Maternal embryonic leucine zipper kinase serves as a potential prognostic marker and leads to sorafenib chemoresistance modified by miR-142-5p in hepatocellular carcinoma.

BACKGROUND: Chemotherapy is an important treatment strategy for advanced hepatocellular carcinoma (HCC). Sorafenib is a first-line systemic drug that has been commonly used clinically for patients with advanced HCC. However, the high resistance rate of sorafenib in HCC patients often hinders its long-term efficacy. Therefore, it is vital to reveal the molecular mechanisms of sorafenib resistance in patients with HCC. METHODS: In current study, we screened out fourteen genes that over-expressed in HCC specimens through integrative bioinformatics analysis. Here, maternal embryonic leucine zipper kinase (MELK) was highlighted as one of the most probable molecules. The Database for Annotation Visualization and Integrated Discovery (DAVID) program was utilized for functional pathway enrichment analysis. Real-time PCR (RT-PCR) and western blot were used to examine the expression levels of MELK. CCK-8, transwell, colony formation assays and flow cytometry were used to detect cell proliferation, the cell cycle. The dual luciferase assays were performed to study the targeting relationship between MELK and miR-142-5p. RESULTS: MELK expressions were correlated significantly with cell proliferation by regulating cell cycle and DNA replication. High MELK expression in patients with HCC indicated a poor prognosis both the overall and diseases free survival rates. MELK knockdown suppresses cell proliferation, migration and invasion in vitro. miR-142-5p regulates MELK expression through binding to the complementary sequence in the 3'-UTR regions. MELK knockdown enhances sensitivity of sorafenib in HCC sorafenib-resistant (HCC/SR) cells. CONCLUSIONS: MELK may serve as a potential prognostic marker in HCC and MELK knockdown enhanced sensitivity of HepG2/SR cells to sorafenib treatment. Our findings suggest that MELK/miR-142-5p axis could be a potentially therapeutic target for reversing the sorafenib resistance in HCC treatment.

MicroRNA-34a-mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting.

We investigated the role of leukemia stem cells in chemoresistance and recurrence of acute myeloid leukemia. Total RNA was isolated from cells or tissues using TRIzol reagent. Cell viability was assessed with the tetrazolium assay. MicroRNA-34a (miR-34a), which acts on cell death regulation pathways, was noticeably downregulated in non-M3 acute myeloid leukemia stem cells compared with normal hematopoietic stem cells. Furthermore, inhibition of miR-34a-mediated suppression in leukemia stem cells was associated with poor clinical outcomes and impaired treatment efficacy in acute myeloid leukemia. Transfection with a miR-34a mimic triggered leukemia stem cell death and prevented leukemia. Bioinformatics analysis and a dual-luciferase reporter assay showed that miR-34a targeted the 3'-untranslated region of histone deacetylase 2, and the reinforced expression of miR-34a remarkably stimulated the expression of histone deacetylase 2 in leukemia stem cells. Ectopic miR-34a expression triggered death of leukemia stem cells via pathways involving the Janus kinase 1-signal transducer and activator of transcription 2-p53 axis. Targeting leukemia stem cells to trigger cell death through upregulation of miR-34a expression could be used to diagnose and treat acute myeloid leukemia.

Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study.

Ketamine abuse has been shown to have a deleterious impact on brain function. However, the precise mechanisms of ketamine dependence-induced pathological change remain poorly understood. Although there is evidence for white matter changes in drug abuse, the presence of white matter abnormalities in chronic ketamine users has not been studied. White matter volumes were measured using in vivo diffusion tensor magnetic resonance imaging data in 41 ketamine-dependent subjects and 44 drug-free healthy volunteers. White matter changes associated with chronic ketamine use were found in bilateral frontal and left temporoparietal cortices. There was also evidence that frontal white matter fractional anisotropy correlated with the severity of drug use (as measured by estimated total ketamine consumption). We provide direct evidence for dose-dependent abnormalities of white matter in bilateral frontal and left temporoparietal regions following chronic ketamine use. The findings suggest a microstructural basis for the changes in cognition and experience observed with prolonged ketamine use. Moreover, the similarities of these changes to those observed in chronic schizophrenia have implications for the glutamate model of this illness.

