Objective:To investigate the anti-leukemic effects and resistance mechanisms of venetoclax in acute myeloid leukemia (AML). Genomic, transcriptomic, and clinical data from AML patients who underwent venetoclax drug sensitivity testing were downloaded from the Beat AML database. Correlation analysis was performed between these data and venetoclax sensitivity outcomes. Differentially expressed genes (DEGs) associated with venetoclax sensitivity were identified from transcriptomic data and subsequently validated using GEO database transcriptomic results and in vitro experiments (including Western blot). Functional enrichment analyses (KEGG and GSEA), transcription factor enrichment analysis (KnockTF), and data from public databases were employed to further investigate key genes and pathways influencing drug sensitivity.Results:After filtering the Beat AML cohort, data from 52 patient samples with available in vitro venetoclax sensitivity results were included for analysis. Patients with FLT3 mutations exhibited greater sensitivity to venetoclax compared to those with FLT3 wild-type. Correlation analysis between clinical information and drug sensitivity data indicated that higher peripheral blood tumor burden was associated with increased sensitivity to venetoclax. Transcriptomic analysis and in vitro experiments confirmed that venetoclax inhibits the FLT3-related signaling pathway, including downregulation of FLT3 expression and reduced phosphorylation of its downstream targets AKT and STAT5. KEGG pathway and KnockTF transcription factor enrichment analyses indicated that venetoclax resistance was associated with increased transcriptional activity of FOXM1 and STAT3. Moreover, high expression of FOXM1 and STAT3 correlated with shorter overall survival in patients.Conclusion:Venetoclax can inhibit the activation of FLT3-related signaling pathways. The activation of STAT3 and FOXM1 transcription factors is a potential key mechanism contributing to venetoclax resistance in AML.

Objective Piperazine derivatives are a group of emerging psychoactive substances with excitatory and hallucinogenic effects on the central nervous system.This study established a high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)screening method for the detection of 40 piperazine compounds in urine.Methods A 200 μL urine sample(spiked with an internal standard at 1 ng/mL)was subjected to liquid-liquid extraction with ethyl acetate.After nitrogen evaporation,the residue was redissolved in 200 μL methanol and injected for analysis.Separation was performed on a Waters Acquity UPLC? HSS T3 column(100 mm × 2.1 mm,1.8 μm).The mobile phase consisted of(A)20 mmol/L ammonium acetate buffer containing 0.1％formic acid and 5％acetonitrile,and(B)acetonitrile.Gradient elution was applied,and detection was carried out in multiple reaction monitoring(MRM)mode.Quantification was achieved using an internal standard calibration curve.Results The 40 piperazine substances demonstrated good linearity within the range of 1-50 ng/mL,with correlation coefficients of 0.995-0.998.The extraction recovery ranged from 51.51％to 104.1％.Intra-day precision was below 5％,while inter-day precision ranged from 1.61％to 10.17％.Accuracy was between-7.84％and 8.77％.The limits of detection were 0.2-1 ng/mL,and the limit of quantification was 1 ng/mL.Conclusion The proposed method requires only a small sample volume,exhibits high sensitivity,selectivity,and stability,and offers short run times.It is suitable for the qualitative and quantitative determination of piperazine derivatives in urine in forensic toxicology practice.

Objective Piperazine derivatives are a group of emerging psychoactive substances with excitatory and hallucinogenic effects on the central nervous system.This study established a high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)screening method for the detection of 40 piperazine compounds in urine.Methods A 200 μL urine sample(spiked with an internal standard at 1 ng/mL)was subjected to liquid-liquid extraction with ethyl acetate.After nitrogen evaporation,the residue was redissolved in 200 μL methanol and injected for analysis.Separation was performed on a Waters Acquity UPLC? HSS T3 column(100 mm × 2.1 mm,1.8 μm).The mobile phase consisted of(A)20 mmol/L ammonium acetate buffer containing 0.1％formic acid and 5％acetonitrile,and(B)acetonitrile.Gradient elution was applied,and detection was carried out in multiple reaction monitoring(MRM)mode.Quantification was achieved using an internal standard calibration curve.Results The 40 piperazine substances demonstrated good linearity within the range of 1-50 ng/mL,with correlation coefficients of 0.995-0.998.The extraction recovery ranged from 51.51％to 104.1％.Intra-day precision was below 5％,while inter-day precision ranged from 1.61％to 10.17％.Accuracy was between-7.84％and 8.77％.The limits of detection were 0.2-1 ng/mL,and the limit of quantification was 1 ng/mL.Conclusion The proposed method requires only a small sample volume,exhibits high sensitivity,selectivity,and stability,and offers short run times.It is suitable for the qualitative and quantitative determination of piperazine derivatives in urine in forensic toxicology practice.

