There is a lack of personalized treatment options for women with recurrent platinum-resistant ovarian cancer. Outside of bevacizumab and a group of poly ADP-ribose polymerase inhibitors, few options are available to women that relapse. We propose that efficacious drug combinations can be determined via molecular characterization of ovarian tumors along with pre-established pharmacogenomic profiles of repurposed compounds. To that end, we selectively performed multiple two-drug combination treatments in ovarian cancer cell lines that included reactive oxygen species inducers and HSP90 inhibitors. This allowed us to select cell lines that exhibit disparate phenotypes of proliferative inhibition to a specific drug combination of auranofin and AUY922. We profiled altered mechanistic responses from these agents in both reactive oxygen species and HSP90 pathways, as well as investigated PRKCI and lncRNA expression in ovarian cancer cell line models. Generation of dual multi-gene panels implicated in resistance or sensitivity to this drug combination was produced using RNA sequencing data and the validity of the resistant signature was examined using high-density RT-qPCR. Finally, data mining for the prevalence of these signatures in a large-scale clinical study alluded to the prevalence of resistant genes in ovarian tumor biology. Our results demonstrate that high-throughput viability screens paired with reliable in silico data can promote the discovery of effective, personalized therapeutic options for a currently untreatable disease.

Infantile hemangioma (IH) is the most common vascular tumour in infants. The pathogenesis of IH is complex and poorly understood. Therefore, achieving a deeper understanding of IH pathogenesis is of great importance. Here, we used the Ribo-Zero RNA-Seq and HiSeq methods to examine the global expression profiles of protein-coding transcripts and non-coding RNAs, including miRNAs and lncRNAs, in IH and matched normal skin controls. Bioinformatics assessments including gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were performed. Of the 16370 identified coding transcripts, only 144 were differentially expressed (fold change ≥ 2, P ≤ 0.05), including 84 up-regulated and 60 down-regulated transcripts in the IH samples compared with the matched normal skin controls. Gene ontology analysis of these differentially expressed transcripts revealed 60 genes involved in immune system processes, 62 genes involved in extracellular region regulation, and 35 genes involved in carbohydrate derivative binding. In addition, 256 lncRNAs and 142 miRNAs were found to be differentially expressed. Of these, 177 lncRNAs and 42 miRNAs were up-regulated in IH, whereas 79 lncRNAs and 100 miRNAs were down-regulated. By analysing the Ribo-Zero RNA-Seq data in combination with the matched miRNA profiles, we identified 1256 sponge modulators that participate in 87 miRNA-mediated, 70 lncRNA-mediated and 58 mRNA-mediated interactions. In conclusion, our study uncovered a competitive endogenous RNA (ceRNA) network that could further the understanding of the mechanisms underlying IH development and supply new targets for investigation.

MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients. We selected two high expressing models and two low expressing models for in vivo testing. One xenograft model using an MISIIR over-expressing SKOV3ip cell line (Z3) was a positive control. The primary endpoint was change in tumor size. The secondary endpoint was final tumor mass. We observed no statistically significant differences between control and treated animals. The lack of response could be secondary to a number of variables including the lack of known biomarkers of response, the low membrane expression of MISIIR, and a limited ability of 3C23K to induce ADCC in PDX models. Further study is needed to determine the magnitude of ovarian cancer response to 3C23K and also if there is a threshold surface expression to predict response.

Pancreatic cancer (PC) is an almost uniformly lethal disease with inflammation playing an important role in its progression. Sustained stimulation of purinergic receptor P2X7 drives induction of NLRP inflammasome activation. To understand the role of P2X7 receptor and inflammasome, we performed transcriptomic analysis of p48Cre/+-LSL-KrasG12D/+ mice pancreatic tumors by next generation sequencing. Results showed that P2X7R's key inflammasome components, IL-1β and caspase-1 are highly expressed (p < 0.05) in pancreatic tumors. Hence, to target P2X7R, we tested effects of two P2X7R antagonists, A438079 and AZ10606120, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PC in p48Cre/+-LSL-KrasG12D/+ mice. Following dose optimization studies, for chemoprevention efficacy, six-week-old p48Cre/+-LSL-KrasG12D/+ mice (24-36/group) were fed modified AIN-76A diets containing 0, 50 or 100 ppm A438079 and AZ10606120 for 38 weeks. Pancreata were collected, weighed, and evaluated for PanINs and PDAC. Control diet-fed male mice showed 50% PDAC incidence. Dietary A438079 and AZ10606120 showed 60% PDAC incidence. A marginal increase of PanIN 3 (carcinoma in-situ) was observed in drug-treated mice. Importantly, the carcinoma spread in untreated mice was 24% compared to 43-53% in treatment groups. Reduced survival rates were observed in mice exposed to P2X7R inhibitors. Both drugs showed a decrease in caspase-3, caspase-1, p21 and Cdc25c. Dietary A438079 showed modest inhibition of P2X7R, NLRP3, and IL-33, whereas AZ10606120 had no effects. In summary, targeting the P2X7R pathway by A438079 and AZ10606120 failed to show chemopreventive effects against PC and slightly enhanced PanIN progression to PDAC. Hence, caution is needed while treating high-risk individuals with P2X7R inhibitors.