[Follow-up study on refractory schizophrenia with brain stereotaxis therapy].

OBJECTIVE: To determine the long-term effect and security of refractory schizophrenia with brain stereotaxis multi-target therapy technique. METHODS: A total of 87 patients with refractory schizophrenia were treated with brain stereotaxis multi-target therapy and were followed up over 2 years. The scores of Clinical Global Impression, Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale, Wechsler Adult Intelligence Scale, Wechsler Memory Scale, Actives of Daily Living, and Social Disability Screening Schedule were compared before and after the operation. RESULTS: Of the 87 patients, 40 obviously improved, 24 improved, 12 improved little, 7 did not change. None grew worse, 1 died, and 3 shed. There was a significant difference in the scales before and after the operation (P<0.01). No severe complications and sequelae occurred. CONCLUSION: Stereotaxic multi-target therapy is effective and safe for refractory schizophrenia. After the operation, drug therapy should be maintained and recovery of social function is helpful.

miR-200b regulates breast cancer cell proliferation and invasion by targeting radixin.

Radixin is an important member of the Ezrin-Radixin-Moesin protein family that is involved in cell invasion, metastasis and movement. microRNA (miR)-200b is a well-studied microRNA associated with the development of multiple tumors. Previous bioinformatics analysis has demonstrated that miR-200b has a complementary binding site in the 3'-untranslated region of radixin mRNA. The present study aimed to investigate the role of miR-200b in regulating radixin expression, cell proliferation and invasion in breast cancer. Breast cancer tissues at different Tumor-Node-Metastasis (TNM) stages were collected; breast tissues from patients with hyperplasia were used as a control. miR-200b and radixin mRNA expression levels were tested by reverse transcription-quantitative PCR. Radixin protein expression was detected by western blotting. The highly metastatic MDA-MB-231 cells were divided into four groups and transfected with a miR-negative control (NC), miR-200b mimic, small interfering (si)RNA-NC or siRNA targeting radixin. Cell invasion was evaluated by Transwell assay and cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine staining. Compared with the control group, radixin mRNA expression was significantly higher in breast cancer tissues and increased with TNM stage. miR-200b expression levels exhibited the opposite trend. Radixin mRNA expression in breast cancer cells was notably higher, whereas miR-200b expression was lower compared with that in normal breast epithelial MCF-10A cells. The expression of radixin was higher, whereas miR-200b was lower in MDA-MB-231 cells compared with that in MCF-7 cells. miR-200b mimic or siRNA-radixin transfection downregulated the expression of radixin in MDA-MB-231 cells and attenuated the invasive and proliferative abilities of these cells. miR-200b-knockdown and radixin overexpression were associated with enhanced cell invasion in breast cancer. In conclusion, miR-200b regulates breast cancer cell proliferation and invasion by targeting radixin expression.

Effects of various treatment approaches for treatment efficacy for late stage breast cancer and expression level of TIMP-1 and MMP-9.

