OBJECTIVE: To investigate the effect of Arsenic trioxide (ATO) combined with Norcantharidin (NCTD) on the proliferation and apoptosis of Jurkat cells, and to evaluate its effect on the proliferation and apoptosis of acute T-lymphoblastic leukemia (T-ALL) based on the Wnt/β-catenin signaling pathway. METHODS: Jurkat cell lines were used as the study subjects and treated with different concentrations of ATO (0, 2, 4, 8, 16 μmol/L) and NCTD (0, 10, 25, 50, 100 μmol/L) for 72 hours, and the cell proliferation was detected by CCK-8. Meanwhile, flow cytometry was used to detect the apoptosis rate, EdU staining to detect cell proliferation viability, cell clone formation assay to assess cell cloning ability, Transwell assay to assess cell invasion ability, and Western blot to detect apoptosis and the expression of Wnt/β-catenin signaling pathway-related proteins. RESULTS: Compared with the control group, both ATO and NCTD effectively inhibited Jurkat cell proliferation when used alone, and the inhibition effect was more significant when used in combination ( P < 0.05). The combination significantly increased the apoptosis rate of Jurkat cells ( P < 0.05). Meanwhile, the combination significantly decreased the proliferation vitality and clone formation ability of the cells ( P < 0.05), and inhibited the invasion ability of Jurkat cells ( P < 0.05). Western blot analysis showed that the combination of ATO and NCTD significantly up-regulated the expression of pro-apoptotic proteins Bax and E-cadherin, and down-regulated the expression of anti-apoptotic proteins Bcl-2, c-myc and Cyclin D1 ( P < 0.05). CONCLUSION The combination of ATO and NCTD had a synergistic effect in inhibiting proliferation and promoting apoptosis in Jurkat cells, which may be related to the inhibition of Wnt/β-catenin signaling pathway.
Humans ; Apoptosis/drug effects* ; Jurkat Cells ; Cell Proliferation/drug effects* ; Arsenic Trioxide ; Wnt Signaling Pathway/drug effects* ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology* ; beta Catenin/metabolism* ; Arsenicals/pharmacology* ; Oxides/pharmacology*

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from ¹³C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Objective To investigate the relieving effects of knockdown of long non-coding RNA(lncRNA)taurine up-regulated gene 1 (TUG1) on inhibiting nucleotide binding oligomerization domain like receptor protein 1 (NLRP1) inflammasome and the progression of Alzheimer’ s disease. Methods Wild-type (WT group, 10 mice) or amyloid precursor protein (APP) / presenilin-1 (PS1) transgenic mice (30 mice) with a genetic background of C57 / BL6 aged 9-10 weeks were used in this study. APP / PS1 transgenic mice were randomly divided into model group, model+lncRNA TUG1 short hairpin RNA (shRNA) group and model + shRNA non target (NT) group (n = 10) . Blood samples, cerebral cortex tissues, primary microglial cells and primary astrocytes were collected from mice 12 weeks of age on day 1 (3-month-old) and 32 weeks of age on day 1 (8-month-old), with 5 mice per group at each time point. Real-time PCR analysis was used to detect the expression levels of lncRNA TUG1 and macrophage migration inhibitory factor (MIF) mRNA in cerebral cortex tissues and primary microglial cells, and C1r and C1s mRNA levels in primary astrocytes of 3-month-old and 8-month-old mice in the above 4 groups, respectively. ELISA was used to determine the MIF in plasma samples of the above 4 groups of mice. Primary microglia and astrocytes from the cerebral cortex of 3-month-old and 8-month-old mice were co-cultured. CCK-8 method was used to determine the proliferation ability of the above cells. Western blotting was used to determine the expression levels of MIF, pro interleukin-1β (pro-IL-1β), apoptosis associated speck-like protein containing a caspase recrult domain(ASC), Caspase-1 (p20), Caspase-1 (full), NLRP1 and NLRP3 in cerebral cortex tissues of 3-month-old and 8-month-old mice. Immunofluorescent staining was used to determine amyloid beta(Aβ) in cerebral cortex of 8-month-old mice. Results At the age of 3-month-old and 8-month-old, compared with the WT group, the relative expression level of lncRNA TUG1 and MIF in cerebral cortex tissues and primary microglia of model group mice was significantly up-regulated, with primary microglial cells and astrocytes proliferation ability enhanced (P<0. 05) . Compared with the model group, the relative expression level of lncRNA TUG1 and MIF cerebral cortex tissues and primary microglia of model + lncRNA TUG1 shRNA group were significantly down-regulated, with primary microglial cells and astrocytes proliferation ability decreased (P<0. 05) . Compared with the WT group, MIF factor in the peripheral plasma of model group increased significantly, with pro-IL-1β,ASC,Caspase-1 (p20),Caspase-1 (full), NLRP1 and NLRP3 expression level up-regulated in the model group mice cerebral cortex tissues, with increased Aβ immunofluorescent indensity (P<0. 05) . Compared with the model group, MIF factor in the peripheral plasma, and pro-IL-1β, ASC, Caspase-1 (p20), Caspase-1 (full) and NLRP1 expression in the model + lncRNA TUG1 shRNA group mice cerebral cortex tissues were down-regulated, and Aβ immunofluorescent indensity decreased (P<0. 05), while NLRP3 expression level were not changed (P>0. 05) . There was no significant difference between the model group and the model+shRNA NT group mice of all the above factors (P>0. 05) . Conclusion In APP / PS1 transgenic mice, up-regulation of lncRNA TUG1 and MIF are positively associated with the activation of NLRP1 inflammasome in mice cerebral cortex tissues and primary microglia. Knock-down of lncRNA TUG1 can ameliorate the progression of Alzheimer’ s disease.

