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 evaluate the efficacy of plasma exchange therapy on crescentic IgA nephropathy (IgAN). METHODS: A retrospective analysis was performed in a cohort of patients with crescentic IgAN from January 2012 to September 2020 at 9 sites across China. Clinical and pathological data, as well as therapeutic regimens, were collected. In order to minimize the effect of potential confounders in baseline characteristics, propensity score matching using a 1 ∶1 ratio nearest neighbor algorithm was performed between the adjunctive plasma exchange therapy group and the intensive immunosuppressive therapy group. The primary outcome was end-stage of kidney disease (ESKD). Kaplan-Meier method was used to compare the difference in renal survival between the two groups. RESULTS: A total of 95 crescentic IgAN patients with acute kidney disease were included in this study, including 37 (38.9%) patients receiving adjunctive plasma exchange therapy, and 58 (61.1%) patients receiving intensive immunosuppressive therapy. In the whole cohort, the baseline eGFR was 12.77 (7.28, 21.29) mL/(min·1.73 m²), 24-hour urinary protein quantification was 5.9 (4.0, 8.9) g, and crescent percentage was 64.71% (54.55%, 73.68%). In the study, 23 patients in each group were matched after propensity score matching The median follow-up time was 7 (1, 26) months. As a whole, 29 patients (63.0%) reached ESKD, including 16 patients (69.6%) in the adjunctive plasma exchange therapy group and 13 (56.5%) patients in the intensive immunosuppressive therapy group.. There were no stastical difference between the two groups in terms of baseline eGFR [14.30 (9.31, 17.58) mL/(min·1.73 m²) vs. 11.45 (5.59, 20.79) mL/(min·1.73 m²)], 24-hour urinary protein (7.4±3.4) g vs. (6.6±3.8) g, crescent percentage 64.49%±13.23% vs. 66.41%±12.65% and the proportion of patients received steroid therapy[23 (100.0%) vs. 21 (91.3%)] (All P>0.05). Kaplan-Meier survival analysis demonstrated that there was no significant difference in renal survival rate between the two groups (Log-rank test, P=0.933). CONCLUSION The adjunctive plasma exchange therapy in addition to conventional intense immunosuppressive therapy did not additionally improve the prognosis of crescentic IgA nephropathy.
Cohort Studies ; Glomerulonephritis, IGA/pathology* ; Humans ; Kidney Failure, Chronic/therapy* ; Plasma Exchange ; Prognosis ; Retrospective Studies ; Steroids/therapeutic use*

Nardostachyos Radix et Rhizoma is the dry root and rhizome of Nardostachys jatamansi （Valerianaceae） with a long medical history and a broad range of application， which is effective in regulating Qi， relieving pain， resolving depression， and enlivening spleen， as well as dispelling dampness and relieving swelling by external application. It can be used for the treatment of abdominal distension， loss of appetite， and vomiting. Besides， it can also relieve toothache and treat dermatophytosis and pyogenic infection by external use. Moreover， it serves as a common medicinal material in ancient Ayurveda and Unani medical systems in India and also as an ingredient in spices， foods， and cosmetics. Modern pharmacological studies have shown that Nardostachyos Radix et Rhizoma possesses multiple pharmacological activities， such as sedation， anti-epilepsy， anti-convulsion， anti-depression， anti-arrhythmia， anti-malaria， anti-inflammation， anti-bacteria， anti-oxidation， and blood sugar metabolism improvement due to its multiple compounds contained， including terpenes， flavonoids， coumarins， and lignans. The main active components are sesquiterpenoids represented by nardosinone. The pharmacological activities， chemical compositions， and clinical applications of Nardostachyos Radix et Rhizoma have been investigated， but the research on resources， distribution， quality control， cultivation status， and applications are rarely reported. As an important genuine medicinal material from the Qinghai-Tibet plateau， Nardostachyos Radix et Rhizoma is obtained mainly from wild N. jatamansi. Accordingly， the conservation and sustainable utilization of N. jatamansi have attracted much attention all around the world. Based on the resource survey， cultivation research， and relevant literature available， the present study reviewed resources， geographical distribution， chemical compositions， pharmacological activities， quality control， cultivation， and applications of N. jatamansi， aiming to provide references for the conservation and development of N. jatamansi.

