Pharmacological treatment of Tourette's syndrome: from the past to the future.

Tourette's syndrome (TS) is a neuropsychiatric disease featuring tics and vocal tics, with a prevalence of approximately 1%, including 75% of the total number of male patients. TS seriously disturbs the patients' career, education, and life and brings a serious and unbearable psychological burden to the patients themselves and their families. At present, there are no specific clinical medications recommended for treating TS. Therefore, it is necessary to select the appropriate medication for symptomatic treatment based on the doctor's personal experience and the patient's symptoms, with the main goal of relieving symptoms, thus improving the patient's social skills and psychological problems. Here we conducted a comprehensive search on PubMed to review and organize the history and current status of the development of drug therapy for TS through a timeline format. We also systematically evaluated the effects of each drug for TS treatment to summarize the current problems and new research directions and to provide some ideas for clinical treatment.

Construction of a novel nomogram based on competing endogenous RNAs and tumor-infiltrating immune cells for prognosis prediction in elderly patients with colorectal cancer.

Competitive endogenous RNAs (ceRNAs) and tumor-infiltrating immune cells play essential roles in colorectal cancer (CRC) tumorigenesis. However, their prognostic role in elderly patients with CRC is unclear. Gene expression profiles and clinical information for elderly patients with CRC were downloaded from The Cancer Genome Atlas. Univariate, LASSO, and multivariate Cox regression analyses were utilized for screening key ceRNAs and prevent overfitting. A total of 265 elderly patients with CRC were included. We constructed a novel ceRNA network consisting of 17 lncRNAs, 35 miRNAs, and 5 mRNAs. We established three prognosis predictive nomograms based on four key ceRNAs (ceRNA nomogram), five key immune cells (immune cell nomogram), and their combination (ceRNA-immune cell nomogram). Among them, the ceRNA-immune cell nomogram had the best accuracy. Furthermore, the areas under the curve of the ceRNA-immune cell nomogram were also significantly greater than the TNM stage at 1 (0.818 vs. 0.693), 3 (0.865 vs. 0.674), and 5 (0.832 vs. 0.627) years. Co-expression analysis revealed that CBX6 was positively correlated with activated dendritic cells (R = 0.45, p < 0.01), whereas negatively correlated with activated mast cells (R =- 0.43, p < 0.01). In conclusion, our study constructed three nomograms to predict prognosis in elderly patients with CRC, among which the ceRNA-immune cell nomogram had the best prediction accuracy. We inferred that the mechanism underlying the regulation of activated dendritic cells and mast cells by CBX6 might play a crucial role in tumor development and prognosis of elderly patients with CRC.

Comprehensive analysis of lncRNAs as biomarkers for diagnosis, prognosis, and treatment response in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common histological type of renal carcinoma and has a high recurrence rate and poor outcome. Accurate patient risk stratification based on genetic markers can help to identify the high-risk patient for early and further treatments and would promote patient survival. Long non-coding RNAs (lncRNAs) have attracted widespread attention as biomarkers for early diagnosis, treatment, and prognosis because of their high specificity and sensitivity. Here, we performed a systematic search in NCBI PubMed and found 44 lncRNAs as oncogenes, 18 lncRNAs as tumor suppressors, 199 lncRNAs as diagnostic biomarkers, 62 lncRNAs as prognostic biomarkers, and 3 lncRNAs as predictive biomarkers for ccRCC. We also comprehensively discuss the biological functions and molecular regulatory mechanisms of lncRNAs in ccRCC. Overall, the present study is a systemic analysis to assess the expression and clinical value of lncRNAs in ccRCC, and lncRNAs hold promise to be diagnostic, prognostic, and predictive biomarkers.

High TXLNA Expression Predicts Favourable Outcome for Pancreatic Adenocarcinoma Patients.

