Ovarian cancer (OC) is the highest frequent malignant gynecologic tumor with very complicated pathogenesis. The purpose of the present academic work was to identify significant genes with poor outcome and their underlying mechanisms. Gene expression profiles of GSE36668, GSE14407 and GSE18520 were available from GEO database. There are 69 OC tissues and 26 normal tissues in the three profile datasets. Differentially expressed genes (DEGs) between OC tissues and normal ovarian (OV) tissues were picked out by GEO2R tool and Venn diagram software. Next, we made use of the Database for Annotation, Visualization and Integrated Discovery (DAVID) to analyze Kyoto Encyclopedia of Gene and Genome (KEGG) pathway and gene ontology (GO). Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). There were total of 216 consistently expressed genes in the three datasets, including 110 up-regulated genes enriched in cell division, sister chromatid cohesion, mitotic nuclear division, regulation of cell cycle, protein localization to kinetochore, cell proliferation and Cell cycle, progesterone-mediated oocyte maturation and p53 signaling pathway, while 106 down-regulated genes enriched in palate development, blood coagulation, positive regulation of transcription from RNA polymerase II promoter, axonogenesis, receptor internalization, negative regulation of transcription from RNA polymerase II promoter and no significant signaling pathways. Of PPI network analyzed by Molecular Complex Detection (MCODE) plug-in, all 33 up-regulated genes were selected. Furthermore, for the analysis of overall survival among those genes, Kaplan–Meier analysis was implemented and 20 of 33 genes had a significantly worse prognosis. For validation in Gene Expression Profiling Interactive Analysis (GEPIA), 15 of 20 genes were discovered highly expressed in OC tissues compared to normal OV tissues. Furthermore, four genes (BUB1B, BUB1, TTK and CCNB1) were found to significantly enrich in the cell cycle pathway via re-analysis of DAVID. In conclusion, we have identified four significant up-regulated DEGs with poor prognosis in OC on the basis of integrated bioinformatical methods, which could be potential therapeutic targets for OC patients.

ABSTRACT:The metabolism and disposition of [ 14 C]apixaban, a potent, reversible, and direct inhibitor of coagulation factor Xa, were investigated in mice, rats, rabbits, dogs, and humans after a single oral administration and in incubations with hepatocytes. In plasma, the parent compound was the major circulating component in mice,

PurposeOral squamous cell carcinoma (OSCC) is one of the most common malignant diseases worldwide, yet its molecular mechanisms are largely unknown. We aimed to construct gene co-expression networks to identify key modules and hub genes involved in the pathogenesis of OSCC.Patients and methodsWe used dataset GSE30784 to construct co-expression networks by weighted gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). Hub genes were screened and validated by other datasets.ResultsTurquoise and brown modules were found to be the most significantly related to tumorigenesis. Functional enrichment analysis showed that the turquoise module was associated with cell–cell adhesion, extracellular matrix and collagen catabolic process. A total of 10 hub genes (MMP1, TNFRSF12A, PLAU, FSCN1, PDPN, KRT78, EVPL, GGT6, SMIM5 and CYSRT1) were identified and validated at transcriptional and translational levels. Their genetic alteration and survival analysis were also revealed.ConclusionWe identified two modules and 10 hub genes, which were associated with the tumorigenesis of OSCC. The two modules provided references that will advance the understanding of mechanisms of tumorigenesis in OSCC. Moreover, the hub genes may serve as biomarkers and therapeutic targets for precise diagnosis and treatment of OSCC in the future.

The study aimed to compare the reported oncological outcomes based on satisfactory lymph node dissection (LND) or lymph node sampling (LNS), systemic and loco-regional recurrence rate and long-term survival rate of patients with early-stage non-small-cell lung cancer (NSCLC) who underwent video-assisted thoracic surgery (VATS) lobectomy or thoracotomy lobectomy. A systematic review was conducted using PubMed, EMBASE and OVID-EBMR databases ranging from 1990 to 2011. The studies compared VATS and thoracotomy for patients with NSCLC, with results including LND or LNS where recurrence as well as survival rates were identified. Data were abstracted by two reviewers independently. Mean difference or risk ratio (RR) were pooled using RevMan 5.0 statistical software. 5389 cases were included, of which 2380 underwent VATS and 3009 underwent thoracotomy. There was no significant difference in the number of total LND or LNS procedures (MD: -0.63; 95% confidence intervals (95% CI): -1.47 to 0.21; P = 0.14) or mediastinal LND or LNS (MD: -0.51; 95% CI: -1.58 to 0.56; P = 0.35) between the two groups. Systemic (RR: 0.61; 95% CI: 0.48 to 0.78; P < 0.01) and loco-regional (RR: 0.66; 95% CI: 0.46 to 0.95; P = 0.03) recurrence rates were significantly lower in the VATS group. Moreover, a significantly higher survival rate (RR: 1.09; 95% CI: 1.03 to 1.15; P < 0.01) was also demonstrated by a Forest plot in the VATS group. These results suggest that VATS lobectomy might be an eligible alternative in place of thoracotomy in patients with early-stage NSCLC by reducing recurrence and improving survival rates.