Gene fusions play a critical role in some cancers and can serve as important clinical targets. In epithelial ovarian cancer (EOC), the contribution of fusions, especially by histological type, is unclear. We therefore screened for recurrent fusions in a histologically diverse panel of 220 EOCs using RNA sequencing. The Pipeline for RNA-Sequencing Data Analysis (PRADA) was used to identify fusions and allow for comparison with The Cancer Genome Atlas (TCGA) tumors. Associations between fusions and clinical prognosis were evaluated using Cox proportional hazards regression models. Nine recurrent fusions, defined as occurring in two or more tumors, were observed. CRHR1-KANSL1 was the most frequently identified fusion, identified in 6 tumors (2.7% of all tumors). This fusion was not associated with survival; other recurrent fusions were too rare to warrant survival analyses. One recurrent in-frame fusion, UBAP1-TGM7, was unique to clear cell (CC) EOC tumors (in 10%, or 2 of 20 CC tumors). We found some evidence that CC tumors harbor more fusions on average than any other EOC histological type, including high-grade serous (HGS) tumors. CC tumors harbored a mean of 7.4 fusions (standard deviation [sd] = 7.4, N = 20), compared to HGS EOC tumors mean of 2.0 fusions (sd = 3.3, N = 141). Few fusion genes were detected in endometrioid tumors (mean = 0.24, sd = 0.74, N = 55) or mucinous tumors (mean = 0.25, sd = 0.5, N = 4) tumors. To conclude, we identify one fusion at 10% frequency in the CC EOC subtype, but find little evidence for common (> 5% frequency) recurrent fusion genes in EOC overall, or in HGS subtype-specific EOC tumors.

Hepatitis causes hepatic cell injury, regeneration and different levels of fibrogenesis, and severe liver fibrogenesis progresses into cirrhosis with liver dysfunction. Serum amyloid A (SAA) is an acute phase protein that is predominantly secreted by hepatocytes during early injury or infection. Nevertheless, the relationship of SAA and development of cirrhosis as well as the underlying molecular mechanisms is largely unknown. Here, we found that macrophages are the major SAA-binding cells in the injured liver. in vitro, macrophages treated with SAA exhibited high production of IL-10 but low production of IL-12, as features for M2 macrophages. Moreover, these polarized M2 macrophages by SAA also produced IL-1, IL-6 and TNFa, characteristics for an M2b subtype, rather than an alternative M2a or fibrogenic M2c subtype. In a mouse model of carbon tetrachloride (CCl4)-induced hepatic fibrogenesis/cirrhosis, anti-SAA sera were used to block the effects of SAA, resulting in increases in the severity of hepatic fibrosis, suggesting an overall anti-fibrogenic effect of SAA. Isolated macrophages from mouse liver showed that anti-SAA appeared to alter the polarization of macrophages from M2b to M2c, suggesting that SAA may induce M2b-like macrophage polarization during liver inflammation, which prevents the liver from fibrogenesis.

Prostate cancer diagnosis and treatment continues to be a major public health challenge. The heterogeneity of the disease is one of the major factors leading to imprecise diagnosis and suboptimal disease management. The improved resolution of functional multi-parametric magnetic resonance imaging (mpMRI) has shown promise to improve detection and characterization of the disease. Regions that subdivide the tumor based on Dynamic Contrast Enhancement (DCE) of mpMRI are referred to as DCE-Habitats in this study. The DCE defined perfusion curve patterns on the identified tumor habitat region are used to assess clinical significance. These perfusion curves were systematically quantified using seven features in association with the patient biopsy outcome and classifier models were built to find the best discriminating characteristics between clinically significant and insignificant prostate lesions defined by Gleason score (GS). Multivariable analysis was performed independently on one institution and validated on the other, using a multi-parametric feature model, based on DCE characteristics and ADC features. The models had an intra institution Area under the Receiver Operating Characteristic (AUC) of 0.82. Trained on Institution I and validated on the cohort from Institution II, the AUC was also 0.82 (sensitivity 0.68, specificity 0.95).

Previous studies have evaluated the effects of metformin use on survival outcomes in endometrial cancer, but their results are inconsistent. We conducted a systematic review and meta-analysis to provide a quantitative assessment of the drug's effects based on available evidence. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify relevant studies that evaluated the association between metformin use on survival outcomes in endometrial cancer. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the association of metformin use with overall survival and with progression-free survival using a fixed-effects model. A total of nine studies involving 2,016 patients with endometrial cancer were identified. In a meta-analysis of eight studies involving 1,594 individuals, metformin use was associated with significant improvements in overall survival (HR, 0.51; 95% CI, 0.41 to 0.64). Metformin users similarly showed improved progression-free survival in a meta-analysis of two studies involving 632 individuals (HR, 0.63; 95% CI, 0.46 to 0.87). In conclusion, endometrial cancer patients who use metformin show improved overall survival and progression-free survival. Further studies are required to confirm the full potential effects of metformin use on survival outcomes in endometrial cancer.