The role and mechanism of AZD5363 anti-leukemia activity in T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous hematologic malignancy. Chemotherapy resistance and refractory relapses are the most important challenges in T-ALL. PI3K/Akt/mTOR pathway has been implicated in regulating cell survival, T-ALL development and resistance to chemotherapy. We explored the effects of AZD5363 (a potent pan-Akt inhibitor) alone and in combination with autophagy inhibitor hydroxycholoroquine sulfate (HCQ) in cultured CCRF-CEM, Jurkat and PF382 cells and a T-ALL xenograft mouse model. METHODS: A xenograft mouse model was used to investigate the effect of AZD5363 on T-ALL progression. MTT assay, flow cytometry, siRNA, transmission electron microscopy and western blotting were performed in cultured CCRF-CEM, Jurkat and PF382 cells. The interaction between AZD5363 and HCQ was explored by molecular docking. RESULTS: AZD5363 delayed T-ALL progression and increased the expression of cleaved caspase-3 and LC3B-II in mice. AZD5363 decreased cells viability by arresting cell cycle in the G1 phase and inducing apoptosis, and, significantly increased the number of autophagosomes (p < 0.01). The increased expression of cleaved caspase-3 and LC3B-II, and phosphorylation of Akt and mTOR were significantly, inhibited by AZD5363. HCQ blocked AZD5363-induced autophagy and enhanced AZD5363-induced cell death (p < 0.01). CONCLUSIONS: AZD5363 suppressed T-ALL progression and its anti-leukemia activity was enhanced by HCQ in T-ALL cells, which might provide a potential therapeutic strategy for human T-ALL.

A case report of neurosyphilis coexisting with a positive MOG antibody manifested as optic neuritis.

Background: Neurosyphilis refers to an infection of the central nervous system by Treponema pallidum. The clinical manifestations of neurosyphilis are diverse, making it easy to miss or misdiagnose. Anti-myelin oligodendrocyte glycoprotein antibody-associated disease is a recently defined immune-mediated inflammatory demyelinating central nervous system disease. Few studies have reported the coexistence of the two diseases. Case presentation: This case report presents a 37 years-old male patient with neurosyphilis manifested as optic neuritis with a positive myelin oligodendrocyte glycoprotein (MOG) antibody. This patient received intravenous administration of 3.2 million units of procaine penicillin every 4 h for 2 weeks, followed by a two-week intramuscular injection of benzathine penicillin. Additionally, methylprednisolone sodium succinate was administered intravenously at 1,000 mg/day, gradually reduced to 500 mg/day and 240 mg/day every 3 days. Subsequently, prednisone tablets at a dosage of 60 mg/day were orally administered, with a gradual reduction of 5 mg/day every 3 days until reaching a dosage of 30 mg/day. The patient's visual acuity was improved after 26 days of hospitalization. However, the visual field and color vision did not. At 3 months of follow-up, the symptoms remained unchanged despite the patient continued taking oral prednisone tablets at a dosage of 30 mg/day. Conclusion: Neurosyphilis could be a potential triggering factor for MOGAD. In patients with neurosyphilis, it is strongly recommended to perform testing for MOG antibody along with other brain disease antibodies.

Targeted delivery of AZD5363 to T-cell acute lymphocytic leukemia by mSiO2-Au nanovehicles.

T-cell acute lymphocytic leukemia (T-ALL) is the most common cancer in children, with a low survival rate because of drug resistance and a high recurrence rate. Targeted delivery of chemotherapy drugs can reduce their side effects and improve their efficacy. The abnormality of phosphatidylinositol-3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway plays a key role in T-ALL occurrence. AZD5363 is a selective Akt inhibitor with promising therapeutic potential for tumors encoded by the PI3K/Akt/mTOR pathway. However, the toxicity and side effects have limited its application in treating T-ALL. This study aimed to design a delivery system for targeting AZD5363 to T-ALL by sgc8c aptamer designed as mesoporous silica (mSiO2) decorated with Au nanoparticles. The cell-specific targeting and cytotoxicity of mSiO2-Au-AZD5363-Apt were investigated. The mSiO2-Au nanovehicles were found feasible for AZD5363 delivery, with high loading efficiency and pH-responsive release in the acidic lysosome. More importantly, mSiO2-Au-AZD5363-Apt nanovehicles could specifically recognize and enter T-ALL cells in vitro and in vivo, effectively inhibiting the proliferation of CCRF-CEM cells. In conclusion, mSiO2-Au-AZD5363-Apt provided an effective therapeutic method for the targeted treatment of T-ALL.

The Function of the Autonomic Nervous System in Asian Patients With Chronic Migraine.

