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*

Osteoarthritis (OA) causes chronic pain that significantly impairs quality of life, with current treatments often proving insufficient and accompanied by adverse effects. Recent research has identified the dorsal root ganglion (DRG) and its resident macrophages as crucial mediators of chronic OA pain through neuroinflammation driven by macrophage polarization. We present a novel injectable thermo-sensitive hydrogel system, KAF@PLEL, designed to deliver an anti-inflammatory peptide (KAF) specifically to the DRG. This biodegradable hydrogel enables sustained KAF release, promoting the reprogramming of DRG macrophages from pro-inflammatory to anti-inflammatory phenotypes. Through comprehensive in vitro and in vivo studies, we evaluated the hydrogel's biocompatibility, effects on macrophage polarization, and therapeutic efficacy in chronic OA pain management. The system demonstrated significant capabilities in preserving macrophage mitochondrial function, suppressing neuroinflammation, alleviating chronic OA pain, reducing cartilage degradation, and improving motor function in OA rat models. The sustained-release properties of KAF@PLEL enabled prolonged therapeutic effects while minimizing systemic exposure and side effects. These findings suggest that KAF@PLEL represents a promising therapeutic approach for improving outcomes in OA patients through targeted, sustained treatment.

Objective To investigate the neuroprotective effect of rhein(RHE)on ischemic mice and its potential mechanism of reducing inflammatory response and neuronal apoptosis by inhibiting Notch/nuclear factor(NF)-κB signaling pathway.Methods The classical middle cerebral artery occlusion(MCAO)method was used to construct ischemic stroke mouse models.The mice were randomly divided into 5 groups including the sham operation group(sham),the model group(MCAO),the MCAO+edaravone group(Eda),the MCAO+RHE-treated group(RHE),and the MCAO+RHE+Notch activitor Jagged 1 group(RHE+J).Each group has 18 mice.The Bederson scoring system,balance beam walking test and accelerated rotating rod test were used to assess the neurological function and locomotor ability of mice in each group.2,3,5-triphenyltetrazolium chloride(TTC)staining,hematoxylin eosin staining,and TUNEL method were used to assess cerebral infarction,hippocampal morphological damage,and neuronal apoptosis.ELISA was used to analysis the levels of interleukin(IL)-6 and tumor necrosis factor α(TNF-α)in hippocampal tissue.Western blotting was used to analysis caspase-3,Notch 1,Hes1,and NF-κB p65 protein expression.Results Compared with the sham group,Bederson score,balance beam score,cerebral infarct volume,IL-6 and TNF-α levels,the proportion of TUNEL-positively stained cells,caspase-3,Notch1,Hes1,and p-NF-κB p65 protein expression were significantly increased in the MCAO group,whereas the latency to fall decreased significantly(P＜0.05).Compared with the MCAO group,Bederson score,balance beam score,cerebral infarct volume,IL-6 and TNF-α levels,proportion of TUNEL-positively stained cells,caspase-3,Notch1,Hes1,and p-NF-κB p65 protein expression were significantly lower in both Eda and RHE groups,whereas the latency to fall increased significantly(P＜0.05).Compared with the RHE group,Bederson score,balance beam score,cerebral infarction volume,IL-6 and TNF-α levels,the proportion of TUNEL-positively stained cells,caspase-3,Notch1,Hes1,and p-NF-κB p65 protein expression increased significantly in the RHE+J group,whereas the latency to fall decreased significantly(P＜0.05).Conclusion Rhein can significantly improve nerve function in ischemic mice by inhibiting Notch/NF-κB signaling pathway activation,suggesting that rhein has potential clinical application value.

Two pediatric heart failure patients were treated with pulmonary artery banding(PAB)at Fuwai Hospital,from December 2021 to January 2022.In the first case,an 8-month-old patient presented with left ventricular non-compaction cardiomyopathy(LVNC),left ventricular systolic dysfunction,ventricular septal defect,and atrial septal defect.The second case was a 4-month-old patient with LVNC,left ventricular systolic dysfunction,and coarctation of the aorta.After PAB,the left ventricular function and shape of both patients were significantly improved,without serious surgery-related complications.In these individual cases of pediatric heart failure,pulmonary artery banding exhibited a more satisfactory efficacy and safety compared to pharmacological treatment,especially for those with unsatisfactory medication results.Future clinical data are needed to promote the rational and broader application of this therapeutic option for indicated patients.

