Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Professor Lau Wanyee, a member of the Chinese Academy of Sciences and a pro-fessor at the Chinese University of Hong Kong, actively advocates conducting clinical researches through "planting fruit trees" and "growing orchards", aiming to cultivate a team of dual-skilled talents in clinical practice and research, effectively improve the scientific and technological level of clinical medicine in China, make voice heard in the international medical science field, and better serve human health. He organized a clinical research training course in scholars′ forum for Hepatobiliary Young Expert Working Group of Chinese College of Surgeons. Throughout three sessions of the training course, a distinct theme was focused on how to enhance the level of clinical research in China and make voice heard by the international scholars. A group of multi-dimensional experts were gathered, including experts from surgery, methodology, and management, as well as both renowned experts and young talents. A lively teaching model was adopted, combining guided presentations with interactive discussion and debate sessions. A clean and upright academic spirit was strongly advocated, in which international rules were adopted to conduct in-depth analysis and sharp criticism of seven proposed clinical research projects and four published papers with high international influence to find quarrel in a straw. This clinical research training course provides a new model of guidance for young physicians in conducting clinical research. As a result, all attendees felt deeply educated and benefited greatly from the training session. This training activity not only laid a solid foundation for the development of scientization, standardization, and internationali-zation of clinical research in digestive surgery in China, but also demonstrated a correct path for cultivating a group of young and middle-aged clinical medical scientists with scientific spirit.

The wearable electrochemical sensors exhibit many advantages such as flexibility,miniaturization,portability,biocompatibility and low cost,and can be used for accurate,safe,real-time,and non-invasive monitoring of physiological signals in sweat,which are very helpful to monitor various physiological indicators of athletes during training,predict sports risks,prevent sports injuries and scientifically guide sports training,showing enormous potential in the field of sports monitoring. In this paper,the latest research progress of wearable electrochemical sweat sensors based on the relationship between biomarkers in sweat and exercise training was reviewed,such as the sensor substrate materials,sweat sampling strategies,sensing unit,signal transmission,and power supply systems. In addition,the current application status,the opportunities and challenges in the field of motion monitoring of wearable electrochemical sensors were discussed,and their future development was prospected.

Objective To explore the protective mechanism of honey-processed Hedysari Radix in regulating intestinal mucosal injury in rats with spleen qi deficiency.Methods The three-factor composite modeling method of bitter cold diarrhea,overwork and hunger and satiety disorder was used to construct a spleen qi deficiency model rats.After the model was successfully made,they were randomly divided into model group,honey-processed Hedysari Radix group and probiotic group,with 15 animals in each group.Another 15 normal rats were taken as the blank group.The honey-processed Hedysari Radix group was given 12.6 g·kg-1 water decoction of honey-processed Hedysari Radix by gavage,the probiotics group was given Bifidobacterium Lactobacillus triple viable tablets suspension at a dose of 0.625 g·kg-1,and the blank group and the model group were given the same dose of distilled water.The rats in the four groups were administered once a day for 15 days.Enzyme-linked immunosorbent assay was used to detect diamine oxidase(DAO)in serum,D-lactic acid(D-LA),secretory immunoglobulin A factor,and Western blotting was used to detect the expression levels of AMP-activated protein kinase(AMPK),zonula occludens-1(ZO-1)and occludin in colon tissues.Results The serum levels of DAO in the blank group,model group,honey-processed Hedysari Radix group and probiotic group were(138.93±9.78),(187.95±12.90),(147.21±6.92)and(166.47±3.37)pg·mL-1;the contents of D-LA were(892.23±49.17),(1 099.84±137.64),(956.56±86.04)and(989.61±51.75)μg·L-1;the contents of SIgA in colon tissues were(14.04±1.42),(11.47±2.39),(11.84±1.49)and(12.93±1.65)μg·mL-1;the relative expression levels of ZO-1 protein in colon tissues were 1.18±0.11,0.42±0.04,0.77±0.05 and 0.95±0.07;the relative expression levels of occludin protein were 1.35±0.31,0.61±0.17,1.19±0.19 and 0.88±0.13;the relative expression levels of AMPK protein were 0.91±0.02,0.35±0.09,0.74±0.08 and 0.59±0.11.Compared with the model group,there were significant differences in the serum content of DAO and D-LA,SIgA content in colon,and the content of ZO-1,occludin and AMPK protein in the honey-processed Hedysari Radix group(P＜0.01,P＜0.05).Conclusion Honey-processed Hedysari Radix can enhance the protective effect on the intestinal mucosa of rats with spleen qi deficiency by regulating the expression of related inflammatory cytokines,intestinal mucosal upper cell enzymes and tight junction proteins in rats with spleen qi deficiency.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To plan microwave antenna puncture direction effectively and realize personalized preoperative simulation by exploring microwave ablation(MWV)outcomes of lung cancer based on real anatomical model.Methods Firstly,a personalized MWA simulation model consisting of the lung tissue,tumor and vascular system was constructed based on the lung CT data of real patients.Secondly,the MWA effect was simulated by coupling 2 physical fields including an electromagnetic field and a biological heat transfer field,so as to determine the volume of the ablation thermocoagulation zone and the temperature distribution of the lung tissue.Finally,the effects of the vascularized network on the ablation results were quantitatively evaluated in terms of conductivity and blood perfusion,and the ablation results were analyzed with different distances between the large vessels and the antennae(5 and 10 mm from the antennae tips)and puncture angles(large vessels parallelling or intersecting with the antennae tips).Results The vascularized network reduced the volume of the thermocoagulation zone by 0.5％to 3.7％,and blood perfusion made the ablation temperature and the volume of the thermocoagulation zone decreased significantly.The cooling effect gradually diminished with the increase of the distance between the large vessels and the antenna.With the same treatment parameters,the thermocoagulation zone formed when the large vessels paralleled with the antenna was obviously larger than that when the vessles intersected with the antenna.Conclusion Personalized MWA simulation analysis based on real CT data contributes to clarifying the temperature distribution and damage estimation close to the actual situation,which provides guidance and reference for precise treatment of the lung tumor and determination of microwave antenna puncture direction.[Chinese Medical Equipment Journal,2024,45(9):27-34]