Objective: To investigate the effects of artesunate treatment on chronic graft-versus-host disease (cGVHD). Methods: Recipient BALB/c mice received 8 × 10(6) bone marrow cells with 8×10(6) spleen cells from B10D2 mice. Artesunate solubilized in acetone was injected intraperitoneally every day at the dose of 1 mg/kg at Day 28 after BMT. The clinical scores, survival and histopathological damage were analyzed. The frequency of Th17 and Tregs in PB and spleens from the mice were evaluated by flow cytometry. In addition, CD4(+) T cells from the spleens of mice were cultured in vitro, then stimulated with artesunate, the frequency of Th17 and Tregs in these splenocytes were evaluated by flow cytometry. Results: Artesunate administration diminished clinical and histopathological damage, and improved the survival of cGVHD mice[(46.57±7.83)% vs (55.71±6.99)%, χ(2)=5.457, P=0.020]; Artesunate contributed to Tregs development [(4.45±0.04)% vs (8.40±0.23)%, t=15.679, P<0.001; (6.62±0.24)% vs (10.48±0.48)%, t=6.587, P=0.003] while decreased Th17 cells [(1.51±0.18)% vs (0.58±0.19)%, t=7.233, P<0.001; (1.48±0.38)% vs (0.71±0.18)%, t=3.653, P=0.011] expressions in both PB and spleens, and decreased the Th17/Treg ratio (0.34±0.05 vs 0.09±0.03, t=7.621, P=0.002; 0.19±0.03 vs 0.06±0.02, t=6.993, P=0.002). Moreover, artesunate suppressed the Th17 cells expressions [(0.82±0.37) % vs (3.39±1.22) %, t=4.044, P=0.007] and contributed to Tregs development [(34.63±1.29) % vs (14.28±1.69) %, t=19.119, P<0.001], and also decreased the Th17/Treg ratio (0.24±0.09 vs 0.02±0.01, t=4.780, P=0.003) in vitro. Conclusions: Artesunate suppressed the Th17 cells expressions and contributed to Tregs development, which provided new sights into the development of a novel drug for cGVHD, e.g., artemisinin.
Animals ; Artesunate ; Graft vs Host Disease ; Mice ; Mice, Inbred BALB C ; T-Lymphocytes, Regulatory ; Th17 Cells

BackgroundThe influence of different right ventricular lead locations on ventricular arrhythmias (VTA) in patients with a cardiac resynchronization therapy (CRT) is not clear. This study aimed to evaluate the influence on VTA in patients with a CRT when right ventricular lead was positioned at the right ventricular middle septum (RVMS) and the right ventricular apical (RVA).

MethodsA total of 352 patients implanted with a CRT-defibrillator (CRT-D) between May 2012 and July 2016 in the Department of Cardiology of Anhui Provincial Hospital were included. Two-year clinical and pacemaker follow-up data were collected to evaluate the influence of the right ventricular lead location on VTA. Patients were divided into the RVMS group (n = 155) and the RVA group (n = 197) based on the right ventricular lead position. The VTA were compared between these two groups using a Kaplan-Meier curve and Cox multivariate analysis.

ResultsWhen the left ventricular lead location was not considered, RVMS and RVA locations did not affect VTA. However, the subgroup analysis results showed that when the left ventricular lead was positioned at the anterolateral cardiac vein (ALCV), the RVMS group had an increased risk of ventricular arrhythmias and appropriate defibrillation (hazard ratio [HR] = 3.29, P = 0.01 and HR = 4.33, P < 0.01, respectively); when the left ventricular lead was at the posterolateral cardiac vein (PLCV), these risks in the RVMS group decreased (HR = 0.45, P = 0.02 and HR = 0.33, P < 0.01, respectively), and when the left ventricular lead was at the lateral cardiac vein, there was no difference between the two groups. In regard to inappropriate defibrillation, there was no significant difference among all these groups.

