OBJECTIVE: To establish venetoclax-resistant acute myeloid leukemia (AML) cell lines, assess the sensitivity of venetoclax-resistant cell lines to the BCL-2 protein family, and investigate their resistance mechanisms. METHODS: CCK-8 method was used to screen AML cell lines (MV4-11, MOLM13, OCI-AML2) that were relatively sensitive to venetoclax. Low concentrations of venetoclax continuously induced drug-resistance development in the cell lines. Changes in cell viability and apoptosis rate before and after resistance development were measured using the CCK-8 method and flow cytometry. BH3 profiling assay was performed to anayze the transform of mitochondrion-dependent apoptosis pathway as well as the sensitivity of resistant cell lines to BCL-2 family proteins and small molecule inhibitors. Real-time fluorescence quantitative PCR (RT-qPCR) was utilized to examine changes in the expression levels of BCL-2 protein family members in both venetoclax-resistant cell lines and multidrug-resistant patients. RESULTS: Venetoclax-resistant cell lines of MV4-11, MOLM13, and OCI-AML2 were successfully established, with IC₅₀ values exceeding 10-fold. Under the same concentration of venetoclax, the apoptosis rate of resistant cells decreased significantly (P < 0.05). BH3 profiling assay revealed that the drug-resistant cell lines showed increased sensitivity to many pro-apoptotic proteins (such as BIM,BID and NOXA). RT-qPCR showed significantly upregulated MCL1 and downregulated NOXA1 were detected in drug-resistant cell lines. Expression changes in MCL1 and NOXA1 in venetoclax-resistant patients were consistent with our established drug-resistant cell line results. CONCLUSION The venetoclax-resistant AML cell lines were successfully established through continuous induction with low concentrations of venetoclax. The venetoclax resistance resulted in alterations in the mitochondrial apoptosis pathway of the cells and an increased sensitivity of cells to pro-apoptotic proteins BIM, BID, and NOXA, which may be associated with the upregulation of MCL1 expression and downregulation of NOXA1 expression in the drug-resistant cells.
Humans ; Sulfonamides/pharmacology* ; Drug Resistance, Neoplasm ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology* ; Leukemia, Myeloid, Acute/pathology* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis ; Antineoplastic Agents/pharmacology*

Objective To establish the finite element model of spinal canal reconstruction and internal fixation,analysis influence of spinal canal reconstruction and internal fixation on spinal stability,and verify the effectiveness and reliability of spinal canal reconstruction and internal fixation in spinal canal surgery.Methods A 30-year-old male healthy volunteer with a height of 172 cm and weight of 75 kg was selected and his lumbar CT data were collected to establish a finite element model of normal lumbar Lo3-L,and the results were compared with in vitro solid results and published finite element analysis results to verify the validity of the model.They were divided into normal group,laminectomy group and spinal canal reconstruction group according to different treatment methods.Under the same boundary fixation and physiological load conditions,six kinds of ac-tivities were performed,including forward bending,backward extension,left bending,right bending,left rotation and right rota-tion,and the changes of range of motion(ROM)of L3-L4,L4-L5 segments and overall maximum ROM of L3-L5 were analyzed under the six conditions.Results The ROM displacement range of each segment of the constructed L3-L5 finite element model was consistent with the in vitro solid results and previous literature data,which confirms the validity of the model.In L3-L4,ROM of spinal canal reconstruction group was slightly increased than that of normal group during posterior extension(＞5％dif-ference),and ROM of other conditions was similar to that of normal group(＜5％difference).ROM in laminectomy group was significantly increase than that in normal group and spinal canal reconstruction group under the condition of flexion,extension,left and right rotation.In L4-L5,ROM in spinal canal reconstruction group was similar to that in normal group(＜5％differ-ence),while ROM in laminectomy group was significantly higher than that in normal group and spinal canal reconstruction group(＞5％difference).In the overall maximum ROM of L3-L5,spinal canal reconstruction group was only slightly higher than normal group under the condition of posterior extension(＞5％difference),while laminectomy was significantly higher than normal group and spinal canal reconstruction group under the condition of anterior flexion,posterior extension,left and right rotation(＞5％difference).The changes of each segment ROM and overall ROM of L3-L5 showed laminectomy group＞spinal canal reconstruction group＞normal group.Conclusion Laminectomy could seriously affect biomechanical stability of the spine,but application of spinal canal reconstruction and internal fixation could effectively reduce ROM displacement of the responsi-ble segment of spine and maintain its biomechanical stability.

