Latest ArticlesSince the first Chimeric Antigen Receptor T Cell (CAR-T) therapeutic drug was approved in 2017, cellular immunotherapy drugs have continued to develop and become a hot spot in the field of biopharmaceuticals. In recent years, with the development of biotechnology, new CAR-T designs have emerged, and their indications have also expanded from hematological tumors to solid tumors, autoimmune diseases, and viral infections. Through optimized design, the activity of novel CAR-T cells has been continuously enhanced, while the toxicity reduced. Meanwhile, in order to further explore the safety and efficacy of CAR-T cells, its non-clinical evaluation models and methods have constantly been improving. In order to provide new ideas and considerations for the safety evaluation of immune cell therapy products, the latest research progress of CAR-T cell therapy and related new non-clinical evaluation methods are reviewed.
To compare the efficacy and safety of iguratimod or methotrexate combined with leflunomide in patients with active elderly-onset rheumatoid arthritis.
A single-center, randomized, double-blinded, controlled clinical trial was conducted in elderly-onset patients. The patients were randomly assigned to two groups of iguratimod combined with leflunomide (Group Iguratimod) or methotrexate combined with leflunomide (Group Methotrexate) treatments at a ratio of 1∶1. The efficacy and safety of both groups were evaluated at weeks 4, 12, 24 and 52, respectively. The primary endpoint was the American Colleague of Rheumatology 20 (ACR20) response rates at week 52 and disease activity score (DAS28) (CRP) at 52 weeks after treatment.
A total of 104 patients with elderly-onset rheumatoid arthritis were enrolled in the study. The comparison of the two groups on the baseline demographic data and RA activity showed that the iguratimod group was older (67.0 and 64.0, Z=-2.874, P=0.004), and the methotrexate group had a higher DAS28 (CRP) score (4.7 and 6.0, Z=-3.163, P=0.002). There was no statistically significant difference between the remaining results of the two groups. After 52 weeks of treatment, the ACR20 compliance rates in the iguratimod group and the methotrexate group were 90.0% and 93.9%, respectively (χ2=0.115, P=0.735). There was no statistically significant difference in compliance rates of ACR20, ACR50 and ACR70 between the groups at other time points compared to the baseline. There was no statistically significant difference in the DAS28 (CRP) score between the two groups at the end point of 52 weeks. Fewer adverse events were observed in the iguratimod group compared to the methotrexate group (26.0% and 46.9%, χ2=4.689, P=0.030). No serious adverse events were found in Group Iguratimod, but 3 cases of pneumonia were hospitalized in Group Methotrexate.
Iguratimod combined with leflunomide is an effective regimen with good safety for the treatment of active elderly-onset rheumatoid arthritis, with comparable efficacy and better safety compared to methotrexate combined with leflunomide.
To develop a highly sensitive, efficient, and stable cell-based platform for detection of anti-adeno-associated virus 8 (AAV8) neutralizing antibody titer in monkey plasma and perform preliminary validation of the relevant performance of the method.
In vitro, an equal volume of diluted monkey plasma was incubated with AAV8-Luciferase and then the mixture was added to a 96-well plate lined with HEK293 cells and incubated overnight to infect HEK293 cells; after cell lysis, the cells were added to a firefly luciferase reporter gene assay and the fluorescence signal (RLU) was detected using ELISA to assess the plasma levels of anti-AAV8 neutralising antibodies and subsequently obtain the corresponding antibody titres. The assay's sensitivity (LOD) and titer reproducibility, precision, method robustness and sample stability were preliminary were preliminary validated.
A highly sensitive, efficient and stable method for the detection of anti-AAV8 neutralizing antibody titer in monkey plasma at the cellular level was developed and preliminarily validated. The LOD value of the method was 10.36 ng·mL-1. The repeatability, precision and method robustness of the titer assay were good, and the positive control samples were stable after being placed at room temperature and 2 ℃~8 ℃ for 24 h and after freeze-thawing for 6 times at -65 ℃~-90 ℃/room temperature.
