This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/ US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.In July 2013, a Think Tank jointly sponsored by Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and the US Food and Drug Administration (FDA) proposed a new cardiac safety paradigm, Comprehensive in Vitro Proarrhythmia Assay (CiPA). CiPA uses a new mechanistic, model-informed approach to predict the risk of Torsade de Pointes (TdP), a rare but potentially lethal form of ventricular tachycardia that can be induced by drugs and lead to sudden death. 1 Since its inception, global stakeholders including regulatory agencies (the FDA, European Medicines Agency, Health Canada, and the Japan Pharmaceuticals and Medical Devices Agency), industry, and academia have assembled various

Abstract. Accumulating evidence suggests that aberrant expression of microRNAs (miRNAs) is involved in several diseases, including cancer. This study aimed to investigate the miRNA expression pattern and its alteration following celecoxib intervention for human colorectal cancer (CRC). The miRNA expression profiles of CRC tissues, matched adjacent normal colorectal mucosae and HT-29 cells treated with celecoxib were determined using miRNA microarray, and further confirmed using the quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR). The target genes of the aberrant miRNAs in HT-29 cells treated with celecoxib were further assessed through bioinformatic analysis. Results from this study demonstrated a significant increase in the expression of 35 miRNAs and a decrease in 30 miRNAs in the carcinoma tissues compared to the normal tissues (P<0.001). Of the 28 aberrantly expressed miRNAs, 20 were upregulated and 8 were downregulated in the HT-29 cells treated with celecoxib compared to the matched control cells (P<0.01). Furthermore, miR-552 was found to be correlated with clinical stage, lymph node and distant metastases (P<0.05). Stage and distant metastases revealed differential expression of miR-139-3p and grade disclosed aberrant expression of miR-142-3p. In addition, multiple target genes involved in several essential survival pathways were found be modulated by the aberrantly expressed miRNAs in HT-29 cells treated with celecoxib. Our data revealed that a common pattern of miRNA expression in the colorectum could distinguish malignant tissue from normal mucosa. Celecoxib inhibited HT-29 cell growth in vitro which was partly attributable to the altered expression of miRNAs. miRNAs may be involved in CRC tumorigenesis and can serve as potential therapeutic targets.

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Serum deprivation response (SDPR) gene has been recently characterized as a gene signature marker or serving a tumor suppressor role in specific types of cancer. However, gene expression alterations of SDPR in various types of cancer and their relevance to clinical outcomes remain unclear. In the present study, SDPR expression was profiled using the Oncomine database, and SDPR downregulation was indicated in most types of cancer. In agreement with previously reported breast cancer cases, downregulation of SDPR was indicated to be significantly associated with poor survival in patients with lung cancer, glioma and sarcoma. To clarify why SDPR expression was altered in these types of cancer, both DNA methylation patterns and potential transcriptional factors of SDPR were analyzed. Altered DNA methylation levels of SDPR were found in 17/18 cancer types using MethHC. To the best of our knowledge, the present study for the first time, identified the CpG site (cg10082589) as one of the best survival methylation markers for lung adenocarcinoma, and the CpG site (cg07488576) for sarcoma using Methsurv. In addition, GATA binding protein 2 was identified as a potential transcription factor for SDPR, by integrating and analyzing both the co-expressed genes and the potential transcription factor binding sites of SDPR. In the present study, the systematic analysis of SDPR provided insight for the underlying molecular mechanisms in cancer progression, revealing novel perspectives for the clinical prognostic evaluation of lung adenocarcinoma and sarcoma.

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