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 develop an intelligent model for differential diagnosis of atrioventricular nodal re-entrant tachycardia(AVNRT)and atrioventricular re-entrant tachycardia(AVRT)using 12-lead wearable electrocardiogram devices.Methods A total of 356 samples of 12-lead supraventricular tachycardia(SVT)electrocardiograms recorded by wearable devices were randomly divided into training and validation sets using 5-fold cross validation to establish the intelligent classification model,and 101 patients with the diagnosis of SVT undergoing electrophysiological studies and radiofrequency ablation from October,2021 to March,2023 were selected as the testing set.The changes in electrocardiogram parameters before and during induced tachycardia were compared.Based on multiscale deep neural network,an intelligent diagnosis model for classifying SVT mechanisms was constructed and validated.The 3-lead electrocardiogram signals from Ⅱ,Ⅲ,and V1 were extracted to build new classification models,whose diagnostic efficacy was compared with that of the 12-lead model.Results Of the 101 patients with SVT in the testing set,68 were diagnosed with AVNRT and 33 were diagnosed with AVRT by electrophysiological study.The pre-trained model achieved a high area under the precision-recall curve(0.9492)and F1 score(0.8195)for identifying AVNRT in the validation set.The total F1 scores of the lead Ⅱ,Ⅲ,V1,3-lead and 12-lead intelligent diagnostic models in the testing set were 0.5597,0.6061,0.3419,0.6003 and 0.6136,respectively.Compared with the 12-lead classification model,the lead-Ⅲ model had a net reclassification index improvement of-0.029(P=0.878)and an integrated discrimination index improvement of-0.005(P=0.965).Conclusion The intelligent diagnostic model based on multiscale deep neural network using wearable electrocardiogram devices has an acceptable accuracy for classifying SVT mechanisms.

Objective To develop an intelligent model for differential diagnosis of atrioventricular nodal re-entrant tachycardia(AVNRT)and atrioventricular re-entrant tachycardia(AVRT)using 12-lead wearable electrocardiogram devices.Methods A total of 356 samples of 12-lead supraventricular tachycardia(SVT)electrocardiograms recorded by wearable devices were randomly divided into training and validation sets using 5-fold cross validation to establish the intelligent classification model,and 101 patients with the diagnosis of SVT undergoing electrophysiological studies and radiofrequency ablation from October,2021 to March,2023 were selected as the testing set.The changes in electrocardiogram parameters before and during induced tachycardia were compared.Based on multiscale deep neural network,an intelligent diagnosis model for classifying SVT mechanisms was constructed and validated.The 3-lead electrocardiogram signals from Ⅱ,Ⅲ,and V1 were extracted to build new classification models,whose diagnostic efficacy was compared with that of the 12-lead model.Results Of the 101 patients with SVT in the testing set,68 were diagnosed with AVNRT and 33 were diagnosed with AVRT by electrophysiological study.The pre-trained model achieved a high area under the precision-recall curve(0.9492)and F1 score(0.8195)for identifying AVNRT in the validation set.The total F1 scores of the lead Ⅱ,Ⅲ,V1,3-lead and 12-lead intelligent diagnostic models in the testing set were 0.5597,0.6061,0.3419,0.6003 and 0.6136,respectively.Compared with the 12-lead classification model,the lead-Ⅲ model had a net reclassification index improvement of-0.029(P=0.878)and an integrated discrimination index improvement of-0.005(P=0.965).Conclusion The intelligent diagnostic model based on multiscale deep neural network using wearable electrocardiogram devices has an acceptable accuracy for classifying SVT mechanisms.

