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Pulmonary hypertension has a high mortality rate,and although targeted therapy is available,it is still incurable,and the long-term prognosis for patients is poor.As a tyrosine kinase inhibitor,imatinib was approved for marketing in China in 2002 for the treatment of chronic myelogenous leukemia and other tumor diseases.In addition to the antitumor effects,imatinib was found to improve hemodynamics and exercise tolerance in patients with severe pulmonary arterial hypertension,but the safety was suboptimal.With the emergence of new formulations of imatinib targeted at the lungs,it is expected to become a new targeted drug for pulmonary arterial hypertension.
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Objective:To explore the pathogenesis of primary hemophagocytic syndrome with UNC13D and MYO5A gene mutations.Methods:A case of adult hemophagocytic syndrome with gene mutation of UNC13D and MYO5A admitted to The 940th Hospital of the Joint Logistic Support Force of the PLA on January 28, 2022 was retrospectively analyzed in terms of laboratory examination, gene atlas of its close relatives and prognosis, and related literature was reviewed.Results:The patient was finally diagnosed with primary hemophagocytic syndrome, and chemotherapy was performed twice with hemophagocytic lymphohistiocytosis(HLH)-2004 regimen. The HLA matching of his cytoplasm was semi-compatible. Considering that his cytoplasm carried blood-macrophage related genes, it was not suitable to be selected as a donor, and there were no other suitable relatives. He was transferred to another hospital for allogeneic hematopoietic stem cell transplantation, but failed to receive allogeneic hematopoietic stem cell transplantation during telephone follow-up, and died.Conclusion:The gene mutation of primary hemophagocytic syndrome is the gold standard for the diagnosis of primary HLH. There may be dual gene inheritance pattern in primary HLH, and the combination of immune disorder caused by viral infection and genetic factors may lead to the pathogenesis of primary HLH.
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Mesenchymal stem cells (MSCs) are pluripotent stem cells with self-renewing differentiation, immunoactivity and anti-inflammatory potentials.Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the most effective treatment for hematologic malignancies.However, the presence of graft-versus-host disease (GVHD) after transplantation has hindered the development of allo-HSCT.MSC-derived exosomes (MSC-exo) derived from mesenchymal stem cells have been confirmed to have broad therapeutic prospects in allo-HSCT and GVHD.This review focused upon immunomodulatory effects of MSC, biological activities of MSC-exo and research advances of MSC-exo on managing GVHD, aiming to provide new therapeutic rationales for GVHD in the future.
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Objective:To investigate any effect of repeated transcranial magnetic stimulation (rTMS) on the expression of P2X7 receptor (P2X7R) and glial fibrillary acid protein (GFAP) in the prefrontal cortex and hippocampus of mice modeling depression.Methods:Thirty C57BL/6 mice were divided into a control group ( n=10) and a depression group ( n=20). The mice of the control group were raised in group (five mice per cage), while those of the depression group were kept alone for six weeks to induce depression. Among them, 16 were successfully modeled and randomly divided into a model group ( n=8) and an rTMS group ( n=8). The rTMS group received five sessions per week of 10Hz rTMS for 4 weeks. Any changes in depression-like behavior were observed and the expression of P2X7R and GFAP in the prefrontal cortex and hippocampus was measured. Results:Compared to the control group, a significant decrease was observed in the sucrose consumption rate in the sucrose preference test, in the distance moved in the open field test and in the expression of GFAP protein. But there was a significant increase in the immobile time in the tail suspension test and in the expression of P2X7R protein in the prefrontal cortex and hippocampus in the model group. At the conclusion of the experiment the differences in the sucrose consumption rate, the distance moved, GFAP protein expression, immobile time and P2X7R protein expression between the rTMS and the model group were all statistically significant.Conclusion:rTMS can reduce depression-like behavior, at least in mice. That may be related to inhibiting P2X7R expression and promoting GFAP expression in the prefrontal cortex and hippocampus.
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Objective:Analyze the ethical issues encountered or potential in the use of ChatGPT and explore its ethical norms and requirements.Methods:Based on the ethical perspective of medical scientific research, this paper analyzed the disputes existing in ChatGPT from the perspectives of morality, fairness, responsibility and supervision, and explored the reasons for the disputes from both subjective and objective aspects.Results:ChatGPT has ethical issues, fairness issues, accountability issues, and regulatory issues.Conclusions:Ethical issues in ChatGPT should be regulated from the perspectives of people-oriented, limiting monopoly, strengthening responsibility and insisting on development, to reduce potential risks and negative effects.
