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*

OBJECTIVES: To develop a risk prediction model for left ventricular adverse remodeling (LVAR) based on cardiac magnetic resonance (CMR) parameters in patients undergoing percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 329 acute STEMI patients undergoing primary PCI at 8 medical centers from January, 2018 to December, 2021 were prospectively enrolled. The parameters of CMR, performed at 7±2 days and 6 months post-PCI, were analyzed using CVI42 software. LVAR was defined as an increase >20% in left ventricular end-diastolic volume or >15% in left ventricular end-systolic volume at 6 months compared to baseline. The patients were randomized into training (n=230) and validation (n=99) sets in a 7∶3 ratio. In the training set, potential predictors were selected using LASSO regression, followed by univariate and multivariate logistic regression to construct a nomogram. Model performance was evaluated using receiver-operating characteristic (ROC) curves, area under the curve (AUC), calibration curves, and decision curve analysis. RESULTS: LVAR occurred in 100 patients (30.40%), who had a higher incidence of major adverse cardiovascular events than those without LVAR (58.00% vs 16.16%, P<0.001). Left ventricular global longitudinal strain (LVGLS; OR=0.76, 95% CI: 0.61-0.95, P=0.015) and left atrial active strain (LAAS; OR=0.78, 95% CI: 0.67-0.92, P=0.003) were protective factors for LVAR, while infarct size (IS; OR=1.05, 95% CI: 1.01-1.10, P=0.017) and microvascular obstruction (MVO; OR=1.26, 95% CI: 1.01-1.59, P=0.048) were risk factors for LVAR. The nomogram had an AUC of 0.90 (95% CI: 0.86-0.94) in the training set and an AUC of 0.88 (95% CI: 0.81-0.94) in the validation set. CONCLUSIONS LVGLS, LAAS, IS, and MVO are independent predictors of LVAR in STEMI patients following PCI. The constructed nomogram has a strong predictive ability to provide assistance for management and early intervention of LVAR.
Humans ; Percutaneous Coronary Intervention ; Prospective Studies ; ST Elevation Myocardial Infarction/diagnostic imaging* ; Ventricular Remodeling ; Magnetic Resonance Imaging ; Male ; Female ; Middle Aged ; Risk Factors ; Aged ; Risk Assessment

BACKGROUND:Minipigs are often used in research fields such as skin injury,vascular trauma and cosmetic medicine because they are highly similar to human beings in terms of skin tissue structure and cardiovascular system.Hydrogel as a wound repair drug possesses a variety of excellent physicochemical properties such as strong water retention and adhesion,which can provide isolation moisturization and drug release for wounds. OBJECTIVE:To summarize and conclude the progress of the application of trauma models for different experimental purposes of hydrogel therapy for minipigs,to reveal the development status of various types of minipig trauma models,to analyze the deficiencies of minipig trauma models at the present stage. METHODS:The relevant articles published in Web of Science database and CNKI database from the establishment of each database to 2023 were checked,using"piglet,miniature pig,minipig,miniature pig;gel,hydrogel;trauma,injury,wound,lesion,incision"as Chinese search terms and"Miniature Swine,Miniature pig,minipig;gel,hydrogel;injury,wound,lesion,incision"as English search terms.A total of 438 Chinese and English documents were retrieved,and 59 documents were included in the study through the inclusion and exclusion criteria. RESULTS AND CONCLUSION:(1)At present,the main models used clinically for trauma repair are large animal species(dogs and pigs),rabbits,and rodents(rats and mice).Because the skin structure of the minipig is more like that of humans,the minipig is the most ideal animal model for trauma repair.(2)In the in-vitro skin injury model,skin defect model is the basic wound model,which can be divided into full skin defect model and medium-thickness skin defect model according to the depth of the wound defect.Burn wound model and infected wound model are multidimensional models with hot metal scald and bacterial culture imposed on the basis of the skin defect model,which have the advantages of high safety coefficient and low operation difficulty.(3)In the in-vivo trauma repair model,mini-pigs are used as esophageal cricothyrotomy model which is more in line with the pathological state of clinical diseases.Mini-pigs are used in the gastric perforation and vascular hemostasis model,which can visually demonstrate the stronger organ adhesion,hemostatic properties and tissue regeneration-promoting effects of the hydrogel.(4)The specific parts of the pig also has the corresponding mode of use:pig ear is usually used to evaluate the hydrogel drug delayed-release effect.Porcine cellular proteins and pig skin collagen are mostly used to prepare composite hydrogels of tissue origin.