TXLNA (taxilin alpha), a binding partner of the syntaxin family, was identified as a key factor in the coordination of intracellular vesicle trafficking and highly expressed in various tumor cells. However, the accurate relation between TXLNA and tumorigenesis and progression of pancreatic adenocarcinoma (PAAD) is still unclear. The present study was designed to examine the expression profile of TXLNA and explore its prognostic significance in PAAD patients and the possible molecular regulatory mechanism by analyzing a series of data from databases, including GEPIA, LOGpc, STRING, and GeneMANIA. The results indicate that TXLNA mRNA and protein were remarkably increased in PAAD tissues compared with normal pancreatic tissues. The high TXLNA expression was significantly correlated with superior overall survival (OS), disease-free interval (DFI), disease specific survival (DSS), and progression-free interval (PFI) for PAAD patients. In summary, high TXLNA expression could predict favourable OS, DFI, DSS, and PFI for PAAD patients, and it might be as potential prognostic biomarkers and targets for PAAD.

Development of polypyrrole/collagen/nano-strontium substituted bioactive glass composite for boost sciatic nerve rejuvenation in vivo.

A novel nerve conductor made out of polypyrrole (PPY), collagen (Coll) and nano-strontium substituted bioactive glass (n-Sr@BG) (PPY/Coll/n-Sr@BG) was fabricated by electrospinning. SEM demonstrated that the mean distances across of the pores in the nerve channels were under 15 mm and more prominent than 2 mm. These biocomposite films had biomimetic morphology, bigger porosity and moderately higher surface territory than customary nerve channels, consequently not just allowing the transportation of nerve development factor and glucose yet, in addition, hindering the section of lymphatic tissue and fibroblasts. The consistent filaments of the nerve can copy the characteristic ECM, which is valuable to cell bond, cell multiplication, and cell movement. PPY/Coll/n-Sr@BG demonstrated great cell fondness rate, which is useful for neurilemma cell cells bond, relocation and expansion. Its great viability empowers its wellbeing animal models. Sciatic nerve deformity was crossed over an animal model with PPY/Coll/n-Sr@BG in rodents. PPY/Coll and autotransplants were utilized as control gatherings. Contrasted with PPY/Coll and PPY/Coll/n-Sr@BG accomplished fundamentally increasingly viable recovery of sciatic nerve wounds following 24 weeks implantation and the mean distance across of muscle fibres occasions bigger than that in PPY/Coll/n-Sr@BG, and it was nearer to that in control. The rejuvenated nerve filaments in PPY/Coll/n-Sr@BG had an increasingly standard round shape, the thickness of neuro-filaments in c was more than those in PPY/Coll, and was near that in control.

Diagnostic and prognostic significance of serum CD26 level in Asian women with high-grade serous ovarian carcinoma.

Aim: The aim of this study was to reveal the diagnostic and prognostic significance of serum CD26 level in high-grade serous ovarian carcinoma women in China. Methods: There were 229 high-grade serous ovarian carcinoma women and 365 controls. Baseline serum CD26 level was measured using ELISA. A 36-month post-operation follow-up was performed. Results: Baseline serum CD26 level ≤601.5 pg/ml was associated with the increased risk of ovarian carcinoma (OR: 1.67; 95% CI: 1.20-2.32). Baseline serum level of CD26 ≤589.7 pg/ml was related to the elevated risk of cancer death (HR: 1.33; 95% CI: 1.04-1.69). Conclusion: Baseline serum CD26 level might be an independent diagnostic and prognostic marker for high-grade serous ovarian carcinoma.

Clinicopathological significance and prognostic role of chemokine receptor CXCR4 expression in pancreatic ductal adenocarcinoma, a meta-analysis and literature review.

