Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of inter-tumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103) and dogs (n=34) were generated using RNA-sequencing. Conserved inter- tumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) to quantify inter-tumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

BackgroundmicroRNAs (miRNAs) are crucially important in the development of cancer. Their dysregulation, commonly observed in various types of cancer, is largely cancer-dependent. Thus, to understand the tumor biology and to develop accurate and sensitive biomarkers, we need to understand pan-cancer miRNA expression.ConstructionsAt the University of Minnesota, we developed the OncomiR Cancer Database (OMCD), hosted on a web server, which allows easy and systematic comparative genomic analyses of miRNA sequencing data derived from more than 9500 cancer patients tissue samples available in the Cancer Genome Atlas (TCGA). OMCD includes associated clinical information and is searchable by organ-specific terms common to the TCGA.ConclusionsFreely available to all users (www.oncomir.umn.edu/omcd/), OMCD enables (1) simple visualization of TCGA miRNA sequencing data, (2) statistical analysis of differentially expressed miRNAs for each cancer type, and (3) exploration of miRNA clusters across cancer types.Database URL www.oncomir.umn.edu/omcd

In the current study, we have characterized the global miRNA expression profile in mouse pancreatic acinar cells and during acute pancreatitis using next-generation RNA sequencing. We identified 324 known and six novel miRNAs that are expressed in mouse pancreatic acinar cells. In the basal state, miR-148a-3p, miR-375-3p, miR-217-5p, and miR-200a-3p were among the most abundantly expressed, whereas miR-24-5p and miR-421-3p were the least abundant. Treatment of acinar cells with caerulein (100 nM) and taurolithocholic acid 3-sulfate [TLC-S (250 μM)] induced numerous changes in miRNA expression profile. In particular, we found significant overexpression of miR-21-3p in acini treated with caerulein and TLC-S. We further looked at the expression of miR-21-3p in caerulein, l-arginine, and caerulein + LPS-induced acute pancreatitis mouse models and found 12-, 21-, and 50-fold increased expression in the pancreas, respectively. In summary, this is the first comprehensive analysis of global miRNA expression profile of mouse pancreatic acinar cells in normal and disease conditions. Our analysis shows that miR-21-3p expression level correlates with the severity of the disease.

Aims Pulmonary vein isolation (PVI) is the gold standard for atrial fibrillation (AF) ablation. Recently, catheter ablation targeting rotors or focal sources has been developed for treatment of AF. This study sought to compare the safety and effectiveness of Focal Impulse and Rotor Modulation (FIRM)-guided ablation as the sole ablative strategy with PVI in patients with paroxysmal AF. Methods and results We conducted a multicentre, randomized trial to determine whether FIRM-guided radiofrequency ablation without PVI (FIRM group) was non-inferior to PVI (PVI group) for treatment of paroxysmal AF. The two primary efficacy end points were (i) acute success defined as elimination of AF rotors (FIRM group) or isolation of all pulmonary veins (PVI group) and (ii) long-term success defined as single-procedure freedom from AF/atrial tachycardia (AT) recurrence 12 months after ablation. The study was closed early by the sponsor. At the time of study closure, any pending follow-up visits were waived. A total of 51 patients (mean age 63 ± 10.6 years, 57% male) were enrolled. All PVs were successfully isolated in the PVI group and all rotors were successfully eliminated in the FIRM group. Single-procedure effectiveness was 31.3% (5/16) in the FIRM group and 80% (8/10) in the PVI group at 12 months. Three vascular access complications occurred in the FIRM group. Conclusion These partial study effectiveness results reinforce the importance of PVI in paroxysmal AF patients and indicate that FIRM-guided ablation alone (without PVI) is not an effective strategy for treatment of paroxysmal AF in most patients.

Airway smooth muscle (ASM) cells play a critical role in the pathophysiology of asthma due to their hypercontractility and their ability to proliferate and secrete inflammatory mediators. microRNAs (miRNAs) are gene regulators that control many signaling pathways and thus serve as potential therapeutic alternatives for many diseases. We have previously shown that miR-708 and miR-140-3p regulate the MAPK and PI3K signaling pathways in human ASM (HASM) cells following TNF-α exposure. In this study, we investigated the regulatory effect of these miRNAs on other asthma-related genes. Microarray analysis using the Illumina platform was performed with total RNA extracted from miR-708 (or control miR)-transfected HASM cells. Inhibition of candidate inflammation-associated gene expression was further validated by qPCR and ELISA. The most significant biologic functions for the differentially expressed gene set included decreased inflammatory response, cytokine expression and signaling. qPCR revealed inhibition of expression of CCL11, CXCL10, CCL2 and CXCL8, while the release of CCL11 was inhibited in miR-708-transfected cells. Transfection of cells with miR-140-3p resulted in inhibition of expression of CCL11, CXCL12, CXCL10, CCL5 and CXCL8 and of TNF-α-induced CXCL12 release. In addition, expression of RARRES2, CD44 and ADAM33, genes known to contribute to the pathophysiology of asthma, were found to be inhibited in miR-708-transfected cells. These results demonstrate that miR-708 and miR-140-3p exert distinct effects on inflammation-associated gene expression and biological function of ASM cells. Targeting these miRNA networks may provide a novel therapeutic mechanism to down-regulate airway inflammation and ASM proliferation in asthma.