Breast cancer is one common female specific malignant tumor and has gradually increased incidence. Matrix metalloproteinase-9 (MMMP-9) and its inhibitor TIMP-1 participate in tumor invasion and metastasis. This study analyzed the effect of various treatment approaches on TIMP-1 and MMP-9 levels in terminal stage breast cancer. Post-op breast cancer patients including chemo-radio therapy group, radio-chemo therapy group and simultaneously chemo- and radio-therapy group were compared for efficacy, along with assays for TIMP-1 and MMP-9 levels for analyzing their correlation with clinical-pathological features of breast cancer. Chemo + radio-therapy group had lower focal recurrence and distal metastasis than the other two groups, plus higher 5-year survival rates (p<0.05). After treatment, all patients showed lower serum MMP-9 level, activity and higher TIMP-1 levels than those before treatment (p< 0.05). Concurrent radio + chemo-therapy group showed lower serum MMP-9 level, activity and higher TIMP-1 levels (p< 0.05 compared to the other two groups). Serum MMP-9 and TIMP-1 levels after treatment are correlated with patient age, pathological grade, tumor size and lymph node metastasis (p< 0.05). Simultaneous chemo- and radio-therapy on breast cancer patients after surgery could reduce focal recurrent rate or distal metastasis rate, thus improving 5-year survival rate. MMP-9 and TIMP-1 levels are correlated with age, pathological grade, tumor size and lymph node metastasis of breast cancer patients.

Effects of Jinkui Shenqi and Wuzi Yanzong pill on sperm motility and sperm DNA fragmentation rate in asthenospermia

This study was designed to compare the effects of Jinkui Shenqi and Wuzi Yanzong pill on sperm motility and sperm DNA fragmentation rate in patients with asthenospermia. 130 cases were randomly divided into an observation and control group (n=65). The control group was treated with the Wuzi Yanzong pill while the observation group with the Jinkui Shenqi pill. The sperm motility parameters rate (PR), semen concentration, sperm motility, DFI and α-glucosidase, fructose, seminal plasma zinc (Zn), acid phosphatase (ACP) in seminal plasma biochemistry and other indexes of were observed. The biochemical indexes of seminal plasma of α-glucosidase, fructose, Zn, ACP in two groups were significantly (p<0.05) improved after treatment. Compared with the control group, the indexes of the observation group improved more obviously after treatment. Pearson correlation analysis of DFI and PR indexes in 130 patients before treatment showed that sperm DFI and PR percentage were negatively correlated in asthenospermia patients (r =-0.572, P<0.05). There was no significant difference in DFI, semen concentration, PR, and sperm motility between the two groups before treatment. The DFI, semen concentration, PR and sperm viability of the two groups showed a tendency to improve after treatment, and the effect of the observation group was less significant than that of the control group (p<0.05). Two groups of patients have completed treatment successfully, no adverse events occurred during treatment. Jinkui Shenqi pill can effectively treat asthenospermia, which can effectively improve the effect of sperm motility in patients. It has less adverse reactions, safe and reliable, and is worthy of promotion.

The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and antisocial personality disorder in male heroin-dependent Chinese subjects.

OBJECTIVE: To explore the association between the 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR polymorphisms with comorbidity of antisocial personality disorder in male heroin-dependent patients. SUBJECTS AND METHODS: In case control study, we compared the polymorphic distributions of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR in 588 male heroin-dependent patients (including 311 patients with antisocial personality disorder and 277 patients without antisocial personality disorder) and 194 normal males by genotypes, alleles, and interaction between genes. RESULTS: Between male heroin-dependent patients with antisocial personality disorder and normal males, and between male heroin-dependent patients with and without antisocial personality disorder, the distributions of 5-HTTVNTR polymorphic genotypes and alleles were in statistical significance. Individuals carrying 10R allele were in higher risk of the comorbidity of antisocial personality disorder and heroin dependence. By MDR analyses, the interaction between 5-HTTVNTR and DATVNTR was close to statistical significance in predicting the risk of antisocial personality disorder in male heroin dependent patients. In male heroin dependent patients, individuals carrying 5-HTTVNTR 10R allele or/and DATVNTR 9R allele were in higher risks of co-occurring antisocial personality disorder, while individuals with 5-HTTVNTR 12R/12R and DATVNTR 10R/10R genotypes together were in lower risks of antisocial personality disorder. CONCLUSION: 5-HTTVNTR, and the interaction between 5-HTTVNTR and DATVNTR may be associated with the comorbidity of antisocial personality disorder in male heroin-dependent patients.