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: Asthma imposes a significant global health burden. This study examines changes in the asthma-related disease burden from 1990 to 2021 and projects future burdens for 2050 under different scenarios. METHODS: Using data from the Global Burden of Disease 2021 study, we analyzed asthma incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021. We projected the disease burden for 2050 based on current trends and hypothetical scenarios in which all risk factors are controlled. Temporal trends in age-standardized incidence, prevalence, mortality, and DALY rates were explored using Annual Percent Change. RESULTS: In 2021, the age-standardized rates for asthma incidence, prevalence, mortality, and DALYs in China were 364.17 per 100,000 (95% uncertainty interval [ UI]: 283.22-494.10), 1,956.49 per 100,000 (95% UI: 1,566.68-2,491.87), 1.47 per 100,000 (95% UI: 1.15-1.79), and 103.76 per 100,000 (95% UI: 72.50-145.46), respectively. A higher disease burden was observed among Chinese men and individuals aged 70 years or older. Compared to the current trend, a combined scenario involving improvements in environmental factors, behavioral and metabolic health, child nutrition, and vaccination resulted in a greater reduction in the disease burden caused by asthma. CONCLUSION Addressing modifiable risk factors is essential for further reducing the asthma-related disease burden.
Humans ; Asthma/mortality* ; China/epidemiology* ; Male ; Female ; Adult ; Middle Aged ; Aged ; Child ; Adolescent ; Global Burden of Disease/trends* ; Child, Preschool ; Young Adult ; Infant ; Cost of Illness ; Disability-Adjusted Life Years ; Prevalence ; Incidence ; Infant, Newborn ; Aged, 80 and over ; Risk Factors

OBJECTIVE: To determine the prevalence of lumbar spondylolysis (LS) and the proportion of spondylolytic spondylolisthesis (SS) in China, and to evaluate the musculoskeletal status of patients with LS and SS. METHODS: Spine Computed Tomography (CT) images were collected from community populations aged 40 and above in a nationwide multi-center project. LS was diagnosed, and SS was graded by an experienced radiologist. Bone mineral density (BMD) and paraspinal muscle parameters were quantified based on CT images. RESULTS: One hundred and seventeen patients of a total of 3,317 individuals were diagnosed with LS, corresponding to a prevalence rate of 3.53%. 63 of the 1,214 males (5.18%) and 54 of the 2,103 females (2.57%) were diagnosed with LS. SS occurred in 64/121 vertebrae (52.89%). BMD was not associated with LS ( P = 0.341). The L5 extensor paraspinal muscle density was higher in the LS group than in the non-LS group. In the LS group, patients with SS had a smaller L5 paraspinal extensor muscle cross-sectional area than those without SS ( P = 0.003). CONCLUSION The prevalence of LS in Chinese adults was 3.53%, with prevalence rates of 5.18% in males and 2.57% in females. Patients with LS have higher muscle density, whereas those with SS have smaller muscle cross-sectional areas at the L5 level.
Humans ; Male ; Female ; Middle Aged ; China/epidemiology* ; Prevalence ; Adult ; Lumbar Vertebrae/diagnostic imaging* ; Spondylolysis/diagnostic imaging* ; Aged ; Bone Density ; Tomography, X-Ray Computed ; Aged, 80 and over ; Spondylolisthesis/epidemiology* ; East Asian People

BACKGROUND:Medium-and large-diameter polytetrafluoroethylene artificial blood vessels have been widely used in clinical practice.However,most of the products were imported from other countries.Small-diameter porous polytetrafluoroethylene vessels are easy to form thrombosis and intimal hyperplasia,resulting in an extremely low long-term patency rate,which is difficult to fulfill clinical requirements. OBJECTIVE:To review and summarize the research progress of polytetrafluoroethylene in the field of artificial blood vessels,which can provide a reference for the functional modification of small-diameter polytetrafluoroethylene artificial blood vessels and the improvement of their long-term patency rate. METHODS:The relevant articles published from October 2022 to March 2023 in CNKI,Web of Science,Wiley Online Library,SpringerLink,Science Direct and IOP Science databases were searched by the first author.The search terms in Chinese were"porous polytetrafluoroethylene,vascular graft,electrospinning,medical application,functional modification".The search terms in English were"ePTFE,porous polytetrafluoroethylene,vascular graft,electrospinning,medical application,functional modification".All the articles about the preparation and modification of polytetrafluoroethylene artificial blood vessels were retrieved. RESULTS AND CONCLUSION:The preparation and functional modification of porous polytetrafluoroethylene artificial blood vessels were still research hotspots and difficult problems.From the research progress in and outside China in recent years,the preparation of porous polytetrafluoroethylene artificial blood vessels mainly adopted the rapid thermal stretching method,but the preparation of polytetrafluoroethylene artificial blood vessels by electrospinning was a promising new method.By analyzing and summarizing different functional modification methods,it was found that the long-term patency rate of porous polytetrafluoroethylene artificial blood vessels had been improved.However,the functional modification of small-diameter polytetrafluoroethylene artificial blood vessels still needed further exploration and optimization.