Background: The pathogenic mechanisms underlying the autonomic nervous system (ANS) dysfunction in patients with chronic migraine (CM) remain unclear. This study investigated the pathogenesis of ANS dysfunction in this population. Methods: A total of 60 patients diagnosed with CM and 60 healthy subjects were recruited to participate in this study. The pupil diameter, pupil contraction velocity, latency, amplitude, and the maximum gradient recovery time were examined before, at 2 min and at 5 min after the cold pressor test, which was combined with the pupillary light reflex method. A brain 3D T1-weighted structural imaging scan, resting-state functional magnetic resonance imaging scan, and diffusion tensor imaging (DTI) scan were also acquired. Results: Patients with CM exhibited a longer recovery time to the maximum gradient at 2 min and at 5 min after cold pressing compared with the control group (P < 0.01 and P < 0.05, respectively). There was no significant difference in the pupil diameter, pupillary contraction velocity, latency, amplitude, blood pressure, or heart rate between the two groups (all P > 0.05). In the CM group, the regional homogeneity (ReHo) values of the left amygdala and left lateral hypothalamic area were significantly higher than those of other brain areas (P < 0.001, Alphasim corrected). The DTI scan of the whole brain area showed a lack of significant difference in DTI indices, including FA, MD, AD, and RD values between the two groups (P > 0.05, Alphasim corrected). Conclusion: The dysfunction of the left amygdala and left lateral hypothalamic area may be related to ANS dysfunction in patients with CM.

Identification of four novel hub genes as monitoring biomarkers for colorectal cancer.

BACKGROUND: It must be admitted that the incidence of colorectal cancer (CRC) was on the rise all over the world, but the related treatment had not caught up. Further research on the underlying pathogenesis of CRC was conducive to improving the survival status of current CRC patients. METHODS: Differentially expressed genes (DEGs) screening were conducted based on "limma" and "RobustRankAggreg" package of R software. Weighted gene co-expression network analysis (WGCNA) was performed in the integrated DEGs that from The Cancer Genome Atlas (TCGA), and all samples of validation were from Gene Expression Omnlbus (GEO) dataset. RESULTS: The terms obtained in the functional annotation for primary DEGs indicated that they were associated with CRC. The MEyellow stand out whereby showed the significant correlation with clinical feature (disease), and 4 hub genes, including ABCC13, AMPD1, SCNN1B and TMIGD1, were identified in yellow module. Nine datasets from Gene Expression Omnibus database confirmed these four genes were significantly down-regulated and the survival estimates for the low-expression group of these genes were lower than for the high-expression group in Kaplan-Meier survival analysis section. MEXPRESS suggested that down-regulation of some top hub genes may be caused by hypermethylation. Receiver operating characteristic curves indicated that these genes had certain diagnostic efficacy. Moreover, tumor-infiltrating immune cells and gene set enrichment analysis for hub genes suggested that there were some associations between these genes and the pathogenesis of CRC. CONCLUSION: This study identified modules that were significantly associated with CRC, four novel hub genes, and further analysis of these genes. This may provide a little new insights and directions into the potential pathogenesis of CRC.

Neural tube defects: role of lithium carbonate exposure in embryonic neural development in a murine model.

BACKGROUND: Lithium carbonate (Li2CO3) is widely used in the treatment of clinical-affective psychosis. Exposure to Li2CO3 during pregnancy increases the risk of neural tube defects (NTDs) in offspring, which are severe birth defects of the central nervous system. The mechanism of Li2CO3-induced NTDs remains unclear. METHODS: C57BL/6 mice were injected with different doses of Li2CO3 intraperitoneally on gestational day 7.5 (GD7.5), and embryos collected at GD11.5 and GD13.5. The mechanisms of Li2CO3 exposure-induced NTDs were determined utilizing immunohistochemistry, western blotting, EdU imaging, enzymatic method, gas chromatography-mass spectrometry (GC-MS), ELISA and HE staining. RESULTS: The NTDs incidence was 33.7% following Li2CO3 exposure. Neuroepithelial cell proliferation and phosphohistone H3 level were significantly increased in NTDs embryos, compared with control group (P < 0.01), while the expressing levels of p53 and caspase-3 were significantly decreased. IMPase and GSK-3ß activity was inhibited in Li2CO3-treated maternal and embryonic neural tissues (P < 0.01 and P < 0.05, respectively), along with decreased levels of inositol and metabolites, compared with control groups (P < 0.01). CONCLUSIONS: Lithium-induced NTDs model in C57BL/6 mice was established. Enhanced cell proliferation and decreased apoptosis following lithium exposure were closely associated with the impairment of inositol biosynthesis, which may contribute to lithium-induced NTDs. IMPACT: Impairment of inositol biosynthesis has an important role in lithium exposure-induced NTDs in mice model. Lithium-induced NTDs model on C57BL/6 mice was established. Based on this NTDs model, lithium-induced impairment of inositol biosynthesis resulted in the imbalance between cell proliferation and apoptosis, which may contribute to lithium-induced NTDs. Providing evidence to further understand the molecular mechanisms of lithium-induced NTDs and enhancing its primary prevention.

