Latest ArticlesA small GTPase encoded by Kirsten rat sarcoma viral proto oncogene (RAS) is a key regulatory protein in multiple cellular signaling pathways. The mutation of glycine to cysteine (G12C) at position 12 often leads to abnormal activation of cellular pathways, which plays an important role in the occurrence and development of tumors. Small molecule covalent inhibitors targeting KRASG12C protein can directly inhibit the abnormal activation of cellular pathways caused by KRASG12C mutation. In this paper, the structure and function of KRAS protein, as well as the research and development progress, challenges and possible solutions of covalent inhibitors of its G12C mutant are reviewed. The development direction of (K) RAS inhibitors in the future is prospected in order to provide a useful reference for the research and development of such inhibitors.
To provide reference for the compliance management of sponsors and research institutions in drug clinical trial cooperation.
Based on the typical cases of drug clinical trials in Chinese Judgment Documents Online, this paper studies the legal risks, causes and countermeasures in the process of drug clinical trial cooperation from both macro and micro perspectives.
Overall, violations of drug clinical trial cooperation are probably subject to civil liability, administrative penalties, and criminal sanctions. At the micro level, both sponsors and research institutions generally neglect to review the clinical trial contracts, improperly manage clinical trial quality, and neglect subject protection. At the macro level, the legal policies of drug clinical trials are non-systematic, and the supervision of drug clinical trials is becoming stricter.
The sponsors and research institutions should adapt to the new requirements under the new policy, improve the main responsibility, and pursue higher standards of compliance requirements, in order to ensure the safety of subjects in clinical trials, while maximizing their legitimate rights and interests, thus preventing legal risks.
Compared with other administration methods such as intravenous injection, oral administration is simple and feasible with low medical cost and high safety, and can relieve the pain of patients and enhance humanistic care. However, due to the harsh gastrointestinal environment, many oral drugs cannot reach their target sites with effective concentrations to exert therapeutic effects. Therefore, there are many challenges in developing oral drugs. Exosomes are extracellular vesicles secreted by cells, which transport proteins, nucleic acids, miRNA and other bioactive substances to receptor cells for intercellular communication. Recently, a number of researchers have reported that vesicles with structures similar to those secreted by mammalian cells can be extracted from vegetables, fruits and dairy products, and named them as food-derived exosomes (FDEs). FDEs have attracted wide attention due to their low immunogenicity, high biocompatibility, non-toxic and environmental properties. This review summarizes the medical application of FDEs as oral preparations, hoping to provide theoretical reference for the development and application of oral preparations based on FDEs.
Photodynamic therapy (PDT) is a tumor treatment method that uses photosensitizers to convert oxygen into reactive oxygen species and stimulate multiple pathways to kill cells. PDT can break through some limitations in tumor treatment with the help of nano-drug delivery system, but it still cannot solve the key problem of poor biocompatibility of photosensitizers. The cell membrane-modified biomimetic nano-drug delivery system formed by introducing natural cell membrane into nano-drug delivery system can give full play to the low immunogenicity of the cell membrane, improve the biocompatibility of photosensitizers, and enhance the anti-tumor effect of PDT. This review focuses on the progress of nanoparticles modified with cancer cell membrane, red blood cell membrane, leukocyte membrane and hybrid cell membrane, and their applications in PDT against tumors. The advantages and disadvantages of every type of cell membrane-modified nanoparticles based on PDT have been summarized to provide reference for its clinical application.
225Ac is one of the most promising radionuclides in alpha particle targeting therapy (targeted alpha therapy, TAT). The alpha particles produced by 225Ac decay have the characteristics of higher linear energy transfer, shorter tissue action distance, less side effects and so on. Therefore, TAT drugs such as small molecules and antibodies labeled with 225Ac have good application prospects in tumor treatment. This paper introduces the decay properties and sources of 225Ac, summarizes the commonly used chelating agents for 225Ac labeling, exemplifies the process of 225Ac labeling, and summarizes the application of 225Ac-labeled compounds in non-clinical and clinical research in the past three years. Finally, the challenges and prospects of 225Ac-labeled TAT drugs are analyzed, which provides a basis for the follow-up development of TAT drugs.
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 screen potential small-molecule inhibitors of monkeypox virus thymidylate kinase from traditional Chinese medicine databases using virtual screening technology.
Based on the published monkeypox virus thymidylate kinase sequence, the three-dimensional structure of monkeypox virus thymidylate kinase was constructed using homology modeling technology, and multiple rounds of screening were performed using docking-based virtual screening technology, including high-throughput virtual screening, standard precision virtual screening, high precision virtual screening and Prime MMGBSA.
Fifteen compounds with potential inhibitory activity against monkeypox virus thymidylate kinase were obtained by screening. The binding modes of compounds MOL002468, MOL009538, MOL000416 and MOL009237 with thymidylate kinase were analyzed for receptor-ligand interactions including hydrogen bonding, hydrophobic interactions, conjugation and salt bridges.
A virtual screening strategy for monkeypox virus thymidylate kinase was successfully constructed in order to discover new drugs that can be used to prevent and treat monkeypox virus, promoting further development and utilization of traditional Chinese medicine databases.
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 status of clinical trials registered on ClinicalTrials.gov on diseases in the list of rare diseases in China and analyze the registration characteristics.
All clinical trials involved in the list of rare diseases in China were searched on ClinicalTrials.gov from inception to April 5th, 2022. The relevant information of clinical trial registration was collected, and WPS Office was used for data analysis.
A total of 12 904 rare disease-related clinical trials were screened out, and the overall trend was increasing year by year. The information of clinical trial stages was missing a lot, and the sample size was mainly 0~100 cases. The types of trials were mainly interventional studies (9 042 trials, 70.1%) and observational studies (3 760 trials, 29.1%). There were three main statuses of trials: completed (6 467 trials, 50.1%), recruiting (2 388 trials, 18.5%), and unknown status (1 207 trials, 9.4%). The number of drug therapy trials was the largest (5 992 trials, 46.3%). The countries/regions participating in clinical trials were mainly developed countries in Europe and the United States. All of the top three single/multi-center rare disease-related clinical trials were conducted in European and American countries. There were a small percentage of clinical trials conducted in China (460 trials, 3.6%), but the proportion of single center-clinical trials was the highest (260 trials, 56.5%). The research institutions were mainly universities and medical institutions, and in China they were mainly medical institutions (358 trials, 77.8%). The sponsoring institutions were mainly European and American countries. The design of rare disease-related clinical trials was mainly non-randomized, open label and parallel allocation of therapeutic regimens. The outcome indicators were mainly related to safety and efficacy.
The development of clinical trials of rare diseases in China is on the rise, but there is a big gap with European and American countries. We should establish a systematic research and development incentive mechanism and introduce relevant laws and regulations as soon as possible to promote the high-quality development of clinical trials of rare diseases.
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.
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