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OBJECTIVES@#Hyperhomocysteinaemia (Hcy) is an independent risk factor for cardiovascular and cerebrovascular diseases. MicroRNA (miR)-18a-5p is closely related to cardiovascular diseases. This study aims to investigate the effects of miR-18a-5p on homocysteine (Hcy)-induced myocardial cells injury.@*METHODS@#H9c2 cells were transfected with miR-18a-5p mimic/miR-18a-5p mimic negative control (NC) or combined with Hcy for intervention, and untreated cells were set as a control group. The transfection efficiency was verified by real-time RT-PCR, and cell counting kit-8 (CCK-8) assay was used to determine cell viability. Flow cytometry was used to detect apoptosis and reactive oxygen species (ROS) levels. Western blotting was performed to measure the protein levels of microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, Beclin1, p62, Bax, Bcl-2, and Notch2. Dual luciferase reporter assay was used to detect the interaction of miR-18a-5p with Notch2.@*RESULTS@#Compared with the control, treatment with Hcy or transfection with miR-18a-5p mimic alone, or combined treatment with Hcy and miR-18a-5p mimic/miR-18a-5p mimic NC significantly reduced the H9c2 cell viability, promoted apoptosis and ROS production, up-regulated the expressions of Bax and Beclin, down-regulated the expressions of Bcl-2, p62, and Notch2, and increased the ratio of LC3-II/LC3-I (all P<0.05). Compared with the combined intervention of miR-18a-5p mimic NC and Hcy group, the above indexes were more significantly changed in the combined intervention of miR-18a-5p mimic and Hcy group, and the difference between the 2 groups was statistically significant (all P<0.05). There is a targeted binding between Notch2 and miR-18a-5p.@*CONCLUSIONS@#MiR-18a-5p could induce autophagy and apoptosis via increasing ROS production in cardiomyocytes, and aggravate Hcy-induced myocardial injury. Notch2 is a target of miR-18a-5p.
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Ratas , Animales , Apoptosis/genética , Autofagia/genética , Proteína X Asociada a bcl-2 , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Especies Reactivas de Oxígeno , Miocitos Cardíacos/efectos de los fármacos , Homocisteína/efectos adversos , HiperhomocisteinemiaRESUMEN
Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA. 5. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such convergent evolution and its impact on humoral immunity remain unclear. Here, we demonstrate that these convergent mutations can cause striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability. BQ.1.1.10, BA.4.6.3, XBB, and CH. 1.1 are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents. Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions in the epitope diversity of NAbs and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted convergent evolution. Moreover, we showed that the convergent RBD mutations could be accurately inferred by integrated deep mutational scanning (DMS) profiles, and the evolution trends of BA.2.75/BA.5 subvariants could be well-simulated through constructed convergent pseudovirus mutants. Together, our results suggest current herd immunity and BA.5 vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be highly prioritized, and the constructed mutants could help to examine their effectiveness in advance.
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Multiple BA.4 and BA.5 subvariants with R346 mutations on the spike glycoprotein have been identified in various countries, such as BA.4.6/BF.7 harboring R346T, BA.4.7 harboring R346S, and BA.5.9 harboring R346I. These subvariants, especially BA.4.6, exhibit substantial growth advantages compared to BA.4/BA.5. In this study, we showed that BA.4.6, BA.4.7, and BA.5.9 displayed higher humoral immunity evasion capability than BA.4/BA.5, causing 1.5 to 1.9-fold decrease in NT50 of the plasma from BA.1 and BA.2 breakthrough-infection convalescents compared to BA.4/BA.5. Importantly, plasma from BA.5 breakthrough-infection convalescents also exhibits significant neutralization activity decrease against BA.4.6, BA.4.7, and BA.5.9 than BA.4/BA.5, showing on average 2.4 to 2.6-fold decrease in NT50. For neutralizing antibody drugs, Bebtelovimab remains potent, while Evusheld is completely escaped by these subvariants. Together, our results rationalize the prevailing advantages of the R346 mutated BA.4/BA.5 subvariants and urge the close monitoring of these mutants, which could lead to the next wave of the pandemic.