It has been preliminarily validated that the method can be used for the analysis and detection of anti-AAV8 neutralizing antibody titer in monkey plasma, which is useful for grasping the process of drug treatment and adjusting the treatment protocol in time and is suggestive for the development of AAV8 serotype gene therapy drugs and individualized treatment.
To establish a scientific applicability evaluation index system of real-world data (RWD), and provide a quantitative analysis basis for the transformation of RWD into real-world evidence (RWE).
Hierarchical extraction analysis of factors affecting the applicability of RWD was carried out by studying domestic and international guides, documents and literature. Analytic hierarchy process (AHP) and group eigenvalue method (GEM) were used in combination to establish the hierarchical structures of the selected indicators, expert scoring matrix was constructed, and MATLAB software for index system was used to compute the weights.
Applicability evaluation index was constructed from two aspects: relevance and reliability. Relevance included five sub-criteria level indexes and 26 specific evaluation indicators: data source and sample, exposure/intervention and event outcome definition, integration of multi-source data, regulatory requirements, ethics. Reliability consisted of three sub-criteria level indexes and 27 specific evaluation indicators: data validity, quality control, and quality assurance.
When gathering and applying RWD, attention should be paid to the data source, validity, and quality control, to ensure that the data is closely related to the demand and is reliable, and then to upgrade the applicability from RWD to RWE.
To prepare the β-cyclodextrin inclusion complexes of volatile oil in Qizhu granules.
The technology parameters like inclusion time, inclusion temperature, and the ratio of volatile oil to β-cyclodextrin in the preparation process of inclusion complexes were investigated by single factor experiment with inclusion rate as the index. With inclusion rate and inclusion yield as indexes, Box-Behnken response surface method was used to optimize the preparation process of inclusion complexes. Thin-layer chromatography, infrared spectroscopy and differential scanning calorimetry were utilized to characterize the inclusion complexes.
The optimal conditions were as follows: 9∶1 for volatile oils-(β-cyclodextrin) ratio, 64 ℃ for inclusion temperature, and 1 h for inclusion time. The inclusion rate and yield of the obtained inclusion complexes were 90.68% and 80.40%, respectively. All characterization results revealed the formation of inclusion complexes.
The established method is stable and feasible, which can be used for preparing the β-cyclodextrin inclusion complexes of volatile oil in Qizhu granules．
While significant advancements have been made in recent years in target identification and drug discovery, there is a general lack of validated targets for diseases. In the meantime, the number of new molecular entities approved per year has dramatically declined over the past decades. There is still much room for further improvement to optimize the drug discovery process. Activity-based protein profiling (ABPP) is a chemical proteomic method for functional investigation of complex proteomes directly in native biological systems. ABPP is widely used for target identification and drug discovery by using chemical probes that label active site residues in proteins. This review summarizes the design strategy of ABPP and introduces the related applications of ABPP technology in the field of target identification and drug discovery.
To establish a method of accelerated release of brexpiprazole sustained release microspheres for injection in vitro and discuss the in vivo and in vitro relationship, so as to provide reference for prescription screening and quality control of this preparation.
The effects of surfactant type, salt type and temperature on the release behavior were investigated by the method of constant temperature water bath. The in vitro accelerated release method was finally determined by the analysis of distinguishing ability and in vivo and in vitro relationship (IVIVR).
A method for accelerated release of pH 7.4 HEPES (containing 0.2% cetyltrimethylammonium bromide) at 45 ℃ in vitro was established, which showed a good correlation with in vivo release (r2>0.99).
The method of accelerated release in vitro established in this paper can guide prescription screening and process modification in all stages of drug development, and it is of great significance for product quality control.