ConclusionsWhen the left ventricular lead was positioned at ALCV or PLCV, the right ventricular lead location was associated with VTA and appropriate defibrillation after CRT. Greater distances between leads not only improved cardiac function but also may reduce the risk of VTA.

Objective To discuss the liver function damage mechanism of patients with clonorchiasis by analyzing the ultrasound characteristics, liver function, change of the serum inflammatory factors and cell apoptosis factors. Methods Color Doppler ultrasound technique was adopted to detect the portal vein and blood flow change of patients with clonorchiasis; ELISA was used to determine the level of different serum inflammatory factors. The levels of serum total bilirubin, serum albumin and glutamic-pyruvic transaminase were detected by automatic biochemical analyzer. Western blot was used to determine the expression of proteins relevant to apoptosis. Results Compared with the health control group, the trunk diameter of portal vein and the thickness of spleen, as well as the hepatic artery pulsation index of clonorchiasis patients increased obviously, the mean blood flow velocity of portal vein (P < 0.05 or P < 0.01) decreased. The content of total bilirubin and transaminase in plasma increased significantly, but albumin decreased (P < 0.05). Levels of TNF-α, IL-6 and IFN-γ increased remarkably, and the level of every factor was significantly different among patients with Child-Pugh, Child-Pugh II and Child-Pugh III classification of liver function (P < 0.05 or P < 0.01). With the exacerbation of liver dysfunction, levels of TNF-α, IL-6 and IFN-γ gradually increased (P < 0.05). Compared with the healthy control group, the expression quantity of apoptosis protein Fas, FasL, Bax and Caspase-3 increased significantly (P < 0.05 or P < 0.01), but Bcl-2 decreased (P < 0.05). Conclusions Changes of ultrasonic characteristics and liver dysfunction, caused by liver fluke infection, may be related to that both inflammatory response and apoptosis response have participated in the pathogenic process and liver damage course of clonorchiasis.

PURPOSE: This study was done to analyze how a death preparation education program have the effects on awareness of hospice palliative care and withdrawing life sustaining treatment in older adults. METHODS: This study employed a non-equivalent control group design among quasi-experimental designs. The experimental group was comprised with 35 adults and the control group with 40 adults. The death preparation program consisted of five two-hour sessions and was administered once a week for five straight weeks. Data were analyzed by descriptive statistics, t-test, chi2 test, Fisher's exact test, and ANCOVA using SPSS version 18.0. RESULTS: The mean age of the participants was 66.2 years. A significant difference between the experimental and control groups was observed in withdrawing life sustaining treatment (F=3.380, P=0.040). However, no significant difference was found in awareness of hospice palliative care (F=0.163, P=0.850). CONCLUSION: The study results indicate that death preparation training could positively affect people's awareness of withdrawing life sustaining treatment. More studies should be conducted to explore effects of death preparation education for all ages and help people better understand hospice palliative care.
Adult ; Education* ; Hospices* ; Humans ; Life Support Care ; Palliative Care*

Objective To evaluate the diagnostic value of cardiac magnetic resonance (CMR) in suspected coronary heart disease patients with electrocardiogram abnormalities but normal coronary angiography. Methods The data of 25 suspected coronary heart disease patients with electrocardiogram abnormalities but normal coronary angiography were collected from Taiyuan central hospital between October 2010 and April 2012. Comparison was done in terms of anterior interventricular septal thickness, left ventricular posterior wall thickness, left ventricular end diastolic dimension, left ventricular end systolic dimension, left atrial diameterand ejection fraction measured by CMR and by UCG. Correlation of the aboved paremeters between the 2 imaging exams. Results 40%of patients had their diagnosis changed after CMR exam, 32%of the patients with adjusted assessment. The differences in anterior interventricular septal thickness, left ventricular posterior wall thickness, left ventricular enddiastolic dimension, left ventricular end systolic dimension, left atrial diameter, ejection fraction by CMR and by UCG were similar (P>0.05) with positive correlation (P<0.01). Conclusions CMR can provide diagnosis and evaluation information to chest pain patients with ECG abnormalities but normal CAG, and it is a good supplement for routine examination.