Objective: To investigate the safety and efficacy of troxatabine in advanced or relapsed malignant tumors resistant to standard therapy in China. Methods: This is a phase Ⅰ prospective study. During dose escalation, patients in Cancer Hospital, Chinese Academy of Medical Sciences received a single-dose intravenous infusion of troxacitabine. The planned dosing groups were 1.8, 3.6, 4.8, 6.4 and 8.0 mg/m(2) on days 1 and 8 every 3 weeks. The data of all patients were collected for safety analyses. Safety and tolerability were evaluated by monitoring adverse events. Results: Nineteen patients were enrolled from April 2018 to May 2019. The major adverse events were fatigue (89.5%, 17/19), leukopenia (84.2%, 16/19) and neutropenia (78.9%, 15/19). The dose limiting toxicity was neutropenia. The maximum tolerated dose was 6.4 mg/m(2). The best effect was stable disease (43.8%). The half-life of elimination phase from 15.91 hours to 76.63 hours in each dose group. Conclusions: The toxicity of troxacitabine is well tolerant. We recommend that the dose for Phase Ⅱ clinical trial should be 6.4 mg/m(2).
Humans ; Antineoplastic Agents/adverse effects* ; Maximum Tolerated Dose ; Neoplasms/drug therapy* ; Neutropenia/chemically induced* ; Prospective Studies

Humans ; Philadelphia Chromosome ; Neoplasms ; Myelodysplastic Syndromes/genetics* ; Disease Progression

OBJECTIVE: To report on a case with severe hemophilia A (HA) due to a large duplication of F8 gene. METHODS: Inversion detection, Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used to detect the mutation in the proband and his mother. RESULTS: The patient, a 7-year-old boy, was diagnosed with severe HA at 8 months. No inhibitor was developed over 150 exposure days. Intronic inversion detection and Sanger sequencing have failed to identify pathogenic variants, while MLPA revealed a large duplication [Ex 1_22 dup (2 copies)] in the proband, for which his mother was a carrier [Ex 1_22 dup (3 copies)]. Large duplications of the F8 gene have so far been found in 24 HA patients, all of whom had a severe phenotype, only one had a history of inhibitors. CONCLUSION Large duplications of F8 gene are associated with severe HA. The diagnostic rate for HA may be increased by MLPA.
Child ; Factor VIII/genetics* ; Gene Duplication ; Hemophilia A/genetics* ; Humans ; Introns ; Male ; Mutation ; Phenotype