Chemical constituents in soft coral Sarcophyton glaucum were separated and purified by various chromatographic methods. Based on the spectral data, physicochemical properties, and comparison with the data reported in the literature, nine cembranoids, including a new cembranoid named sefsarcophinolide(1) together with eight known cembranoids, namely(+)-isosarcophine(2), sarcomilitatin D(3), sarcophytonolide J(4),(1S,3E,7E,13S)-11,12-epoxycembra-3,7,15-triene-13-ol(5), sarcophytonin B(6),(-)-eunicenone(7), lobophytin B(8), and arbolide C(9), were identified. As revealed by biological activity experiment results, compounds 2-6 had weak acetylcholinesterase inhibitory activity, and compound 5 displayed weak cytotoxicity against K562 tumor cell line.
Animals ; Anthozoa ; Acetylcholinesterase ; Cell Line, Tumor

Objective: To understand the current situation of vaccination services for adults in China, explore how to establish a stable and efficient vaccination service system for adults, and provide reference for formulating corresponding policies. Methods: The vaccination information systems of nine provinces in China were used to obtain information on urban and rural vaccination of influenza vaccine, 23-valent pneumococcal polysaccharide vaccine (PPV23), and human papillomavirus vaccine (HPV) from 2019 to 2021. The indicator, vaccination rate/full vaccination rate, was used for statistical description. Results: The vaccination rate/full vaccination rate of the three vaccines in eastern China was generally higher than that in central and western China. The vaccination rate/full vaccination rate in urban areas was generally higher than that in rural areas. From 2019 to 2021, the vaccination rates of influenza vaccine among people aged 60 years and above in urban and rural areas were 2.96%, 6.29%, 6.14% and 1.29%, 2.58%, 2.94%, respectively. The vaccination rates of the PPV23 among people aged 60 years and above in urban and rural areas increased year by year, with rates of 0.38%, 1.05%, 1.15% and 0.14%, 0.49%, 0.59%, respectively. From 2019 to 2021, the HPV coverage of female adults aged 27-45 years in urban and rural areas increased year by year, with rates of 0.46%, 0.93%, 1.88% and 0.17%, 0.40%, 1.08%, respectively. Conclusion: The vaccination rates of influenza vaccine,PPV23 vaccine and HPV vaccine for adults in China are relatively low, with higher rates in the eastern region than in the central and western regions, and higher rates in urban areas than in rural areas. It is recommended to formulate corresponding health and economic policies and explore a suitable vaccination service system for adults in China to improve vaccination rates.
Adult ; Female ; Humans ; Influenza Vaccines/therapeutic use* ; Papillomavirus Infections ; Vaccination ; China ; Papillomavirus Vaccines/therapeutic use*

Objective: To understand the current situation of vaccination services for adults in China, explore how to establish a stable and efficient vaccination service system for adults, and provide reference for formulating corresponding policies. Methods: The vaccination information systems of nine provinces in China were used to obtain information on urban and rural vaccination of influenza vaccine, 23-valent pneumococcal polysaccharide vaccine (PPV23), and human papillomavirus vaccine (HPV) from 2019 to 2021. The indicator, vaccination rate/full vaccination rate, was used for statistical description. Results: The vaccination rate/full vaccination rate of the three vaccines in eastern China was generally higher than that in central and western China. The vaccination rate/full vaccination rate in urban areas was generally higher than that in rural areas. From 2019 to 2021, the vaccination rates of influenza vaccine among people aged 60 years and above in urban and rural areas were 2.96%, 6.29%, 6.14% and 1.29%, 2.58%, 2.94%, respectively. The vaccination rates of the PPV23 among people aged 60 years and above in urban and rural areas increased year by year, with rates of 0.38%, 1.05%, 1.15% and 0.14%, 0.49%, 0.59%, respectively. From 2019 to 2021, the HPV coverage of female adults aged 27-45 years in urban and rural areas increased year by year, with rates of 0.46%, 0.93%, 1.88% and 0.17%, 0.40%, 1.08%, respectively. Conclusion: The vaccination rates of influenza vaccine,PPV23 vaccine and HPV vaccine for adults in China are relatively low, with higher rates in the eastern region than in the central and western regions, and higher rates in urban areas than in rural areas. It is recommended to formulate corresponding health and economic policies and explore a suitable vaccination service system for adults in China to improve vaccination rates.
Adult ; Female ; Humans ; Influenza Vaccines/therapeutic use* ; Papillomavirus Infections ; Vaccination ; China ; Papillomavirus Vaccines/therapeutic use*