Objective: To explore the clinical features and prognosis of children with histiocytic necrotizing lymphadenitis (HNL). Methods: The clinical data of 118 children with HNL diagnosed and treated in the Department of Rheumatology and Immunology of Children's Hospital, Capital Institute of Pediatrics from January 2014 to December 2021 were retrospectively analyzed. The clinical symptoms, laboratory examination, imaging examination, pathological findings, treatment and follow-up were analyzed. Results: Among the 118 patients, 69 were males and 49 were females. The age of onset was 10.0 (8.0, 12.0) years, ranging from 1.5 to 16.0 years. All the children had fever lymph node enlargement, blood system involvement in 74 cases (62.7%), skin injury in 39 cases (33.1%). The main manifestations of laboratory examination were increased erythrocyte sedimentation rate in 90 cases (76.3%), decreased hemoglobin in 58 cases (49.2%), decreased white blood cells in 54 cases (45.8%) and positive antinuclear antibody in 35 cases (29.7%). Ninety-seven cases (82.2%) underwent B-mode ultrasound of lymph nodes, showing nodular lesions with low echo in the neck; 22 cases (18.6%) underwent cervical X-ray and (or) CT; 7 cases (5.9%) underwent cervical magnetic resonance imaging. Lymph node biopsy was performed in all 118 cases, and the pathological results did not support malignant diseases such as lymphoma or Epstein-Barr virus infection, suggesting HNL. Fifty-seven cases (48.3%) recovered without treatment, 61 cases (51.7%) received oral steroid therapy, and 4 cases (3.4%) received indomethacin as anal stopper. The 118 cases were followed up for 4 (2, 6) years, ranging from 1 to 7 years, 87 cases (73.7%) had one onset and did not develop into other rheumatological diseases, and 24 cases (20.3%) had different degrees of recurrence, 7 cases (5.9%) had multiple system injuries, and all of the tested autoantibodies were positive for medium and high titers. All of them developed into other rheumatic immune diseases, among which 5 cases developed into systemic lupus erythematosus and 2 cases developed into Sjogren's syndrome; 7 cases were given oral steroid therapy, including 6 cases plus immunosuppressant and 2 cases receiving methylprednisolone 20 mg/kg shock therapy. Conclusions: The first-onset HNL portion is self-healing, hormone-sensitive and has a good prognosis. For HNL with repeated disease and multiple system injury, antinuclear antibody titer should be monitored during follow-up, and attention should be paid to the possibility of developing into other rheumatological diseases, with poor prognosis.
Female ; Male ; Humans ; Child ; Histiocytic Necrotizing Lymphadenitis/drug therapy* ; Antibodies, Antinuclear ; Epstein-Barr Virus Infections ; Retrospective Studies ; Herpesvirus 4, Human ; Prognosis ; Steroids

A new class of potent liver injury protective compounds, phychetins A-D ( 1- 4) featuring an unique 6/6/5/6/5 pentacyclic framework, were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus. Compounds 2- 4 are three pairs of enantiomers that were initially obtained in a racemic manner, and were further separated by chiral HPLC preparation. Compounds 1- 4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step. A bioinspired total synthesis strategy was thus designated, and allowed the effective syntheses of compounds 2- 4 in high yields. Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1β. Notably, compound 4, the most active enantiomeric pair in vitro, displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice, which could serve as a promising lead for the development of acute liver injury therapeutic agent.