Purpose/Significance To analyze the overall competitiveness,secondary discipline competitiveness and trend of 8 strong schools of stomatology in China by constructing the competitiveness index.Method/Process The data of National Natural Science Founda-tion of China of 8 strong schools in stomatology field from 2011 to 2019 is retrieved.By using descriptive statistical methods,the disci-pline competitiveness index is constructed to analyze the discipline competitiveness and trend of 8 strong schools in stomatology field.Result/Conclusion The competitiveness ranking of 8 strong schools is basically solidified,but the gap may be narrowing.

Osteoporotic proximal humeral fracture (OPHF) is one of the common osteoporotic fractures in the aged, with an incidence only lower than vertebral compression fracture, hip fracture, and distal radius fracture. OPHF, secondary to osteoporosis and characterized by poor bone quality, comminuted fracture pattern, slow healing, and severely impaired shoulder joint function, poses a big challenge to the current clinical diagnosis and treatment. In the field of diagnosis, treatment, and rehabilitation of OPHF, traditional Chinese and Western medicine have accumulated rich experience and evidence from evidence-based medicine and achieved favorable outcomes. However, there is still a lack of guidance from a relevant consensus as to how to integrate the advantages of the two medical systems and achieve the integrated diagnosis and treatment. To promote the diagnosis and treatment of OPHF with integrated traditional Chinese and Western medicine, relevant experts from Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine have been organized to formulate Expert consensus on the diagnosis and treatment of osteoporotic proximal humeral fracture with integrated traditional Chinese and Western medicine ( version 2024) by searching related literatures and based on the evidences from evidence-based medicine. This consensus consists of 13 recommendations about the diagnosis, treatment and rehabilitation of OPHF with integrated traditional Chinese medicine and Western medicine, aimed at standardizing, systematizing, and personalizing the diagnosis and treatment of OPHF with integrated traditional Chinse and Western medicine to improve the patients ′ function.

Objective:To investigate the impact of QiliQiangXin Capsules on ventricular remodeling and cardiac contraction and relaxation function in aging rats with heart failure following myocardial infarction.Methods:From August 2022 to August 2023, a total of 30 old rats were randomly assigned to three groups: sham-operated group, model group, and treatment group, with 10 rats in each group selected through a digital lottery method.The model and treatment groups were created by ligating the anterior descending branch of the left coronary artery.The rats in the treatment group received daily administration of Astragalosa hebecarpa Drabanemerosa Strong Heart Capsule(1.0 g/kg)via gavage after 4 weeks.After the 4-week drug administration period, echocardiography was performed to measure various parameters including left ventricular end-diastolic internal diameter(LVIDd), left ventricular end-systolic internal diameter(LVIDs), left ventricular ejection fraction(LVEF), left ventricular anterior wall myocardial thickness(LVAWd), mitral valve early diastolic peak flow velocity(E peak), and early diastolic velocity of mitral annulus(e peak)detected by tissue Doppler(TDI). The E/e value was calculated based on these measurements.Additionally, serum levels of B-type brain natriuretic peptide(BNP), matrix metalloproteinase 2(MMP-2), matrix metalloproteinase 9(MMP-9), and tumor necrosis factor(TNF-α)were measured using enzyme-linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE)staining was employed to observe the morphological changes in myocardial tissue.Results:Compared to rats in the model group, rats in the treatment group exhibited lower left ventricular internal dimension at end-diastole(LVIDd)(9.1±0.6 mm vs.11.4±0.8 mm, P<0.01), lower left ventricular internal dimension at end-systole(LVIDs)(5.9±0.8 mm vs.8.7±0.9 mm, P<0.01), lower E/e ratio(13.4±2.0 vs.16.3±2.8, P<0.05), higher left ventricular ejection fraction(LVEF)(68.8±7.1% vs.52.0±8.4%, P<0.01), and elevated left ventricular anterior wall thickness at end-diastole(LVAWd)(1.5±0.2 mm vs.1.2±0.3 mm, P<0.05). In addition, compared to rats in the model group, the treatment group showed a decrease in brain natriuretic peptide(BNP)(0.26±0.04 μg/L vs.0.34±0.05 μg/L, P<0.01), decreased matrix metalloproteinase-2(MMP-2)(3697.0±857.7 μg/L vs.4719.5±703.5 μg/L, P<0.01), decreased matrix metalloproteinase-9(MMP-9)(87.3±13.8 μg/L vs.116.5±9.6 μg/L, P<0.01), decreased tumor necrosis factor-alpha(TNF-α)(165.3±36.9 μg/L vs.269.8±35.0 μg/L, P<0.01), and lower TNF-α levels(165.3±36.9 μg/L vs.269.8±35.0 μg/L, P<0.01). Histological examination using hematoxylin and eosin(HE)staining revealed that the treatment group had less severe cardiac myocyte arrangement disorder and inflammatory reaction compared to the model group. Conclusions:Qiliqiangxin Capsules were found to effectively delay ventricular remodeling and improve myocardial contraction and relaxation function in aging rats with heart failure after acute myocardial infarction.