BACKGROUND: C-X-C chemokine receptor type 4 (CXCR4) protein level was highly detected in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). The correlation of CXCR4 expression in PDAC and its clinicopathological characteristics remains inconclusive. This study aims at investigating the relationship of CXCR4 expression and clinicopathological characteristics of PDAC patients using a meta-analysis. METHODS: PubMed, Web of Science, Cochrane Library, EMBASE, and EBSCO databases and Google Scholar from January 2000 to August 2018 were searched. The Review Manager 5.2 was used in the analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were measured. This study included a total of 11 relevant articles which involved 1439 PDAC patients. RESULTS: CXCR4 was more frequently overexpressed in PDAC tissues than normal pancreatic samples, OR = 132.07, P = 0.03. The frequency of high CXCR4 expression significantly increased in high grade PDAC than low grade, OR was 1.50, P = 0.03. High CXCR4 expression was more frequently observed in late stage of PDAC than those in early stage, OR was 2.82, P = 0.0009. High CXCR4 expression significantly increased the risk of lymph node and distant metastases in PDAC, OR = 2.69, p < 0.00001, and OR = 1.86, p = 0.009 respectively. In addition, high CXCR4 expression was correlated with poor survival in PDAC patients, HR = 1.27, P = 0.05. CONCLUSIONS: CXCR4 overexpression is a valuable risk factor for PDAC. CXCR4 overexpression is a strong prognostic marker correlated with the risk of lymph node involvement and distant metastasis in PDAC patients.

HAVCR1 expression might be a novel prognostic factor for gastric cancer.

Hepatitis A virus cellular receptor 1 (HAVCR1), which is also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a TIM gene family member. In this study, we aimed to characterize the expression profile of HAVCR1 in GC, its prognostic value and the potential epigenetic mechanism leading to its dysregulation. Bioinformatic analysis was performed by using genomic, clinicopathological and survival data in the human protein atlas (HPA) and the Cancer Genome Atlas (TCGA). Results showed that HAVCR1 was significantly upregulated at the mRNA and protein level in GC tissues compared to the adjacent normal tissues. In addition, HAVCR1 upregulation was an independent indicator of shorter OS (HR: 1.698, 95%CI: 1.221-2.361, p = 0.002), after adjustment of older age, differentiation status, pathological stages and the presence of residual tumor and was also an independent indicator of shorter RFS (HR: 2.577, 95%CI: 1.583-4.197, p<0.001), after adjustment of gender and histological grade. The methylation level of two CpG sites (cg11188031 and cg07320595) was negatively correlated with HAVCR1 expression. However, only high methylation level of cg07320595 was associated with significantly longer OS (p = 0.018) and RFS (p = 0.021). Based on these findings, we infer that HAVCR1 upregulation might serve as a valuable prognostic marker in terms of OS and RFS in GC patients. Cg07320595 might be a critical CpG site influencing HAVCR1 expression.

LncRNA SNHG16 reverses the effects of miR-15a/16 on LPS-induced inflammatory pathway.

Nowadays, neonatal sepsis has gradually become a global problem for its high incidence and increasing mortality. Previous studies have reported that miR-15a and miR-16 are two important modulators in neonatal sepsis. However, the upstream molecular mechanism of miR-15a/16 cluster is still mysterious. This study aims to explore a lncRNA can bind with miR-15a/16 in neonatal sepsis. Microarray analysis helped us found top ten lncRNAs which were downregulated in neonatal sepsis serum. Among these ten lncRNAs, SNHG16 was uncovered to significantly downregulated both miR-15a and miR-16. According to the result of subcellular fractionation assay, SNHG16 was mainly located in the cytoplasm of RAW264.7 cell, indicating the potential ceRNA role of SNHG16. Mechanism investigations revealed that SNHG16 could act as a ceRNA to upregulate TLR4 which is the target mRNA of miR-15a/16 cluster. At last, rescue assays demonstrated that SNHG16 reversed the effects of miR-15a/16 on LPS-induced inflammatory pathway. In summary, SNHG16 can act as a ceRNA to modulate miR-15a/16 cluster, thereby affecting LSP-induced inflammatory pathway which was downregulated by miR-15a/16 cluster.

KCND2 upregulation might be an independent indicator of poor survival in gastric cancer.