The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase–signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2–associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.

Lung cancer is the most common incident cancer, with a high mortality worldwide, and non‐small‐cell lung cancer (NSCLC) accounts for approximately 85% of cases. Numerous studies have shown that the aberrant expression of microRNAs (miRNAs) is associated with the development and progression of cancers. However, the clinical significance and biological roles of most miRNAs in NSCLC remain elusive. In this study, we identified a novel miRNA, miR‐34b‐3p, that suppressed NSCLC cell growth and investigated the underlying mechanism. miR‐34b‐3p was down‐regulated in both NSCLC tumour tissues and lung cancer cell lines (H1299 and A549). The overexpression of miR‐34b‐3p suppressed lung cancer cell (H1299 and A549) growth, including proliferation inhibition, cell cycle arrest and increased apoptosis. Furthermore, luciferase reporter assays confirmed that miR‐34b‐3p could bind to the cyclin‐dependent kinase 4 (CDK4) mRNA 3′‐untranslated region (3′‐UTR) to suppress the expression of CDK4 in NSCLC cells. H1299 and A549 cell proliferation inhibition is mediated by cell cycle arrest and apoptosis with CDK4 interference. Moreover, CDK4 overexpression effectively reversed miR‐34‐3p‐repressed NSCLC cell growth. In conclusion, our findings reveal that miR‐34b‐3p might function as a tumour suppressor in NSCLC by targeting CDK4 and that miR‐34b‐3p may, therefore, serve as a biomarker for the diagnosis and treatment of NSCLC.

Anti-HER2/neu antibody therapy has been reported to mediate tumor regression of HER2/ neu+ tumors. Here we demonstrated the expression of HER2 in a wide range of human melanoma cells including a primary culture and seven cell lines, and we further investigated whether HER2 could be served as a target for T cell mediated immunotherapy of human melanoma. Specific cytolytic activity of activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2Bi-Ab) against Malme-3M-luc cells was evaluated by bioluminescent signal generated by luciferase reporter which did not alter HER2 expression or proliferation ability of Malme-3M cells. Contrast with unarmed ATC, increased cytotoxic activity of HER2Bi-armed ATC against Malme-3M-luc cells was observed at effector/target (E/T) ratios of 1:1, 5:1, and 20:1. Moreover, HER2Bi-armed ATC expressed higher level of activation marker CD69 and secreted significantly higher level of IFN-γ than unarmed ATC counterpart at the E/T ratio of 20:1. In addition, compared with anti-HER2 mAb (Herceptin®) or unarmed ATC, HER2Bi-armed ATC showed remarkable suppression effect on Malme-3M-luc tumor cells. Furthermore, in melanoma tumor cell xenograft mice, infusion of HER2Bi-armed ATC successfully inhibited the growth of melanoma tumors. The anti-tumor effect of HER2Bi-armed ATC may provide a promising immunotherapy for melanoma in the future.

Study Objective To determine whether changes in serum glucose, serum potassium, and plasma insulin levels are correlated in a cohort of hypertensive patients. Design Prespecified subgroup analysis of results from a prospective, multicenter, randomized, open-label, parallel-group study. Setting Primary care clinics at three tertiary care medical centers. Patients Community-based ambulatory population of 202 patients (age range 17–65 yrs) with a new diagnosis of hypertension, untreated hypertension, or known hypertension, who were previously treated with fewer than three antihypertensive drugs and had no evidence of cardiovascular disease or diabetes mellitus. Intervention Monotherapy with oral hydrochlorothiazide 12.5 or 25 mg/day for 9 weeks. Measurements and Main Results Fasting serum glucose, serum potassium, and plasma insulin levels were obtained at baseline (before hydrochlorothiazide therapy was started) and after 9 weeks of therapy. Significant elevations were noted in fasting serum glucose (mean ± SD 3.42 ± 10.38 mg/dl, p<0.0001) and plasma insulin (2.35 ± 9.47 μIU/ml, p<0.0001) levels, and a significant reduction in serum potassium level (0.30 ± 0.44 mEq/L, p<0.0001) was noted. No significant correlation was observed between changes in fasting serum glucose and potassium levels (r = 0.022, 95% confidence interval (CI) −0.120–0.164, p=0.757) or between changes in serum potassium and plasma insulin levels (r = −0.112, 95% CI −0.256–0.037, p=0.140). Changes in serum glucose levels did not differ significantly between patients maintaining serum potassium levels of 4.0 mEq/L or greater and those with levels below 4.0 mEq/L. Conclusion Changes in serum potassium and serum glucose levels were not correlated in individuals receiving hydrochlorothiazide monotherapy; thus maintenance of normal potassium levels may not attenuate the risk of thiazide diuretic–induced hyperglycemia.