Drug re-evaluation system has been developed in some developed countries for many years. In these countries, unique and mature drug re-evaluation systems have been established to make up for the insufficiency of pre-market research and review and further improve the safety and effectiveness of drugs. The importance of drug re-evaluation has been repeatedly verified in the practice of developed countries. China is establishing a pharmacovigilance system and should take advantage of the situation to establish a drug re-evaluation system adapted to China's national conditions, maintain focus on the safety of drugs throughout the life cycle, and ensure the medication safety of Chinese people. The post-marketing re-evaluation system in Japan has been developed for more than 40 years, and it is full of reference. This paper reviews the historical origin of Japan's post-marketing re-evaluation system, systematically analyzes Japan's post-marketing re-evaluation system from the aspects of object and period, change of laws and regulations, responsible subjects, and implementation procedures and so on. In the last part, practical suggestions are put forward for the construction of China's drug re-evaluation system.
At present, our country is facing the unfavorable situation that our independent innovation capability is weak and the key core technologies are subject to foreign countries. The complicated domestic and foreign environment makes it more urgent to reverse the "neck sticking" situation. General Secretary Xi Jinping delivered an important speech at the Central Economic Work Conference, demanding to "solve a number of ‘neck sticking’ problems as soon as possible". This study sorted out the definitions of "neck sticking" from different perspectives in previous studies, combined the differences and connections between "neck sticking" technology and other technologies, and analyzed the conceptual connotation of "neck sticking". It was proposed to define the "neck sticking" technology from multiple dimensions, such as national strategy, technology criticality, technology gap, and industry criticality, and build an evaluation index system of "neck sticking" based on above four dimensions. Finally, combined with our national conditions and domestic and foreign environment, some thoughts were put forward to solve the "neck sticking" problem in the field of biomedicine.
To investigate the mechanism of drug resistance occurring in hepatocellular carcinoma treated with sorafeinib from epigenetic perspective, and examine the effect of sensitivity of sorafeinib on hepatocellular carcinoma after in vita combination of epigenetic drug decitabine (DAC), so as to provide new ideas and methods for clinical treatment of hepatocellular carcinoma.
The GEPIA 2 database was used to retrieve information of 508 primary hepatocellular liver cancer patients, and the correlation between the expression of OATP1B3 and survival time was analyzed by Kaplan-Meier method. The methylation rate of SLCO1B3 promoter was detected by bisulfite methylation method. RT-qPCR and Western blot were used to detect the expression changes of cancer cell lines OATP1B3 before and after liver DAC treatment. RTCA-eSight experiment was performed to monitor the effect of sorafeinib in combination with DAC on the proliferation of hepatocellular carcinoma cells. Changes in the uptake of sorafeinib by hepatocellular carcinoma cells after the combination of the two drugs were detected by experimental LC-MS/MS.
The results of GEPIA2 database analysis showed that the overall survival rate of patients with hepatocellular carcinoma with high OATP1B3 expression was significantly higher than those with low expression. Bisulfite methylation sequencing showed that the promoter methylation rate of SLCO1B3 was higher in Hep3B and HepG2. RT-qPCR and Western blot showed that the mRNA and protein expressions of OATP1B3 in hepatocellular carcinoma cell lines Hep3B and HepG2 were relatively low, and the expression of OATP1B3 was upregulated after incubation with DAC. RTCA-eSight experiment showed that DAC combination treatment significantly enhanced the effect of sorafeinib on Hep3B and HepG2 inhibition. LC-MS/MS determination showed that the uptake of HEK293-OATP1B3 on sorafeinib was 2.10 times higher than that of HEK293-Wild. The uptake of sorafeinib by Hep3B and HepG2 was increased by 1.87-fold and 2.47-fold after being combined with DAC.
DAC can inhibit SLCO1B3 DNA methylation, up-regulate the expression of OATP1B3, improve the capacity of sorafenib transport, increase the accumulation of sorafenib in liver cancer cells, and enhance the sensitivity of liver cancer cells, so as to reverse the resistance of sorafenib.
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