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Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a local growth advantage over BA.2.38, BA.2.76 and BA.5 in India. The underlying mechanism of BA.2.75s enhanced infectivity, especially compared to BA.5, remains unclear. Here, we show that BA.2.75 exhibits substantially higher ACE2-binding affinity than BA.5. Also, BA.2.75 spike shows decreased thermostability and increased "up" RBD conformation in acidic conditions, suggesting enhanced low-pH-endosomal cell-entry pathway utilization. BA.2.75 is less humoral immune evasive than BA.4/BA.5 in BA.1/BA.2 breakthrough-infection convalescents; however, BA.2.75 shows heavier neutralization evasion in Delta breakthrough-infection convalescents. Importantly, plasma from BA.5 breakthrough infection exhibit significantly weaker neutralization against BA.2.75 than BA.5, mainly due to BA.2.75s distinct RBD and NTD-targeting antibody escaping pattern from BA.4/BA.5. Additionally, Evusheld and Bebtelovimab remain effective against BA.2.75, and Sotrovimab recovered RBD-binding affinity. Together, our results suggest BA.2.75 may prevail after the global BA.4/BA.5 wave, and its increased receptor-binding capability could allow further incorporation of immune-evasive mutations.
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SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.21. The new variants receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab4 and Cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.
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Omicron sub-lineage BA.2 has rapidly surged globally, accounting for over 60% of recent SARS-CoV-2 infections. Newly acquired RBD mutations and high transmission advantage over BA.1 urge the investigation of BA.2s immune evasion capability. Here, we show that BA.2 causes strong neutralization resistance, comparable to BA.1, in vaccinated individuals plasma. However, BA.2 displays more severe antibody evasion in BA.1 convalescents, and most prominently, in vaccinated SARS convalescents plasma, suggesting a substantial antigenicity difference between BA.2 and BA.1. To specify, we determined the escaping mutation profiles1,2 of 714 SARS-CoV-2 RBD neutralizing antibodies, including 241 broad sarbecovirus neutralizing antibodies isolated from SARS convalescents, and measured their neutralization efficacy against BA.1, BA.1.1, BA.2. Importantly, BA.2 specifically induces large-scale escape of BA.1/BA.1.1-effective broad sarbecovirus neutralizing antibodies via novel mutations T376A, D405N, and R408S. These sites were highly conserved across sarbecoviruses, suggesting that Omicron BA.2 arose from immune pressure selection instead of zoonotic spillover. Moreover, BA.2 reduces the efficacy of S309 (Sotrovimab)3,4 and broad sarbecovirus neutralizing antibodies targeting the similar epitope region, including BD55-5840. Structural comparisons of BD55-5840 in complexes with BA.1 and BA.2 spike suggest that BA.2 could hinder antibody binding through S371F-induced N343-glycan displacement. Intriguingly, the absence of G446S mutation in BA.2 enabled a proportion of 440-449 linear epitope targeting antibodies to retain neutralizing efficacy, including COV2-2130 (Cilgavimab)5. Together, we showed that BA.2 exhibits distinct antigenicity compared to BA.1 and provided a comprehensive profile of SARS-CoV-2 antibody escaping mutations. Our study offers critical insights into the humoral immune evading mechanism of current and future variants.
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Objective:To build an investigator-initiated clinical research process management indicator system based on the theory of Hazard Analysis and Critical Control Point(HACCP).Methods:A plan was developed according to HACCP principles, and 23 experts were invited to form an expert advisory group. Literature research, panel discussion, and Delphi method were used to collect clinical research process management indicators, and the weight of each indicator was calculated via Analytic Hierarchy Process(AHP).Results:Two rounds of expert consultation were carried out with a high positive coefficient and a high expert authority level, and finally formed 3 primary indicators and 14 secondary indicators. The primary indicators were project establishment, project process management, and project implementation assessment, with weights of 0.142 8, 0.714 4, and 0.142 8, respectively.Conclusions:This study established a clinical research process management system based on HACCP theory from 3 dimensions: project establishment, project process management, and project implementation assessment, carried out precise management of clinical research according to the weights of secondary indicators, focusing on the content of indicators with great weight, and provided an important reference for the management of investigator-initiated clinical research.