Objective:To explore the feasibility of the AI intelligent reconstruction model based on knee joint magnetic resonance data developed by Nuctech Company Limited for evaluating knee cartilage injury.Methods:Thirty-three patients (a total of forty-one knees) who were hospitalized with severe knee osteoarthritis in Beijing Tsinghua Changgung Hospital from May 2021 to April 2022 were selected. All of them were planned to be performed total knee arthroplasty (TKA) for the treatment of knee osteoarthritis. Fifteen males with an average age of 71±5 years old and twenty six females with an average age of 71±9 years old were included in this study. There were 19 cases of left knee and 22 cases of right knee. Thin layer MRI examination on the patients' knee joints was performed before the surgery, and artificial intelligence model based on the thin layer MRI data of the knee joint was reconstructed. The cartilage part of the model was selected and corrected by Principal Component Analysis (PCA) in order to realize model straightening. The tibial plateau cartilage of knee joint which intercepted during operation was classified according to the International Cartilage Repair Society (ICRS). Finally the results were compared with the ICRS classification results of knee artificial intelligence reconstruction model and artificial recognition of knee joint MRI images.Results:Compared with the grade of cartilage injury intercepted during our operation which was according to the ICRS classification, the sensitivity of artificial intelligence reconstruction model for the diagnosis of cartilage injury with ICRS classification grade four was 93.1%. The specificity of artificial intelligence reconstruction model was 91.4%. The positive predictive value (PPV) of artificial intelligence reconstruction model was 92.2%. And the negative predictive value (NPV) of artificial intelligence reconstruction model was 80.3%. The area under ROC curve (AUC) was 0.92. The ICRS classification consistency between artificial intelligence model and physical inspection results was good with kappa value 0.81 ( P<0.001) . In the aspect of artificial recognition of cartilage injury grading in MRI images, the sensitivity of artificial recognition was 92.10% compared with the manual identification of cartilage injury classification in MRI images. The specificity of artificial recognition was 91.60%. The positive predictive value (PPV) of artificial recognition was 97.20% and the negative predictive value (NPV) of artificial recognition was 78.8%. The kappa value of the cartilage injury classification in MRI images consistency between artificial recognition and manual identification was 0.79 ( P<0.001). Conclusion:Based on the evaluation of cartilage injury by AI reconstruction model of knee joint, the sensitivity and specificity of the diagnosis of ICRS grade IV cartilage injury can be acceptable, but still needs to be improved.

Clostridioides difficile/genetics* ; Clostridioides ; Real-Time Polymerase Chain Reaction ; Feces ; Bacterial Proteins/genetics*

Talent is one of the basic and strategic supports for building a modern socialist country in all aspects. Since the 1980s, the establishment of forensic medicine major and the cultivation of innovative talents in forensic medicine have become hot topics in higher education in forensic medicine. Over the past 43 years, the forensic medicine team of Shanxi Medical University has adhered to the joint education of public security and colleges, and made collaborative innovation, forming a training mode of "One Combination, Two Highlights, Three Combinations, Four in One" for innovative talents in forensic medicine. It has carried out "5+3/X" integrated reform, and formed a relatively complete talent training innovation mode and management system in teaching, scientific research, identification, major, discipline, team, platform and cultural construction. It has made a historic contribution to China's higher forensic education, accumulated valuable experience for the construction of first-class major and first-class discipline of forensic medicine, and provided strong support for the construction of the national new forensic talent training system. The popularization of this training mode is conducive to the rapid and sustainable development of forensic science, and provides more excellent forensic talents for national building, regional social development and the discipline construction of forensic science.
Humans ; Forensic Medicine/education* ; Aptitude