BACKGROUND:In addition to apoptosis,recent studies have discovered novel forms of programmed cell death in periprosthetic osteolysis,which is involved in regulating local chronic inflammation and the outcome of osteoblast and osteoclast under pathological conditions.This has an important value for the treatment and prognosis of periprosthetic osteolysis. OBJECTIVE:To provide new ideas and strategies for the prevention and treatment of periprosthetic osteolysis by summarizing studies on the novel forms of programmed cell death. METHODS:The first author used the computer to search the articles published from 2005 to 2022.Chinese search terms"wear particles,periprosthetic osteolysis,programmed cell death,apoptosis,autophagy,pyroptosis,necrotizing apoptosis,iron death"were used to search the databases of CNKI,WanFang and VIP.English search terms"osteolysis,wear debris,wear particles,peri*prosthetic osteolysis,PPOL,aseptic loosening,autophagy,regulated cell death,programmed cell death,apoptosis,pyroptosis,autophagic cell death,autophagy,necroptosis,ferroptosis"were used for search in PubMed and Web of Science databases.A total of 68 articles were finally included according to the inclusion criteria. RESULTS AND CONCLUSION:(1)Inadequate or excessive activation of autophagy can cause cell death,inhibit bone formation,and promote bone resorption,leading to bone metabolism disorders and osteolysis.(2)Recent studies have paid close attention to pyroptosis in periprosthetic osteolysis,where the Nod-like receptor,pyrin containing 3 inflammasome plays an important role in local inflammation.Inhibiting pyroptosis can effectively alleviate osteolysis.(3)In vitro studies have shown that necroptosis can inhibit the formation and function of osteoblasts and osteoclasts,affecting the process of osteolysis and destruction.(4)Ferroptosis is the newest form of programmed cell death,which is regulated by complex signaling pathways and mechanisms,but is not yet fully understood.(5)Autophagy,pyroptosis,necroptosis,and ferroptosis play important roles in the development of periprosthetic osteolysis,and their associated signaling pathways and genes require further investigation.

Objective To construct a Type 1 diabetes model in miniature pigs and explore postoperative care strategies for effectively prolonging the survival time of the model pigs.Methods Seven Banna miniature pigs were selected for pancreatectomy.Glucose,vitamins,and antibiotics were administered for 3-5 days after surgery to aid recovery.Blood glucose and urine glucose levels were measured twice a day in the morning and evening to adjust insulin supplementation accordingly.The model pigs were observed daily and records were kept,including orexis,psychosis,weakness,skin ulcer,and feces and urine.Body weight was measured weekly until the death of the model animals.Based on the model pigs'condition,glucose injection and Ringer's lactate solution were administered to supplement nutrition and correct electrolyte imbalances.Results All seven Banna miniature pigs showed typical symptoms of diabetes:random blood glucose levels higher than 11.1 mmol/L after pancreatectomy,far exceeding the average blood glucose level of 6.0 mmol/L in normal pigs;positive urine glucose;and progressive weight loss.These features indicated the successful construction of Type 1 diabetes model.Additionally,Type 1 diabetic pigs that survived more than 8 weeks showed progressive hair loss and skin ulceration.Euthanasia was performed on model pigs when they were unable to stand or even eat independently,and pathological examination and HE staining were conducted on tissues collected from affected organs such as the liver,kidneys,and skin.Pathological sections revealed liver congestion,massive glycogen accumulation,ballooning degeneration of hepatocytes,and progressive liver fibrosis,along with glomerular congestion,vacuolar degeneration in renal tubular epithelial cells,proteinuria,dermal congestion,thinning of vascular walls,and varying degrees of parakeratosis and dyskeratosis in the liver,kidneys,and skin tissues due to prolonged hyperglycemia.The average survival time of the constructed Banna miniature pig diabetes model was 44 d,with a maximum survival time of 121 d.Conclusion Type 1 diabetes model can be constructed successfully in Banna miniature pigs through pancreatectomy.With meticulous postoperative care,a long-term Type 1 diabetes model with significant complications can be achieved,providing a stable large-animal model for Type 1 diabetes treatment strategies.