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OBJECTIVE:To stu dy the improvement effects o f Trillium tschonos kii total sapo nins(TTM)on adjuvant-induced arthritis model rats and its mechanism. METHODS :SD rats were randomly divided into model group (n=44)and blank group (n=6). Model group was given Complete Freund ’s adjuvant to induce the adjuvant-induced arthritis model ;blank group was given constant volume of normal saline with same method. Model group were divided into model group ,Tripterygium wilfordii polyglycoside tablets group (40 mg/kg),TTM low-dose ,medium-dose and high-dose groups (50,100,200 mg/kg),with 6 rats in each group. Administration groups were given relevant medicine intragastrically ;blank group and model group were given normal saline intragastrically ,once a day ,for consecutive 9 days. After last intragastric administration ,the body weight and foot swelling degree (bilateral)were detected ,and arthritis score was performed. The contents of tumor necrosis fator α(TNF-α), interleukin 1β(IL-1β)and IL- 6 were detected ;the pathomorphological changes of rat ankle were observed ;protein expression of NOD-like receptor protein 3 (NLRP3),apoptosis associated spot-like protein (ASC),caspase-1 were detected ;the protein expression of NLRP 3 in synovial tissue of ankle joint were also determined. RESULTS :Compared with blank group ,foot swelling degree,serum contents of TNF-α,IL-1β and IL-6,the protein expression of NLRP 3,ASC and caspase- 1 in knee tissue as well as the protein expression of NLRP 3 in synovial tissue of ankle joint were increased significantly in model group (P<0.05 or P< 0.01),while the body weight was decreased significantly (P<0.05). The obvious proliferation of synovial cells ,the congestion and inflammatory cell infiltration of synovial tissue were all observed. Compared with model group ,most of the above indexes were all reversed significantly in TTM groups (P<0.05 or P<0.01);the pathological changes such as synovial cell proliferation , congestion of synovial tissue and chondrocyte destruction were all relieved ,and inflammatory cell infiltration was alleviated.CONCLUSIONS:TTM can improve rheumatoid arthritis of rats, the mechanism of which may be associated with 用。E-mail:yulingling@ctgu.edu.cn inhibiting the activity of NLRP 3/caspase-1 signaling pathway and decreasing the expression of inflammatory factors TNF-α,IL-1β,IL-6.
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Objective:To analyze the current situation of human genetic resources management in a tertiary hospital, and propose improvement suggestions for the management of human genetic resources in tertiary hospitals.Methods:According to the review of laws and regulations of human genetic resources management in China, analyze the current situation, challenges and management suggestions of human genetic resources management in this particular tertiary hospital, and further management suggestions are proposed.Results:Main problems were identified in the tertiary hospital, including the knowledge of researchers needs to be improved, and due to lack of supervision and management on process of human genetic resources projects, the management of investigator initiated clinical trials needs to be further strengthened.Conclusions:The tertiary hospital needs to strengthen the researcher training on the management of human genetic resources, establish the whole-process supervision of human genetic resources project and pay more attention to the management of investigator initiated clinical trials.
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Objective:To evaluate the Scientific Research Efficiency in A Tertiary Hospital, and provide recommendations for further improvement based on evaluation results.Methods:We evaluated the scientific research efficiency of 35 disciplines in a Tertiary Hospital from 2015 to 2017 with Slack Based Measure based Data envelopment analysis(DEA).Results:The average efficiency value from 2015 to 2017 is 0.44-0.65.The efficiency of Scientific Research from high to low was: supportive department, surgery department, internal medicine.There are 13 disciplines (37.14%) which efficiency increases gradually and 7 discipline (20%) which efficiency decreases.9 disciplines are DEA valid (efficiency=1) for at least 2 years and 9 is DEA invalid (efficiency<1) in three years.The average slack variable of researchers is 18.6 while average slack variable of input scientific research fund is 23.38 million RMB.Conclusions:The average efficiency of the tertiary hospital shows a rising trend.However, the efficiency of disciplines varies largely.For DEA invalid disciplines, it is important to improve efficiency by increasing output and improving efficiency of scientific research funding.
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Objective:To introduce the experience of international Investigator- initiated Clinical Trials (IIT), provide suggestions for the construction of IIT management system in China. Methods:Applying the literature review research methodologies to analyze the document materials, five aspects including the funding source, technical support, personnel training, management mechanism and policy assurance were analyzed.Comparison was conducted to identify possible problems existed in Chinese IIT, and further explore possible lessons that we can learn in Chinese context.Results:Identified problems of Chinese IIT include insufficient funds, unsound scientific research design, imperfect data information system, lack of standard training for researchers, as well as the urgent need for more optimized whole-process management, quality control, and policy support.Conclusions:Suggested series of measurements that including expand the funding sources, improve the construction of scientific steering committee, improve the construction of data information platform at the national level, standardize the training of researchers, and update the operation mechanism and also the regulatory requirement are proposed to enhance the IIT research quality, as well as the IIT management.