After bathing at a hot spring resort, a 75-year-old man presented to the emergency department because of seizure-like attack with loss of conscious. This is the first case of primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri in Taiwan. PAM was diagnosed based on detection of actively motile trophozoites in cerebrospinal fluid using a wet-mount smear and the Liu's stain. The amoebae were further confirmed by PCR and gene sequencing. In spite of administering amphotericin B treatment, the patient died 25 days later.
Aged ; Amebiasis/*diagnosis/parasitology/*pathology ; Central Nervous System Protozoal Infections/*diagnosis/parasitology/*pathology ; Cerebrospinal Fluid/parasitology ; DNA, Protozoan/chemistry/genetics ; Fatal Outcome ; Humans ; Male ; Microscopy ; Naegleria fowleri/classification/genetics/*isolation & purification ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; Taiwan

OBJECTIVETo study the toxicity features of high glucose on the endothelial cell cycle and the influence of Dan Gua-Fang, a Chinese herbal compound prescription, on the reproductive cycle of vascular endothelial cells cultivated under a high glucose condition; to reveal the partial mechanisms of Dan Gua-Fang in the prevention and treatment of endothelial injury caused by hyperglycemia in diabetes mellitus (DM); and offer a reference for dealing with the vascular complications of DM patients with long-term high blood glucose.

METHODSBased on the previous 3-(4,5)-dimethylthiahiazo (z-y1)-3-5-diphenytetrazoliumromide (MTT) experiment, under different medium concentrations of glucose and Dangua liquor, the endothelial cells of vein-304 (ECV-304) were divided into 6 groups as follows: standard culture group (Group A, 5.56 mmol/L glucose); 1/300 herb-standard group (Group B); high glucose culture group (Group C, 16.67 mmol/L glucose); 1/150 herb-high glucose group (Group D); 1/300 herb-high glucose group (Group E); and 1/600 herb-high glucose group (Group F). The cell cycle was assayed using flow cytometry after cells were cultivated for 36, 72 and 108 h, respectively.

RESULTS(1) The percentage of cells in the G0/G1 phase was significantly increased in Group C compared with that in Group A (P<0.05), while the percentage of S-phase (S%) cells in Group C was significantly reduced compared with Group A (P<0.05); the latter difference was dynamically related to the length of growing time of the endothelial cells in a high glucose environment. (2) The S% cells in Group A was decreased by 30.25% (from 40.23% to 28.06%) from 36 h to 72 h, and 12.33% (from 28.06% to 24.60%) from 72 h to 108 h; while in Group C, the corresponding decreases were 23.05% and 21.87%, respectively. The difference of S% cells between the two groups reached statistical significance at 108 h (P<0.05). (3) The percentage difference of cells in the G2/M phase between Group C and Group A was statistically significant at 72 h (P<0.01). (4) 1/300 Dan Gua-Fang completely reversed the harmful effect caused by 16.67 mmol/L high glucose on the cell cycle; moreover it did not disturb the cell cycle when the cell was cultivated in a glucose concentration of 5.56 mmol/L.

CONCLUSIONSHigh glucose produces an independent impact on the cell cycle. Persistent blocking of the cell cycle and its arrest at the G0/G1 phase are toxic effects of high glucose on the endothelial cell cycle. The corresponding variation of the arrest appears in the S phase. 1/300 Dan Gua-Fang completely eliminates the blockage of high glucose on the endothelial cell cycle.

Cell Cycle ; drug effects ; physiology ; Cells, Cultured ; Culture Media ; pharmacology ; Cytoprotection ; drug effects ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drugs, Chinese Herbal ; pharmacology ; Endothelial Cells ; drug effects ; physiology ; Flow Cytometry ; Glucose ; adverse effects ; Humans