Objective:To investigate the anti-leukemic effects and resistance mechanisms of venetoclax in acute myeloid leukemia (AML). Genomic, transcriptomic, and clinical data from AML patients who underwent venetoclax drug sensitivity testing were downloaded from the Beat AML database. Correlation analysis was performed between these data and venetoclax sensitivity outcomes. Differentially expressed genes (DEGs) associated with venetoclax sensitivity were identified from transcriptomic data and subsequently validated using GEO database transcriptomic results and in vitro experiments (including Western blot). Functional enrichment analyses (KEGG and GSEA), transcription factor enrichment analysis (KnockTF), and data from public databases were employed to further investigate key genes and pathways influencing drug sensitivity.Results:After filtering the Beat AML cohort, data from 52 patient samples with available in vitro venetoclax sensitivity results were included for analysis. Patients with FLT3 mutations exhibited greater sensitivity to venetoclax compared to those with FLT3 wild-type. Correlation analysis between clinical information and drug sensitivity data indicated that higher peripheral blood tumor burden was associated with increased sensitivity to venetoclax. Transcriptomic analysis and in vitro experiments confirmed that venetoclax inhibits the FLT3-related signaling pathway, including downregulation of FLT3 expression and reduced phosphorylation of its downstream targets AKT and STAT5. KEGG pathway and KnockTF transcription factor enrichment analyses indicated that venetoclax resistance was associated with increased transcriptional activity of FOXM1 and STAT3. Moreover, high expression of FOXM1 and STAT3 correlated with shorter overall survival in patients.Conclusion:Venetoclax can inhibit the activation of FLT3-related signaling pathways. The activation of STAT3 and FOXM1 transcription factors is a potential key mechanism contributing to venetoclax resistance in AML.

Background and purpose:In 2016 the National Cancer Institute(NCI)decided stopping to use NCI-60 cell lines for drug screening,suggesting that tumor cell lines were losing their value as a tool for drug discovery and basic research.The reason for NCI-60 cells'retirement'was that the preclinical studies based on traditional cellular and animal models did not obtain the corresponding expected efficacy in clinical trials.Since the major cancer behaviors,such as proliferation and metastasis,are fundamentally altered with long-term culture,the tumor cell lines are not representative of the characteristics of cancer in patients.Currently,scientists hope to create a new cancer model that are derived from fresh patient samples and tagged with details about their clinical past.Our purpose was to create patient-derived breast cancer primary cell lines as new cancer model for drug screening and basic research.Methods:Breast cancer tissues were collected in the Department of Breast Surgery,Affiliated Hospital of Guizhou Medical University.The collection of tumor tissue samples was approved by the Ethics Committee of the Affiliated Hospital of Guizhou Medical University(approval number:2022 ethics No.313),and the collection and use of tumor tissues complied with the Declaration of Helsinki.The primary breast cancer cell lines were isolated from the patient's breast cancer tissues and cultured in BCMI medium.After the cells proliferated,the media were replaced with DEME medium.Cell line STR genotyping was done to determine cell-specific genetic markers and identification.Clone formation assay and transplantation assay were done to analyze the ability of breast cancer primary cell lines to form tumors.Results:We created 6 primary breast cancer cell lines.The 6 primary breast cancer cell lines from the patients were tagged with the definitively clinicopathological features,clinical diagnosis,therapeutic regimens,clinical effectiveness and prognostic outcomes.The STR genotyping assays identified the genetic markers and determined the identities of the 6 primary breast cancer cell lines.Clone formation assays and transplantation assay showed that the proliferative capacities of the patient-derived primary breast cancer cell lines were significantly greater compared with the conventional breast cancer cell lines.Conclusion:We created a panel of 6 patient-derived primary breast cancer cell lines as new cancer model for drug screening and basic research in breast cancer.