AIM: We aimed to investigate the expression of voltage-gated potassium channels KCND1/KCND2/KCND3 in gastric cancer (GC) and normal stomach tissues and to investigate the prognostic value of the upregulated gene KCND2. PATIENTS & METHODS: A retrospective analysis was performed using data from large available databases. RESULTS: KCND2 was significantly upregulated at the mRNA and protein levels in GC compared with that in normal stomach tissues. High KCND2 RNA expression was independently associated with shorter overall survival (HR: 1.634, 95% CI: 1.135-2.352; p = 0.008) and recurrence-free survival (HR: 2.644, 95% CI: 1.438-4.863; p = 0.002). Data mining in the Kaplan-Meier plotter confirmed the prognostic value of KCND2. CONCLUSION: KCND2 upregulation is a valuable prognostic biomarker in GC patients, in terms of overall survival and recurrence-free survival.

Clinicopathological significance of CHFR promoter methylation in gastric cancer: a meta-analysis.

The mitotic checkpoint gene (CHFR) (Checkpoint with Forkhead-associated and Ring finger domains is a G2 phase/mitosis checkpoint and tumor-suppressor gene. Recent studies have reported the relationship of CHFR promoter methylation with clinicopathological significance of gastric cancer. However, the results remain unclear due to small size of sample. We pooled 15 studies including 827 gastric cancer patients and conducted a meta-analysis to investigate the clinicopathological significance of CHFR promoter methylation in gastric cancer. Our data revealed that the frequency of CHFR promoter methylation was higher in gastric cancer than in normal gastric tissue, Odd Ratio (OR) was 10.12 with 95% CI 5.17-19.79, p < 0.00001. Additionally, the rate of CHFR promoter methylation was significantly increased in high grade of gastric cancer compared to low grade, OR was 1.64 with 95% CI 1.00-2.68, p = 0.05. CHFR methylation was significantly associated with the positive lymph node metastasis, OR was 1.56 with 95% CI 1.05-2.32, p = 0.03. We concluded that CHFR could serve as a biomarker for diagnosis of gastric cancer, and a drug target for development of gene therapy in gastric cancer. CHFR promoter methylation is associated with tumor poor differentiation and lymph node metastasis.

A novel agonistic anti-human death receptor 5 monoclonal antibody with tumoricidal activity induces caspase- and mitochondrial-dependent apoptosis in human leukemia Jurkat cells.

An agonistic antibody against TNF-related apoptosis-inducing ligand death receptor 5 (DR5) is a practicable candidate drug for antitumor therapy. In this study, a novel murine anti-human DR5 monoclonal antibody, mDRA-6(IgG1-κ), has been generated. This study aimed to explore the caspase-dependent and mitochondrial mechanisms of mDRA-6 in inducing apoptosis in human leukemia Jurkat cells. The apoptotic effects of mDRA-6 on Jurkat cells, which express DR5 on the cell surface, were detected by flow cytometry and western blot after exposure to different doses of mDRA-6 and at fixed doses of mDRA-6 at different times. It was demonstrated that mDRA-6 can induce Jurkat cell apoptosis via caspase- and mitochondrial-dependent pathways. These results indicate that the novel antibody mDRA-6 against DR5 has an antitumor function and may provide a new reagent for tumor therapy.

Caspase-dependent molecular mechanisms of anti-human DR5 monoclonal antibody mDRA-6 inducing apoptosis of human leukemia Jurkat cells.