Objective: To investigate the clinical characteristics of systemic juvenile idiopathic arthritis combined with coronary artery dilatation. Methods: A retrospective analysis was performed on the clinical data, including clinical manifestations, blood routine, inflammatory factors, echocardiography, vascular ultrasound and CT angiography, treatment and outcomes, etc, of 5 cases with systemic juvenile idiopathic arthritis combined with coronary artery dilation admitted to Department of Rheumatology in the affiliated Children's Hospital of Capital Institute of Pediatrics from May 2019 to June 2021. Results: There were 2 males and 3 females among 5 cases. The onset age ranged from 7 months to 4 years 7 months.The diagnostic time ranged from 1.5 months to 3.0 months.Four cases were diagnosed as atypical Kawasaki disease. Three cases showed unilateral coronary artery dilation.Two cases showed bilateral coronary artery dilation.Four cases developed multiple organ injuries.Three cases developed macrophage activation syndrome.Three cases developed lung injury.Two cases developed pericardial effusion.One case developed pulmonary hypertension.As for treatment, 3 cases treated with methylprednisolone pulse therapy and methotrexate combined with cyclosporine, improved after the final application of biological agents, and have stopped prednisone. The other 2 cases were treated with adequate oral prednisone and gradually reduced, and methotrexate was added at the same time, 1 case relapsed in the process of reduction. No other vascular involvement was found in 5 cases. Coronary artery dilation recovered completely after 1 to 3 months of treatment. Conclusions: Systemic juvenile idiopathic arthritis combined with coronary artery dilatation has the clinical characteristics of small onset age, long diagnostic time, prone to multiple organ injuries. Corticosteroids and conventional immunosuppressive agents are not sensitive, and biological agents should be used as soon as possible.The prognosis of coronary artery dilation is good after timely treatment.
Arthritis, Juvenile/drug therapy* ; Biological Factors/therapeutic use* ; Child ; Coronary Aneurysm/etiology* ; Coronary Artery Disease/therapy* ; Dilatation ; Dilatation, Pathologic ; Female ; Humans ; Infant ; Male ; Methotrexate ; Prednisone/therapeutic use* ; Retrospective Studies

Arthritis, Juvenile/complications* ; Humans ; Rheumatoid Nodule

Objective: To evaluate the efficacy and safety of intra-articular injection of adalimumab (ADA) in the treatment of refractory oligoarticular juvenile idiopathic arthritis (JIA). Methods: This was a retrospective study. Clinical data on age, gender, and symptoms of joint swelling and pain were collected from 11 children with refractory oligoarticular JIA involving only knee joints admitted to Department of Rheumatism and Immunology of Children's Hospital, Capital Institute of Pediatrics from November 2019 to October 2020. The physician and parent-child evaluation of disease activity, the number of active joints, and the level of erythrocyte sedimentation rate (ESR) at different treatment time points were analyzed at every 4-week observation point after drug administration, and the non-parametric Kruskal-Wallis test was used to compare the differences in clinical evaluation indicators and changes in laboratory tests at different treatment times. The follow-up period was 6 months. Results: Among the 11 children, 5 were boys and 6 were girls. The age was 3.0 (2.8) years. All 11 children had symptoms of joint swelling and pain as well as limitation of movement. After 3 intra-articular injections of ADA, the joint symptoms of 11 children were better than before treatment; the joint symptoms of 7 children disappeared completely, and no recurrence occurred during the 6-month follow-up period. At different treatment times, physician and parent-child evaluation of disease activity, a gradual decrease in the number of active joints in the children, ESR, and juvenile arthritis disease activity score with 27 joints were all statistically significant (χ²=53.99, 59.37, 32.87, 40.07, 54.00, all P<0.001).No significant adverse drug reactions were observed in any of the 11 children during treatment and follow-up. Conclusion: Intra-articular injection of ADA in the treatment of refractory oligoarticular JIA has a significant effect in controlling joint symptoms and is relatively safe.
Adalimumab/therapeutic use* ; Arthritis, Juvenile/drug therapy* ; Child ; Child, Preschool ; Female ; Glucocorticoids/therapeutic use* ; Humans ; Injections, Intra-Articular ; Male ; Retrospective Studies ; Treatment Outcome