Humans ; Lymphoma, B-Cell/pathology* ; Lymphoma, Non-Hodgkin/pathology*

Reduced levels of retinal dopamine, a key regulator of eye development, are associated with experimental myopia in various species, but are not seen in the myopic eyes of C57BL/6 mice, which are deficient in melatonin, a neurohormone having extensive interactions with dopamine. Here, we examined the relationship between form-deprivation myopia (FDM) and retinal dopamine levels in melatonin-proficient CBA/CaJ mice. We found that these mice exhibited a myopic refractive shift in form-deprived eyes, which was accompanied by altered retinal dopamine levels. When melatonin receptors were pharmacologically blocked, FDM could still be induced, but its magnitude was reduced, and retinal dopamine levels were no longer altered in FDM animals, indicating that melatonin-related changes in retinal dopamine levels contribute to FDM. Thus, FDM is mediated by both dopamine level-independent and melatonin-related dopamine level-dependent mechanisms in CBA/CaJ mice. The previously reported unaltered retinal dopamine levels in myopic C57BL/6 mice may be attributed to melatonin deficiency.
Animals ; Disease Models, Animal ; Dopamine ; Melatonin ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Myopia ; Retina ; Sensory Deprivation

Objective:To investigate the influencing factors of delayed methotrexate (MTX) elimination after high-dose methotrexate (HD-MTX) treatment in children with acute lymphoblastic leukemia (ALL) and the effects of delayed MTX elimination and HD-MTX reduction on the prognosis of children with ALL.Methods:The clinical data of 242 children with ALL diagnosed and treated in Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2015 to June 2020 in accordance with the Chinese Children's Cancer Group study ALL 2015 (CCCG-ALL 2015) were retrospectively analyzed. Low risk and intermediate/high risk children respectively received 3 g/m 2 and 5 g/m 2 HD-MTX for 4 times, and the serum MTX concentration was monitored. The serum MTX concentration > 1 μmol/L at 44 h of administration was considered as the delayed elimination, which was divided into mild (> 1 μmol/L and ≤ 5 μmol/L), moderate (> 5 μmol/L and ≤ 10 μmol/L) and severe (> 10 μmol/L) delayed elimination. Univariate and multivariate logistic regression analysis were used to analyze the influencing factors of delayed MTX elimination, and univariate Cox proportional hazards model was used to analyze the related factors of ALL relapse. Results:The 242 children with ALL completed 962 times of HD-MTX chemotherapy. The median serum MTX concentration [ M ( Q1, Q3)] at 44 h of administration was 0.45 μmol/L (0.33 μmol/L, 0.72 μmol/L). The total incidence of delayed MTX elimination was 17.7% (170/962). The incidence of mild, moderate and severe delayed elimination was 13.8% (133/962), 2.6% (25/962) and 1.2% (12/962), respectively. Logistic regression analysis showed that age ≥ 7 years old ( OR = 1.68, 95% CI 1.17-2.41, P = 0.005), MTX dose >3 g/m 2 at each course ( OR = 2.14, 95% CI 1.52-3.03, P < 0.001) and the first course of HD-MTX chemotherapy ( OR = 2.05, 95% CI 1.43-2.93, P < 0.001) were independent risk factors for delayed MTX elimination. The median follow-up time was 50 months (34 months, 68 months), 12.8% (31/242) of the children relapsed, and the median relapse time was 30 months (30 months, 39 months). Univariate Cox regression analysis showed that there were no significant differences in the relapse rates among children with different gender, immunophenotype, risk, the number of delayed MTX elimination, and the completion of HD-MTX chemotherapy (the ratio of MTX average dose to initial planned dose) (all P > 0.05). Conclusions:The independent risk factors of delayed elimination of MTX in children with ALL are age ≥ 7 years old, MTX dose > 3 g/m 2 at each course and the first course of HD-MTX chemotherapy. Delayed elimination of MTX and reduction of HD-MTX have no significant effect on ALL relapse.

Objective To explore the performance of mobile health platform for standardized management of pregnant women with gestational diabetes mellitus(GDM). Methods A randomized controlled trial was conducted,in which 295 women with GDM were randomized into two groups(traditional management group and mobile health management group)by a computer-generated sequence.The traditional management group accepted standardized GDM management,and the mobile health management group was supplemented by mobile health management based on the standardized management.The glycemic control rate and the incidences of low birth weight,macrosomia,preterm birth,premature rupture of membranes,postpartum hemorrhage after cesarean section,neonatal asphyxia,malformation,and admission to the neonatal intensive care unit were compared between the two groups. Results The glycemic control rate in mobile health management group was significantly higher than that in the traditional management group [(67.22±22.76)%
Cesarean Section ; Diabetes, Gestational/therapy* ; Female ; Fetal Macrosomia ; Humans ; Infant, Newborn ; Pregnancy ; Pregnancy Outcome ; Premature Birth ; Telemedicine