BACKGROUND AND OBJECTIVE: Both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and some monoclonal agonistic antibodies against TRAIL receptors have antitumor activity. We have previously prepared a novel monoclonal agonistic antibody against human death receptor 5 (DR5) and designated it as mDRA-6. This study was to explore the Caspase-dependent molecular mechanisms of mDRA-6 inducing apoptosis of human leukemia Jurkat cells. METHODS: After exposure to different doses of mDRA-6, DNA fragmentation of Jurkat cells was detected by agarose gel electrophoresis, cell proliferation was detected by MTT assay, and cell apoptosis was detected by flow cytometry after Annexin V-FITC/PI double staining. Jurkat cells were further treated with the inhibitors for Caspase-10, -9, -8 and -3. The active cleavage products of Caspase-10, -9, -8, -3 and poly ADP-ribose polymerase (PARP), BH3 interacting domain death agonist (Bid), truncated Bid (tBid) and cytochrome c (Cyto c), were analyzed by western blot. RESULTS: After mDRA-6 treatment, DNA fragmentation was detected in Jurkat cells. mDRA-6 inhibited cell proliferation in a dose-dependent manner. When treated with 2.0 microg/mL mDRA-6, the apoptosis rates of Jurkat cells were 16.2% at 0.25 h, 28.3% at 0.5 h, 69.2% at 1 h and 78.2% at 2 h. Interestingly, the mDRA-6-induced apoptosis was repressed by 77.9% by Caspase-8 inhibitor ZIF, 54.2% by Caspase-3 inhibitor ZDF, and 8.7% by Caspase-9 inhibitor ZLF, but was not repressed by Caspase-10 inhibitor ZAF. After mDRA-6 exposure, the proenzymes of Caspase-8, -9 and -3 were reduced and their active cleavage products were increased along with the increase of exposure time, the cleavage products of PARP were also increased, Bid was degraded to tBid, and an abundance of Cyto c was released from mitochondria, but the proenzyme of Caspase-10 showed no change and no cleavage products of Caspase-10 were detectable. CONCLUSION: mDRA-6 can induce apoptosis of Jurkat cells via the Caspase-dependent and mitochondrial pathways.

Synthesis, cytotoxicity and apoptosis of naphthalimide polyamine conjugates as antitumor agents.

Several naphthalimide polyamine conjugates were synthesized and evaluated for in vitro cytotoxicity against human leukemia K562, murine melanoma B16, Chinese hamster ovary CHO cell lines. Both triamine moieties and the length of spacers were crucial in elevating the potency of 1,8-naphthalimide. The typical compounds 5a and 5d exhibited excellent cell selectivity to cancer cells through the human hepatoma BEL-7402 and human normal hepatocyte QSG-7701 screens. In addition, 5d could disturb the cell cycle in B16 cells. The research on caspase activity and cytochrome c indicated that 5d could induce B16 cell apoptosis via both the mitochondrial and membrane death receptor pathways, and the Bcl-2 family numbers were involved in the control of apoptosis.

Proteomic identification of malignant transformation-related proteins in esophageal squamous cell carcinoma.

Esophageal cancer (EC) persists to be a leading cancer-related death in northern China. Clinical outcome of EC is the most dismal among many types of digestive tumors because EC at early stage is asymptomatic. The current study used 2-DE-based proteomics to identify differentially expressed proteins between esophageal cancer cell lines and immortal cell line. Fifteen proteins were identified with differences of more than five folds, comprising the down-regulation of annexin A2, histone deacetylase 10 isoform beta and protein disulfide-isomerase ER-60 precursor, and the up-regulation of heat shock 70 kDa protein 9B precursor, solute carrier family 44 Member 3, heterogeneous nuclear ribonucleoprotein L (hnRNP L), eukaryotic translation initiation factor 4A isoform 2, triosephosphate isomerase1 (TPI), peroxiredoxin1 (PRX1), forminotransferase cyclodeaminase form (FTCD), fibrinogen gamma-A chain precursor, kinesin-like DNA binding protein, lamin A/C, cyclophilin A (CypA), and transcription factor MTSG1. Expression pattern of annexin A2 was verified by Western blotting, immunocytochemistry and immunohistochemistry analysis. The implication of these protein alterations correlated to the esophageal malignant transformation is discussed.

Clinical observation on treatment of 2,062 cases of immune infertility with integration of traditional Chinese medicine and western medicine.

To study the therapeutic effect of integrated traditional Chinese medicine and western medicine on female immune infertility. 3,496 women suffering from primary or secondary infertility had their ASAb, EMAb, AOAb and ACAb level tested, with the positive rate of 23.11%, 34.95%, 20.77% and 30.41% respectively. 2,062 positive cases were periodically treated with the Chinese drug Xiaokangwan plus dexamethasone, vitamin E and vitamin C for 2 periods as a course of treatment. At the end of a treatment course, the rate for the antibodies to turn negative reached over 85% and the average pregnant rate reached 36.66%. The treatment of immune infertility with the integrated approach can reduce or eliminate the influence of antibodies in the serum of patients on various links of pregnancy, thus reaching the goal of curing infertility.