Objective: To understand the status and related knowledge requirements of health emergency literacy among college students in Shaanxi Province, so as to provide the basis for improving college students health emergency literacy. Methods: A total of 2 723 students from 18 colleges and universities in Shaanxi Province were selected by multi stage random sampling and simple random sampling methods in November 2023, and the survey of health literacy in emergency and knowledge requirements of health emergency literacy was conducted. Statistical analysis was carried out by using χ 2 test, Wilcoxon rank sum test, Kruskal-Wallis H test and Logistic regression analysis. Results: About 28.98% of the surveyed college students had a high level of health emergency literacy, which varied by students whether being only one child, whether having left behind experience, with different personality types, whether being student cadres, and with different frequencies of community or social activities ( χ 2=9.15, 7.90, 32.73, 16.29 , 120.25, P <0.05). The equivalence scores of the four dimensions of health emergency literacy from high to low were poisoning and nuclear and radiation (0.84), medical rescue (0.83), infectious disease (0.82), and basic knowledge and behavior ( 0.77 ). Logistic regression analysis found that college students with left-behind experience were negatively correlated with health emergency literacy and its four dimensions ( OR =0.74, 0.72, 0.80, 0.80, 0.83), while personality type (rational type), community or social activity frequency were positively correlated with the cognitive levels of health emergency literacy and its four dimensions among college students ( OR =1.57, 1.50, 1.33, 1.27, 1.38)( P <0.05). There was a higher level of basic knowledge and behavioral cognition among only child college students ( OR =3.73), and female students had a higher level of health emergency literacy, as well as awareness of infectious disease outbreaks and medical rescue ( OR =1.21, 1.28, 1.21)( P <0.05). The radar map showed that the level of health emergency literacy was positive development radar map. About 67.68 % of the students had a high willingness to acquire health emergency literacy knowledge, and the demand for basic health emergency knowledge and behavioral knowledge was the highest (52.37%). Conclusions College students have insufficient health emergency literacy, but they have the highest demand for health emergency. Publicity and education should be strengthened for students with left behind experience, irrational type, and low frequency of community or social activities.

Objective:To understand the incidence of diabetes and influencing factors, the trend of FPG change and risk for mortality in HIV-infected individuals after antiretroviral therapy (ART) in Dehong Dai and Jingpo Autonomous Prefecture (Dehong).Methods:The HIV/AIDS treatment database was collected from China Information System for Disease Control and Prevention. This retrospective cohort study was conducted in HIV-infected individuals with access to ART in Dehong during 2004-2020.The Cox proportional hazard regression model was used to analyze the incidence density of diabetes, the influencing factors and risk for mortality in HIV-infected individuals with access to ART, mixed linear effects model was used to analyze the trend of FPG change and predict FPG in those with different glucose metabolic status at baseline survey. Statistical analysis was performed using software SAS 9.4.Results:A total of 8 763 HIV-infected individuals were included, in whom 8 432 (96.2%) had no diabetes, 331 had diabetes. The incidence density of diabetes was 2.31/1 000 person years. Multivariate Cox proportional hazard regression analysis revealed that 30- 59 years old, BMI ≥24.0 kg/m 2, Efavirenz (EFV) based initial treatment regimen and impaired fasting glucose (IFG) at baseline survey were significantly and positively associated with incidence of diabetes. Mixed effect model revealed that FPG was positively correlated with the duration of ART, age and baseline FPG. Suffering from diabetes was a risk factor for mortality in HIV-infected individuals both at baseline survey and during follow-up. Conclusions:The risk for diabetes increased in HIV-infected individuals who were 30-59 years old, baseline BMI ≥24.0 kg/m 2, received EFV based initial treatment, and IFG in HIV-infected individuals after antiretroviral therapy in Dehong, 2004-2020. It is important to pay close attention to their blood glucose, and patients with high blood glucose should receive treatment as early as possible.

