The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an in situ tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL⁺ B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual-conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL⁺ B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of αPD-1 and CAR-T therapies. The application of this in situ tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.

Monoclonal antibodies(mAbs)represent the most extensively utilized class of therapeutic proteins in clinical practice.While the majority of currently marketed mAbs are primarily employed for the treatment of non-infectious diseases,such as tumors and autoimmune disorders,the number of monoclonal antibody drugs approved globally for the prevention or treatment of infectious diseases has been progressively increasing since the onset of the COVID-19 pandemic.On March 25,2023,the World Health Organization(WHO)published the"Guidelines on the Non-Clinical and Clinical Evaluation of Monoclonal Antibodies and Related Products Intended for the Prevention or Treatment of Infectious Diseases".However,China has yet to release analogous guidelines.This article aims to elucidate the non-clinical evaluation aspects of monoclonal antibody drugs for infectious disease prevention and treatment as outlined in the WHO guidelines,with a focus on regulatory considerations,overarching principles of non-clinical evaluation,as well as pharmacodynamics,pharmacokinetics,and toxicology studies.It is intended to serve as a reference for the non-clinical research and evaluation of such novel drugs in China.

There are a large number of drug transporters widely distributed in various tissues and organs in the human body.They are involved in the membrane transport of numerous endogenous substances,toxins,and drugs.The transmembrane transport mediated by transporters not only plays an important role in maintaining the homeostasis of the internal environment,but also closely related to drug absorption,distribution,metabolism,and excretion processes.In clinical practice,drug-drug and drug-endogenous molecule interactions based on drug transporters may affect therapeutic efficacy or lead to toxic side effects.Therefore,it is particularly important to closely monitor and evaluate the risks of transporters mediated drug-drug interactions in the drug development and marketing process.This review summarized the classification,functions,tissue distribution and substrate specificity of typical drug transporters in new drug development.Subsequently,the research progress regarding drug-drug interactions involving 24 drug transporters for 55 newly approved drugs by the US Food and Drug Administration in 2023 is comprehensively reviewed.The aim is to provide reference for further drug-drug interaction research together with its scientific significance during new drug development stage.

There are a large number of drug transporters widely distributed in various tissues and organs in the human body.They are involved in the membrane transport of numerous endogenous substances,toxins,and drugs.The transmembrane transport mediated by transporters not only plays an important role in maintaining the homeostasis of the internal environment,but also closely related to drug absorption,distribution,metabolism,and excretion processes.In clinical practice,drug-drug and drug-endogenous molecule interactions based on drug transporters may affect therapeutic efficacy or lead to toxic side effects.Therefore,it is particularly important to closely monitor and evaluate the risks of transporters mediated drug-drug interactions in the drug development and marketing process.This review summarized the classification,functions,tissue distribution and substrate specificity of typical drug transporters in new drug development.Subsequently,the research progress regarding drug-drug interactions involving 24 drug transporters for 55 newly approved drugs by the US Food and Drug Administration in 2023 is comprehensively reviewed.The aim is to provide reference for further drug-drug interaction research together with its scientific significance during new drug development stage.

Monoclonal antibodies(mAbs)represent the most extensively utilized class of therapeutic proteins in clinical practice.While the majority of currently marketed mAbs are primarily employed for the treatment of non-infectious diseases,such as tumors and autoimmune disorders,the number of monoclonal antibody drugs approved globally for the prevention or treatment of infectious diseases has been progressively increasing since the onset of the COVID-19 pandemic.On March 25,2023,the World Health Organization(WHO)published the"Guidelines on the Non-Clinical and Clinical Evaluation of Monoclonal Antibodies and Related Products Intended for the Prevention or Treatment of Infectious Diseases".However,China has yet to release analogous guidelines.This article aims to elucidate the non-clinical evaluation aspects of monoclonal antibody drugs for infectious disease prevention and treatment as outlined in the WHO guidelines,with a focus on regulatory considerations,overarching principles of non-clinical evaluation,as well as pharmacodynamics,pharmacokinetics,and toxicology studies.It is intended to serve as a reference for the non-clinical research and evaluation of such novel drugs in China.

Objective To understand and evaluate the knowledge, attitude and practice of female human papillomavirus and HPV vaccine in Chinese mainland. Methods We searched the relevant studies about the knowledge, attitude and behavior factors of HPV infection and HPV vaccine published in PubMed, MEDLINE, CNKI and Wanfang databases about Chinese mainland women from January 1, 1995 to January 31, 2021.Two researchers independently screened the literatures, extracted data and the literatures with quality score≥5 points.Chi square test was used to evaluate its heterogeneity.Begg' s test was used to evaluate publication bias. Results A total of 33 literatures were included, with a total number of 46013 people.The results showed that the total awareness rate of HPV in the population was 65.9%, the lowest rates were 16.0%, 41.2% and 14.4% in Northeast, rural areas and middle school students, respectively; while the highest rates of HPV were 77.4%, 56.3% and 71.0% in Central China, cities and towns and college students, respectively.The main source of HPV knowledge was the network/WeChat official account number (38.9%), and the lowest was family/friend (4.5%).The population's awareness rate of HPV vaccine related knowledge was 41.4%, the highest rates were 51.8% and 69.7% in East China and medical staff, respectively, while the lowest were 23.6% and 12.7% in Southwest and middle school students. Conclusion In order to achieve the total elimination of cervical cancer in China by 2030 as soon as possible, people should strengthen their awareness of HPV and HPV vaccine related knowledge.