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Objective:Through the establishment of a tertiary hospital ethics review information system, the information management of ethics review is carried out, thereby improving the quality and efficiency of ethics review.Methods:Four steps that including status quo analysis and problem identifying, corrective action plan making, outcome monitoring, as well as experience analysis were conducted, according to which a full-chain ethical review information system was developed. This system has certain characteristics such as well-featured functions, reasonable structure and user friendly, which fulfilled the expectation of the information management of review work.Results:The updated ethics review information system provides much stronger support for ethics review management and also improves its efficiency.Conclusions:The information system makes the management of ethics review more efficient, standardized and well-organised.
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Objective:To evaluate the scientific research efficiency and its change in a tertiary hospital, provide recommendations for improvement based on evaluation findings.Methods:We evaluated the scientific research efficiency of 35 disciplines in a tertiary hospital from 2015 to 2017 with BCC model of Data Envelopment Analysis and Malmquist index.Results:The number of DEA valid disciplines was 10, 16, 10 respectively. The average efficiency value from 2015 to 2017 of internal medicine, surgery department and supportive department was 0.62, 0.71, 0.74. The Total Factor Productivity of 2017, compared with 2015, was 1.30, which was mainly attributed to increase of Pure Technical Efficiency. There were 23 disciplines which efficiency increased and 12 disciplines which efficiency decreased.Conclusions:The scientific research efficiency of the tertiary hospital showed a rising trend. The efficiency of disciplines varied largely. For disciplines of DEA invalid or with downward trend, it is important to improve efficiency by improving management, cultivating talents, improving technology and increasing scientific output, and so on.
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Objective:Understand the perceptions of research integrity and their attitudes to related integrity violations among newly recruited researchers in a tertiary hospital.Methods:The electronic questionnaire was distributed to a WeChat group of 123 newly recruited researchers in a tertiary hospital in 2018. The questionnaire included the demographic characteristics, the awareness of research integrity and attitude towards behaviors that violate research integrity.Results:The total number of respondents was 87 and 45.98% respondents received research integrity training. Less than 50% of respondents were familiar with the regulatory requirement of research integrity, the definition of research integrity, fabrication, falsification, plagiarism and other common problems violating research integrity. Regarding attitude towards scientific misconduct, most investigators (82.76%~90.8%) thought it incorrect. 64.37% of investigators would like to report to regulatory authorities if they found scientific misconduct. If the researchers strongly violated research integrity, 80.46%~81.61% of respondents voted for suspending his or her promotion, suspending his or her application for being a mentor and 58.62% of respondents voted for being banned for conducting any research forever. Receiving education of research integrity is an independent influence factor of awareness of fabrication, falsification and plagiarism (FFP).Conclusions:The proportion of newly recruited researchers receiving research integrity training in tertiary hospital is not big and most researchers don't know much about research integrity. Their attitudes to academic misconduct need to be further strengthened. Various measures are urgently needed to carry out to improve the integrity awareness and attitude of newly recruited researchers in tertiary hospitals.
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Objective:To build a scientifically applicable scientific research evaluation system based on the Science and Technology Evaluation Metrics (STEM) of Chinese hospitals.Methods:Twenty-four experts were invited to form an expert advisory group, scientific research evaluation indicators were collected according to literature review, panel discussion and expert consultation. Use Delphi method to carry out two rounds of expert consultation, calculate the authority level and positive factor of experts, and use AHP to calculate the weight of each indicator.Results:The experts invited for consultation had a high positive coefficient and a high degree of expert authority, and finally, a scientific research evaluation index system including 3 first-level indicators, 10 second-level indicators and 24 third-level indicators was established.Conclusions:The research based on STEM has developed an evaluation system well combined quantity and quality from three dimensions, including scientific research input, scientific research output and scientific research influence. Taking into full consideration of the regulatory requirement of clinical trials and the research administration of research achievements transformation, this research established an evaluation system and management model applicable to the Tertiary class A general hospitals, provided reference value for the development of the hospital's scientific research.