OBJECTIVES: Diabetic kidney disease is one of the most serious complications of diabetes mellitus (DM), and it is a main cause for chronic kidney disease and end-stage kidney disease (ESRD). It is important to find out the factors that cause the progression of renal function. The study aims to explore the relationship between serum uric acid (SUA) trajectory and the progression of renal function in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 846 patients with T2DM, who were admitted to the Department of Nephrology and Endocrinology, the Third Xiangya Hospital of Central South University, from January 2009 to December 2021 and met the criteria of baseline estimated glomerular filtration rate (eGFR)≥60 mL/(min·1.73 m²), were selected as the research subjects. The SUA data of multiple measurements were collected and identified as different SUA trajectories by group-based trajectory modeling (GBTM). According to the SUA trajectories, the patients were divided into a low trajectory group (105 cases), a middle trajectory group (396 cases), a middle high trajectory group (278 cases), and a high trajectory group (67 cases). Cox regression analysis was used to examine the effect of SUA trajectory on the progression of renal function in patients with T2DM. Subgroup analysis was performed by sex, age, course of disease, body mass index (BMI) and hemoglobin A1c (HbA1c). RESULTS: The median follow-up was 4.8 years. At the end of follow-up, 158 patients had different degrees of decline in renal function. After adjusting for multiple confounding factors by Cox regression analysis, the risks of eGFR<60 mL/(min·1.73 m²), eGFR reduction rate≥50%, serum creatinine (Scr) doubling and composite endpoint (eGFR reduction rate≥50%, Scr doubling or ESRD) in the high trajectory group were significantly higher than those in the low trajectory group, with HR of 3.84 (95% CI 1.83 to 8.05), 6.90 (95% CI 2.27 to 20.96), 6.29 (95% CI 2.03 to 19.52), and 8.04 (95% CI 2.68 to 24.18), respectively. There was no significant difference in the risk of ESRD among the above 4 groups (all P>0.05). Subgroup analysis showed that: compared with the low trajectory group, the risks of eGFR<60 mL/(min·1.73 m²) in patients with high trajectory in the subgroup of male, female, age<65 years, course of disease<10 years, BMI≥24 kg/m² and HbA1c≥7% were increased (all P<0.05). The SUA trajectory had no interaction with sex, age, course of disease, BMI and HbA1c (all interactive P>0.05). CONCLUSIONS The high SUA trajectory increases the risk for progression of renal function in patients with T2DM. Long-term longitudinal changes of SUA should be paid attention to.
Humans ; Male ; Female ; Aged ; Diabetes Mellitus, Type 2/complications* ; Cohort Studies ; Uric Acid ; Glycated Hemoglobin ; Renal Insufficiency, Chronic ; Kidney Failure, Chronic/complications* ; Glomerular Filtration Rate ; Kidney/physiology* ; Risk Factors

Objective:To examine the survival rates and clinical characteristics of people with newly discovered non-M 3 acute myeloid leukemia (AML) who carry the ASXL1 gene mutation. Methods:From January 2016 to April 2021, the clinical information of patients with newly diagnosed non-M 3 AML at Shandong University's Qilu Hospital was retrospectively examined, and their clinical characteristics and survival were compared and analyzed. Gene mutation was detected by next-generation sequencing. Results:① The study included 256 AML patients who were initially diagnosed and had complete data, including 47 cases of ASXL1 gene mutation-positive (ASXL1 +) patients and 209 cases of ASXL1 gene mutation-negative (ASXL1 -) patients. All patients were divided into three groups: elderly (≥60 years old, n=92) , middle-aged (45-59 years old, n=92) , and young (≤44 years old, n=72) . ②WBC, and age were higher in patients with ASXL1 mutations compared to ASXL1 - patients, while complete response after the first round of treatment (CR 1) was lower ( P<0.05) . In the elderly group, WBC and the proportion of aberrant cells in nuclear cells in ASXL1 + patients were higher than those in ASXL1 - patients ( P<0.05) . In the young group, the WBC of ASXL1 + patients was higher than that of ASXL1 - patients ( z=-2.314, P=0.021) . ③IDH2 mutation and ASXL1 mutation was related ( P=0.018, r=0.34) . In ASXL1 + patients, the proportion of peripheral blasts in the high VAF group (VAF>40% ) was higher than that in the low VAF group (VAF<20% ) , and the proportion of aberrant nuclear cells was higher in the duplication and replacement mutation patients than in the deletion mutation patients ( P<0.05) . ④The overall survival (OS) and progression-free survival (PFS) of ASXL1 + patients were shorter than those of ASXL1 - patients (median, 10 months vs 20 months, 10 months vs 17 months; P<0.05) . The proportion number of aberrant cells in nuclear cells (≥20% ) , complex karyotypes, and TET2 mutation were all independent risk variables that had an impact on the prognosis of ASXL1 + patients, according to multivariate analysis ( P<0.05) . Conclusion:ASXL1-mutated non-M 3 AML patients have higher WBC in peripheral blood, a higher proportion of aberrant cells in nuclear cells, lower CR 1 rate, and shorter OS and PFS. Additionally, a poor prognosis is linked to higher VAF, duplication, and substitution mutations in the ASXL1 gene, as well as the high proportion of aberrant cells in nuclear cells, complex karyotype, and TET2 mutation.

Pyroptosis is a way of programmed cell death which is newly discovered in recent years. Animal studies have shown that pyroptosis is involved in the occurrence and development of brain injury from various causes. Inhibition of pyroptosis plays a protective role in the nervous system in animal models by reducing the neurological symptoms. Pyroptosis may provide a target for clinical treatment of neonatal brain injury. This paper reviews pyroptosis's mechanism and its role in the pathogenesis in brain injury in various conditions for a better understanding of neonatal brain injury.