Continuing medical education for general practitioners is an important measure to upgrade the quality of primary health care services in China, which is still facing various challenges and need to be further developed and improved. This article analyzes the status quo and existing problems of continuing medical education for general practitioners in China, and proposes suggestions based on the concept of people centered and integrated health care (PCIC), including faculty development, training contents, assessment methods, and experience learning, to provide references for the improvement of continuing medical education for general practitioners.

Objective To investigate the effect and mechanism of transplantation of neuregulin1(NRG1)gene-modified bone marrow mesenchymal stem cells(BMSCs)on the repair of hemi-transected spinal cord injury(SCI)in rats.Methods Isolated and cultured rat BMSCs,followed by transfection with the NRG1 gene.The levels of NRG1 in BMSCs lysate and culture supernatant was deected by ELISA method,and the proliferation activity of the BMSCs was detected by cell counting method.Forty-three healthy 8-week-old SD rats were randomly divided into control group(n=10),SCI model group(n=10),BMSCs group(n=10),and NRG1-BMSCs group(n=13).After establishing the spinal cord hemisection model,animals received in-situ transplantation of BMSCs or NRG1-BMSCs.On the 1,7,14,21,and 28 days after transplantation,the hind limb motor function was evaluated using BBB score and inclined plate test;on the 7th day after transplantation,the migration and distribution of transplanted cells was monitored using a fluorescence microscope;on the 28th day after transplantation,the pathological changes of rat spinal cord tissues was examined using HE staining and Nissl staining;cell apoptosis using TUNEL staining,and levels of endoplasmic reticulum stress-related proteins[X-box binding protein 1(XBP1),C/EBP homologous protein(CHOP),activating transcription factor 4(ATF4),ATF6,glucose-regulated protein 78(GRP78)]and apoptosis-related proteins[B-cell lymphoma-2(Bcl-2)and Bcl-2-associated protein X(Bax)]in rat spinal cord tissues using Western blotting.Results BMSCs were successfully isolated,cultured,and transfected with the NRG1 gene.ELISA method results showed that the NRG1 contents in the NRG1-BMSCs lysate and culture supernatant were significantly higher than that of BMSCs in a time-dependent manner(P<0.05).The proliferation activity of NRG1-BMSCs was significantly higher than that of BMSCs(P<0.05).On the 21 and 28 days after transplantation,the BBB score and the slope angle of the inclined plate in NRG1-BMSCs group were higher than those in SCI model group or BMSCs group(P<0.05).However,it did not reverse to the level in control group(P<0.05).On the 28th day after transplantation,compared with the SCI model group and BMSCs group,neuronal pyknosis reduced,the Nissl body density increased,the expression levels of XBP1,CHOP,ATF4,ATF6,GRP78,and Bax,and the rate of TUNEL-positive cells significantly reduced in NRG1-BMSCs group(P<0.05),and the expression level of Bcl-2 significantly increased(P<0.05).Conclusion Transplantation of NRG1 gene-modified BMSCs can alleviate SCI and improve the recovery of motor function in rats.The mechanism may be related to promoting the proliferation activity of BMSCs,inhibiting cell apoptosis,and mitigating endoplasmic reticulum stress.