Objective:To establish a predictive model for the progression of acute kidney injury (AKI) to stage 3 AKI (renal failure) in the intensive care unit (ICU), so as to assist physicians to make early and timely decisions on whether to intervene in advance.Methods:A retrospective analysis was conducted. Thirty-eight patients with AKI admitted to the intensive care medicine of the Third People's Hospital of Henan Province from January 2018 to May 2023 were enrolled. Patient data including acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) upon admission, serum creatinine (SCr), blood urea nitrogen (BUN), daily urine output during hospitalization, and the timing of continuous renal replacement therapy (CRRT) intervention were recorded. Based on clinically collected pathological data, standardized creatinine value ratio mean polynomial fitting models were established as the first criterion for judging the progression to stage 3 AKI after data cleansing, screening, and normalization. Additionally, standardized creatinine value ratio index fitting models were established as the second criterion for predicting progression to stage 3 AKI.Results:A total of 38 AKI patients were included, including 25 males and 13 females. The average age was (58.45±12.94) years old. The APACHEⅡ score was 24.13±4.17 at admission. The intervention node was (4.42±0.95) days. Using a dual regression model approach, statistical modeling was performed with a relatively small sample size of statistical data samples, yielding a scatter index non-linear regression model for standardized creatinine value ratio data relative to day " n", with y = 1.246?2 x1.164?9 and an R2 of 0.860?1, indicating reasonable statistical fitting. Additionally, a quadratic non-linear regression model was obtained for the mean standardized creatinine value ratio relative to day " n", with y = -0.260?6 x2+3.010?7 x-1.612 and an R2 of 0.998?9, indicating an excellent statistical fit. For example, using a baseline SCr value of 66 μmol/L for a healthy individual, the dual regression model predicted that the patient would progress to stage 3 AKI within 3-5 days. This prediction was consistent when applied to other early intervention renal injury patients. Conclusion:The established model effectively predicts the time interval of the progression of AKI to stage 3 AKI (renal failure), which assist intensive care physicians to intervene AKI as early as possible to prevent disease progression.

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 investigate the effect of the number of positive preoperative serological tumor markers on the surgical approach and prognosis of patients with intrahepatic cholangiocarcinoma.Methods:This is a retrospective case-series study. Data from 548 patients with intrahepatic cholangiocarcinoma after radical resection from October 2010 to April 2019 were retrospectively collected in 10 hospitals of China. There were 277 males and 271 females with an age of (57.8±10.2)years(range:23 to 84 years). Four hundred and twenty-six patients(77.7%) had at least one positive preoperative serum tumor marker. The data collection included the results of 4 preoperative serological tumor markers,other preoperative indicators(5 prodromal symptoms, 6 medical history,8 preoperative serological indicators,5 preoperative imaging indicators,and 14 preoperative pathological examination indicators),baseline data (gender and age),surgical methods,and prognostic follow-up data. Four preoperative results of serologic tumor marker and surgical procedure were converted into categorical variables. The number of positive preoperative serum tumor markers was used as the treatment variable,the surgical method was used as the mediating variable,and the survival time was used as the outcome variable. Univariate and multivariate analysis were used to screen for other preoperative indicators which were independent factors that influenced the surgical procedure and the prognosis of patients as covariates to analyze the mediating effect.Results:Of the 548 patients included in the study, 176 patients (32.1%) underwent partial hepatectomy,151 patients(27.5%) underwent hemihepatectomy, and 221 patients(40.3%) underwent partial hepatectomy or hemihepatectomy combined with other treatments. The results of the univariate and multivariate analysis showed that the number of positive serum tumor markers,intrahepatic bile duct dilatation,portal vein invasion,pathological differentiation,pathological type,vascular invasion,T stage,N stage and maximum tumor diameter were independent factors influencing the surgical procedure(all P<0.05). Intrahepatic bile duct dilatation,pathological differentiation and T stage were independent prognostic factors for patients with intrahepatic cholangiocarcinoma(all P<0.05). Intrahepatic bile duct dilatation,differentiation and T stage were included as covariates in the mediation effect model. The results showed that the number of positive serum tumor markers before surgery had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma ( β=-0.092, P=0.039),and had a positive predictive effect on the surgical method ( β=0.244, P<0.01). The number of positive serum tumor markers had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma ( β=-0.151, P=0.002). Direct and indirect effects accounted for 71.3% and 28.7% of total effects,respectively. Conclusions:The higher the positive number of preoperative tumor markers,the worse the prognosis of patients with intrahepatic cholangiocarcinoma. The number of positive cells not only directly affects the prognosis of patients,but also indirectly affects the prognosis of patients by affecting the surgical method.

Osteoarthritis(OA)is a chronic progressive osteoarthropathy in the elderly.Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA.However,the specific mechanism of osteoclast differentiation in OA remains unclear.In our study,gene expression profiles related to OA disease progression and osteoclast activation were screened from the Gene Expression Omnibus(GEO)repository.GEO2R and Funrich analysis tools were employed to find differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses demonstrated that chemical carcinogenesis,reactive oxygen species(ROS),and response to oxidative stress were mainly involved in osteoclast differentiation in OA subchondral bone.Furthermore,fourteen DEGs that are associated with oxidative stress were identified.The first ranked differential gene,heme oxygenase 1(HMOX1),was selected for further validation.Related results showed that osteoclast activation in the pathogenesis of OA subchondral bone is accompanied by the downregulation of HMOX1.Carnosol was revealed to inhibit osteoclastogenesis by targeting HMOX1 and upregulating the expression of antioxidant protein in vitro.Meanwhile,carnosol was found to alleviate the severity of OA by inhibiting the activation of subchondral osteoclasts in vivo.Our research indicated that the activation of osteoclasts due to subchondral bone redox dysplasia may serve as a significant pathway for the advancement of OA.Targeting HMOX1 in subchondral osteoclasts may offer novel insights for the treatment of early OA.