Animals ; SARS-CoV-2 ; Antibodies, Neutralizing ; Macaca mulatta ; COVID-19/prevention & control* ; Antibodies, Viral ; Vaccines

In the outbreak of COVID-19,triage procedures based on epidemiology were implemented in a local hospital in Changsha to control the transmission of SARS-CoV-2 and avoid healthcare-associated infection.This re-trospective study analyzed the data collected during the triage period and found that COVID-19 patients were en-riched 7 folds into the Section A designated for patients with obvious epidemiological history.On the other side,nearly triple amounts of visits were received at the Section B for patients without obvious epidemiological history.8 COVID-19 cases were spotted out of 247 suspected patients.More than 50％of the suspected patients were submi-tted to multiple rounds of nucleic acid analysis for SARS-CoV-2 infection.Of the 239 patients who were diagnosed as negative of the virus infection,188 were successfully revisited and none was reported as COVID-19 case.Of the 8 COVID-19 patients,3 were confirmed only after multiple rounds of nucleic acid analysis.Besides comorbidities,delayed sharing of epidemiological history added complexity to the diagnosis in practice.The triaging experience and strategy will be helpful for the control of infectious diseases in the future.

Objective: To compare the clinical efficacy of split liver transplantation (SLT) and living donor liver transplantation(LDLT) in the treatment of children with biliary atresia. Methods: The clinical data of 64 children with biliary atresia who underwent SLT and 44 children who underwent LDLT from June 2017 to May 2022 at Liver Surgery & Liver Transplantation Center,the Third Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. Among the children who received SLT, there were 40 males and 24 females. The median age at transplantation was 8 months (range:4 to 168 months). Among the patients who received LDLT, there were 24 males and 20 females. The age at transplantation ranged from 4 to 24 months,with a median age of 7 months. Sixty-four children with biliary atresia were divided into two groups according to the SLT operation time: 32 cases in the early SLT group(June 2017 to January 2019) and 32 cases in the technically mature SLT group (February 2019 to May 2022). Rank sum test or t test was used to compare the recovery of liver function between the LDLT group and the SLT group,and between the early SLT group and the technically mature SLT group. The incidence of postoperative complications was compared by χ² test or Fisher exact probability method. Kaplan-Meier method and Log-rank test were used for survival analysis. Results: The cold ischemia time(M (IQR)) (218 (65) minutes), intraoperative blood loss(175 (100) ml) and graft-to-recipient body weight ratio (3.0±0.7) in the LDLT group were lower than those in the SLT group(500 (130) minutes, 200 (250) ml, 3.4±0.8) (Z=-8.064,Z=-2.969, t=-2.048, all P<0.05). The cold ischemia time(457(158)minutes) and total hospital stay ((37.4±22.4)days) in the technically mature SLT group were lower than those in the early SLT group(510(60)minutes, (53.0±39.0)days).The differences were statistically significant (Z=-2.132, t=1.934, both P<0.05).The liver function indexes of LDLT group and SLT group showed unimodal changes within 1 week after operation. The peak values of ALT, AST, prothrombin time, activeated partial thromboplasting time, international normalized ratio, fibrinogen and creatinine all appeared at 1 day after operation, and the peak value of prothrombin activity appeared at 3 days after operation. All indicators returned to normal at 7 days after operation. The 1-,2-,and 3-year overall survival rates were 95.5% in LDLT group and 93.5% in the technically mature SLT group, and the difference was not statistically significant. The 1-,2-,and 3-year overall survival rates were 90.2% in the early SLT group and 93.5% in the technically mature SLT group, and there was no significant difference between the two groups(P>0.05). The main complications of the early SLT group were surgery-related complications(28.1%,9/32), and the main complications of the technically mature SLT group were non-surgery-related complications(21.9%,7/32). There were 5 deaths in the SLT group,including 4 in the early SLT group and 1 in the technically mature SLT group. Conclusion: The survival rate of SLT in the treatment of biliary atresia is comparable to that of LDLT.
Adolescent ; Biliary Atresia/surgery* ; Child ; Child, Preschool ; Creatinine ; Female ; Fibrinogen ; Humans ; Infant ; Liver Transplantation/methods* ; Living Donors ; Male ; Postoperative Complications/epidemiology* ; Prothrombin ; Retrospective Studies ; Treatment Outcome