Non-pharmacological treatments for irritable bowel syndrome: study protocol of an umbrella review of systematic review and meta-analyses.

INTRODUCTION: Non-pharmacological treatments are used in the management of irritable bowel syndrome, and their effectiveness has been evaluated in multiple meta-analyses. The robustness of the results in the meta-analyses was not evaluated. We aimed to assess whether there is evidence of diverse biases in the meta-analyses and to identify the treatments without evidence of risk of bias. METHODS AND ANALYSIS: We will search MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science and CINAHL Plus for meta-analyses that evaluate the effectiveness of non-pharmacological treatments. The time of publication will be limited from inception to December 2018. The credibility of the meta-analyses will be evaluated by assessing between-study heterogeneity, small-study effect and excess significance bias. The between-study heterogeneity will be assessed using the Cochrane's Q test, and the extent of the heterogeneity will be classified using the I2 statistics. The existence of a small-study effect in a meta-analysis will be evaluated using the funnel plot method and confirmed by Egger's test. Excess significance bias will be evaluated by comparing the expected number of clinical studies with positive findings with the observed number. ETHICS AND DISSEMINATION: No formal ethical approval is required since we will use publicly available data. We will disseminate the findings of the umbrella review through publication in a peer-reviewed journal and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42018111516.

Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance.

AIM: To study the effect of rescue monotherapy with adefovir (ADV) in patients with chronic hepatitis B (CHB) who developed drug resistance to lamivudine (LAM). METHODS: A total of 76 treated CHB patients with resistance to LAM were enrolled in the present study. The patients' baseline characteristics, such as age, gender, blood tests and hepatitis B virus (HBV) DNA were collected; therapy duration and the response of each patient were also recorded. ADV monotherapy was set as the observation group A. Twenty-four patients with LAM resistance, who were set as group B, accepted combined therapy with LAM + ADV. Patients were followed up at 0, 12, 24, 52, 104 and 156 wk. Hepatitis B surface antigen status, hepatitis B e antigen (HBeAg)/anti-HBe status, HBV DNA level and biochemical indexes were monitored. Sequencer of HBV polymerase gene was performed on the ABI 3730 automated sequencer. If no desired effects had been achieved during the course of treatment, patients' choices were also taken into account. The control group was tested at the same time. RESULTS: In the two groups, 27 cases developed viral breakthrough after LAM treatment response. The remaining 49 cases underwent biochemical rebound accompanied by rtM204I/V or rtL180M mutation. In group A, 52 cases finished 156 wk of ADV monotherapy; of whom, 36 cases were HBeAg positive and 16 HBeAg negative. In patients whose baseline HBV DNAs were 10(3)-10(5) copies/mL, 88.8% of patients' HBV DNAs were lower than the lower test limit (10(3) copies/mL) after 12 to 156 wk of ADV treatment. In patients whose baseline HBV DNAs were ≥ 10(6) copies/mL, 41.1%-47.0% of patients' HBV DNAs were lower than the lower test limit after the same course of ADV therapy (χ(2) were 4.35-5.4, 41.1%-47.0% vs 88.8% group 10(3)-10(5) copies/mL, P < 0.01). In group A, seroconversion of HBeAg developed in 8 of 36 cases (22.2%). In group B, 24 cases finished 156 wk of LAM + ADV; of whom, 17 cases were HBeAg positive and 7 HBeAg negative. In patients whose baseline HBV DNAs were 10(3)-10(5) copies /mL, 81.8% of patients' HBV DNAs were lower than the lower test limit (10(3) copies/mL) after 12 to 156 wk of treatment. In the patients whose baseline HBV DNAs were ≥ 10(6) copies/mL, 46.1%-53.8% of patients' HBV DNAs were lower than the lower test limit after the same course of LAM + ADV therapy (χ(2) were 4.1-5.0, 46.1%-53.8% vs 81.8% group 10(3)-10(5) copies/mL, P < 0.05-0.01). In group B, 4 of 17 cases (23.5%) developed seroconversion of HBeAg. Treatment outcomes in groups A and B were comparable. CONCLUSION: In both group A and B, the ratios of virological response have similar efficacy in patients with lower baseline HBV DNAs.