2018 and October 2020 were prospectively included. The fetal brain was evaluated by neuroultrasound and intrauterine MRI in detail. Amniotic fluid/cord blood obtained by amniocentesis or tissue samples from umbilical cord after birth were collected for WGS. Pregnancy outcomes and postnatal MRI were recorded, and neurodevelopment of live-born infants was followed up for more than 24 months after delivery.Results:During the study period, 28 fetuses with abnormal SF were identified, with a gestational age of 21.3-30.0 (24.8±2.0) weeks. Abnormal SF presented in MCD ( n=15, 53.6%), chromosomal anomalies ( n=3, 10.7%) or single-gene genetic syndromes ( n=3, 10.7%) with the affected fetuses showing developmental delay, hydrocephalus or leukomalacia ( n=4, 14.2%), corpus callosal agenesis with large interhemispheric cysts ( n=1, 3.6%), benign subarachnoid space enlargement with arachnoid cysts ( n=1, 3.6%), and multiple malformations ( n=1, 3.6%). Among the 15 cases with MCD, the most common pathology was lissencephaly/pachygyria, followed by schizencephaly, severe microcephaly, hemimegalencephaly with paraventricular heterotopia, and polymicrogyria. Abnormal SF presented bilaterally in 23 fetuses and unilaterally in 5. All cases were categorized into six types depending on SF morphology in the transthalamic section: no plateau-like or a small insula, linear type, irregular corrugated SF, Z-shaped, and cyst occupying type. In addition to abnormal SF, associated anomalies or mild variations were identified in all fetuses. There were 17 cases underwent intrauterine MRI, and 13 cases underwent postnatal MRI examination.And 25 pregnancies were terminated; 3 were born alive, and 2 had typical syndromic changes with poor neurodevelopmental prognosis. A related pathogenic genetic variant was detected in 57.1% (16/28) fetus, and the incidence of single nucleotide variants(SNVs) was 42.9% (12/28), among which de novo SNVs accounted for 91.7% (11/12). Conclusions:Fetal abnormal SF could be classified based on the ultrasonographic features of transthalamic section. Fetal abnormal SF may indicate MCD, some chromosomal abnormalities or single-gene genetic syndromes that may lead to poor neurodevelopmental outcomes, and may be affected by extra-cortical factors. It is suggested to carry out targeted prenatal genetic diagnosis for fetuses with abnormal SF.

Objective:To understand the cognition and attitude of medical staff towards medical ethics review, analyze possible influencing factors, to put forward relevant suggestions for strengthening ethical management in the future.Methods:From November 2021 to May 2022, a self-designed questionnaire and general data questionnaire on the cognition and attitude of medical staff to ethical issues in clinical research were used to investigate 408 medical staff from two first-class ternary hospitals in Hunan Province, data was analyzed to explore the respondents′ cognition and attitude, as well as related influence factors.Results:The average cognitive score of medical staff was 65.41, and the average attitude score was 91.83. Many possible influence actors regarding the cognition were identified, including degree, technical title, professional field, number of clinical research projects engaged as investigators, number of clinical research projects conducted as principle investigators, whether the hospital has established an ethics committee, and research ethics training experiences. While the influence factors of attitude were experiences of conducting and engaging in clinical research, the construction of hospital ethics committee and research ethics trainings.Conclusions:Medical staffs have the willingness to explore more research ethics knowledge, while their cognition of research ethics should be improved. Root-cause analysis should be conducted to identify influencing factors for improvement. The research management department should strengthen the publicity and training of clinical research ethics of medical staff, to improve their clinical research ethics knowledge literacy, and ensure the well-functioning of clinical research ethics review.

Objective: To explore the effectiveness of preventive treatment for latent tuberculosis infection (LTBI) patients, so as to provide reference for the management and preventive treatment of clustered epidemic in schools. Methods: Data came from the school tuberculosis outbreak of a boarding high school in Kaizhou District, Chongqing, which occurred between June 2017 and March 2018 among 2016 grade high school teachers and students for investigation and analysis. The total incidence, LTBI patients, and the incidence after preventive treatment for 5 years were followed up. Results: A total of 34 cases of pulmonary tuberculosis from June 2017 to March 2018. A total of 1 357 individuals were screened for 6 concentrated contact screenings, with a confirmed tuberculosis rate of 2.43%, a tuberculosis skin test (TST) positive rate of 27.41%, and a strong TST positive rate of 7.39%. Among them, the confirmed tuberculosis rate and TST positive rate in the first case class were much higher than those in other classes, with statistically significant differences ( χ 2=286.30, 98.59, P ＜0.01). 88 cases of LTBI were found, with 31 cases receiving preventive treatment (35.23%), of which 28 completed preventive treatment (90.32%). After five years of follow-up, 73 cases of pulmonary tuberculosis were diagnosed in 2016 by the school senior high school, with a incidence rate of 0.98/10 2 (person/person years). Fifteen of the 88 LTBI patients were diagnosed with pulmonary tuberculosis, and the incidence rate was 3.33/10 2 (person/person years). The incidence rate of the preventive treatment group was 0.7/10 2 (person/person years)lower than that of the medical observation group 4.5/10 2 (person/person years), with a statistically significant difference ( χ 2=4.31, P ＜0.05). Conclusion The classes with higher TST positive rate and strong positive rate have higher incidence rate. Improving the preventive treatment rate of LTBI patients can effectively reduce the incidence rate of tuberculosis.