BackgroundPatients demonstrating depressive disorder with psychotic symptoms often have increased risk of death and poor prognosis. A large amount of research has explored the factors influencing psychotic symptoms in adult patients with depressive disorder， but few has focused on adolescent patients. ObjectiveTo explore the influencing factors of psychotic symptoms in adolescent patients with depressive disorder， so as to provide references for early screening and intervention in clinic. MethodsA total of 96 adolescent patients who met the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） for depressive disorder and were seen in the psychiatry departments of Chaohu Hospital of Anhui Medical University and The Fourth People's Hospital of Hefei from September 2022 to January 2023 were included. Another 56 healthy individuals from the health examination center of Chaohu Hospital of Anhui Medical University were concurrently recruited as control group. Patients were assigned into psychotic group （n=32） and non-psychotic group （n=64） according to the presence or absence of psychotic symptoms. Hamilton Depression Scale-24 item （HAMD-24）， Positive and Negative Syndrome Scale （PANSS）， Positive and Negative Suicide Ideation （PANSI） and Childhood Trauma Questionnaire-Short Form （CTQ-SF） were used for evaluation. Plasma brain-derived neurotrophic factor （BDNF） concentration was obtained using Meso Scale Discovery electrochemiluminescence assay. Pearson and Spearman correlation analysis were adopted to determine the correlation of PANSS positive symptom subscale score with plasma BDNF concentration and clinical characteristics of adolescent depression patients with psychotic symptoms. Binary Logistic regression analysis was used to identify the factors influencing the presence of psychotic symptoms in adolescent patients with depressive disorder， and multiple linear regression analysis was utilized to screen the factors affecting the severity of psychotic symptoms. ResultsThe plasma BDNF concentration of adolescent patients with depressive disorder was lower than that of control group （t=-3.080， P<0.01）.The plasma BDNF concentration of psychotic group was lower than that of non-psychotic group （t=2.418， P<0.05）， while the body mass index （BMI） PANSI scores， CTQ-SF scores and HAMD-24 total scores were all higher than those of non-psychotic group （t=-2.024， -2.530， -2.187， -4.977， P<0.05 or 0.01）. Correlation analysis showed that PANSS positive symptom subscale scores were negatively correlated with anxiety/somatization factor score and weight factor score in HAMD-24 of psychotic group （r=-0.438， -0.498， P<0.05 or 0.01）. Binary Logistic regression showed that BMI， plasma BDNF concentration， HAMD-24 total scores and cognitive dysfunction factor score were the influencing factors of psychotic symptoms in adolescent patients with depressive disorder. Multiple linear regression analysis demonstrated that weight factor scores （β=-0.349， P<0.05） and anxiety/somatization factor score （β=-0.433， P<0.05） in HAMD-24 were the factors influencing the severity of psychotic symptoms. ConclusionHigh BMI， low plasma BDNF concentration， severe depressive symptoms and cognitive dysfunction may be the risk factors of psychotic symptoms in adolescent patients with depressive disorder， furthermore， BMI and anxiety symptoms are found to be associated with the severity of psychotic symptoms. ［Funded by Scientific Research Fund Project of Anhui Institute of Translational Medicine （number， 2022zhyx-B01）； Central Finance Supported Provincial Key Clinical Specialty Construction Project of Anhui Province in 2019］