Drug-drug interactions (DDI) change dose-response relationships, and may result in low efficacy or high toxicity, which are important considerations especially in medical practice with multiple-drug therapies. Predicting clinically significant drug interactions during new drug development is an important part of benefit and risk assessment in drug development and review. This article summarizes the purpose and significance of drug interactions in new drug development, the main content and precautions of DDI studies in vivo and in vitro. Drug interaction studies on novel drug approvals for 2020 in the National Medical Products Administration (NMPA) and US Food and Drug Administration (USFDA) are examined, respectively. It aims to provide reference for DDI studies and regulatory reviews in new drug development in our country.

With the rapid development of nanotechnology, the research and development of nanomedicine has become one of the current development directions of drug innovation. The pharmacokinetic characteristics of nanomedicine are significantly different from general drugs because of the scale effect based on nanostructures, and pharmacokinetics studies of nanomedicine may be different from the general drugs. This article focuses on the research strategies and considerations on non-clinical pharmacokinetics of nanomedicine, including test agents, in vivo/in vitro assays, biological sample analysis, data evaluation and analysis etc., providing references for developers.

Objective: To study the clinical efficacy of Qixie-Huoxue-Tongluo decoction combined with ozagrel sodium injection in treatment of cerebral thrombosis. Methods: According to the random number table method, 91 cerebral thrombosis patients who met the inclusion criteria were divided into the control group (45 cases) and the study group (46 cases). The control group was treated with ozagrel sodium injection on the basis of routine treatment, while the study group was treated with Qixie-Huoxue-Tongluo decoction on the basis of the control group. The two groups were treated for 7 days. The National Institute of Health Stroke Scale (NIHSS)was used to assess the degree of neurological impairment, the Activity of Daily Living (ADL) was used to assess the quality of life; and the levels of MDA, SOD, NO, neuron-specific enolase (NSE) and neuronal protein (S-100β)were detected by ELISA.The clinical efficacy was evaluated. Results: The total effective rate was 93.5% (43/46) in the study group and 71.1% (32/45) in the control group, there was significant difference between the two groups (χ²=7.853, P=0.005). After treatment, the NIHSS score in the study group was significantly lower than that in the control group (16.1 ± 5.0 vs. 20.3 ± 5.3; t=3.889, P<0.01), and the ADL score in the study group (51.9 ± 9.3 vs. 45.3 ± 8.6, t=3.461) was significantly higher than that in the control group (P<0.01); the serum level of MDA (3.10 ± 0.48 mmol/L vs. 4.25 ± 0.76 mmol/L, t=11.427) and NO (41.14 ± 6.74 U/L vs. 62.20 ± 8.43 U/L, t=10.028) in the study group were significantly lower than those in the control group (P<0.01), the SOD (204.36 ± 21.29 vs. 163.39 ± 17.45, t=13.177) level in the study group was significantly higher than that of the control group (P<0.01); the serum NSE (4.85 ± 1.03 μg/L vs. 7.93 ± 1.14 μg/L, t=13.529) and S-100β protein (0.18 ± 0.03 μg/L vs. 1.02 ± 0.15 μg/L, t=37.232) levels in the study group were significantly lower than those in the control group (P<0.01). Conclusions Qixie-Huoxue-Tongluo decoction combined with ozagrel sodium injection can improve the degree of neurological impairment in patients with cerebral thrombosis, improve the quality of life clinical efficacy. And the mechanism may be related to inhibition of lipid peroxidation, anti-free radicals and so on.

OBJECTIVE: To review the clinical features of a male twin affected with glutaric academia type I (GA-I) and analyze the variations of glutaryl-CoA dehydrogenase (GCDH) gene. METHODS: Clinical data of the pair of twins and their parents were collected. Genomic DNA was extracted from peripheral blood samples, and variants of GCDH genes were detected by capture sequencing using a customized panel. Variants of the twins and their parents were verified by Sanger sequencing. RESULTS: The level of glutaric acyl carnitine (C5DC + C6OH) was 3.26 μmol/L in the male twin. The relative level of glutaric acid in urine was 547.51 by gas chromatography mass spectrometry analysis. Cerebral ultrasonography showed that the patient had subependymal hemorrhage, but no serious clinical manifestation was noted. After treating with special formula milk powder and L-carnitine, the boy showed good growth and development. Two heterozygous variants of the GCDH gene were detected in the patient, among which c.416C>G was suspected to be pathogenic, while c.109_110delCA was unreported. The variants were respectively inherited from his parents. The twin girl only carried the c.416C>G variant. CONCLUSION GA-I can be diagnosed by mass spectrometry, urine gas chromatographic mass spectrometry, imaging as well as genetic diagnosis. Early diagnosis and intervention is important.
Amino Acid Metabolism, Inborn Errors ; genetics ; Brain Diseases, Metabolic ; genetics ; Female ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Humans ; Male ; Mutation ; Phenotype