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High-throughput ‘omics’ technologies that generate molecular profiles for biospecimens have been extensively used in preclinical studies to reveal molecular subtypes and elucidate the biological mechanisms of disease, and in retrospective studies on clinical specimens to develop mathematical models to predict clinical endpoints. Nevertheless, the translation of these technologies into clinical tests that are useful for guiding management decisions for patients has been relatively slow. It can be difficult to determine when the body of evidence for an omics-based test is sufficiently comprehensive and reliable to support claims that it is ready for clinical use, or even that it is ready for definitive evaluation in a clinical trial in which it may be used to direct patient therapy. Reasons for this difficulty include the exploratory and retrospective nature of many of these studies, the complexity of these assays and their application to clinical specimens, and the many potential pitfalls inherent in the development of mathematical predictor models from the very high-dimensional data generated by these omics technologies. Here we present a checklist of criteria to consider when evaluating the body of evidence supporting the clinical use of a predictor to guide patient therapy. Included are issues pertaining to specimen and assay requirements, the soundness of the process for developing predictor models, expectations regarding clinical study design and conduct, and attention to regulatory, ethical, and legal issues. The proposed checklist should serve as a useful guide to investigators preparing proposals for studies involving the use of omics-based tests. The US National Cancer Institute plans to refer to these guidelines for review of proposals for studies involving omics tests, and it is hoped that other sponsors will adopt the checklist as well.

A checklist of criteria to determine the readiness of high-throughput ‘omics’-based tests for guiding patient therapy in clinical trials is discussed; the checklist, developed by the US National Cancer Institute in collaboration with additional scientists with relevant expertise, provides a framework to evaluate the strength of evidence for a test and outlines practical issues to consider before using the test in a clinical setting, with an aim to avoid premature advancement of omics-based tests in clinical trials. Guidelines for clinical use of omics data The potential of high-throughput 'omics' in clinical medicine is immense, with oncology leading the way in adopting these technologies. Working with researchers and clinicians from across the spectrum of these disciplines, the US National Cancer Institute (NCI) has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. Published in this Perspective feature, the checklist focuses on best practice in specimen preparation, assays, mathematical modelling, clinical trial design, ethics and more. It will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests guide therapy. The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to ‘omics’-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.

LexA repressor of Escherichia coli is inactivated by a specific cleavage reaction that requires activated RecA protein in vivo. This cleavage reaction can proceed in vitro in the presence of activated RecA or as an intramolecular RecA-independent reaction, termed autodigestion, that is stimulated by alkaline pH. Here we describe a set of LexA mutant proteins that undergo a greatly increased rate of specific cleavage in vivo, compared with wild-type LexA. Efficient in vivo cleavage of these mutant proteins also took place without RecA. Several lines of evidence suggest that cleavage occurred via a mechanism similar to autodigestion. These mutations changed Gln-92, which lies near the cleavage site, to tyrosine, phenylalanine, or tryptophan. The latter mutation increased the rate of cleavage ≈ 500-fold. These findings imply that the rate of wild-type LexA cleavage has been optimized during evolution to make the SOS system properly responsive to DNA-damaging treatments. Availability of these mutants will aid in the understanding of rate-limiting steps in intramolecular reactions.

The development of guidelines for the reporting of tumor marker studies was a major recommendation from the first International Meeting on Cancer Diagnostics. This chapter gives details about how the marker of interest was handled in the analysis, which further variables were available for analysis, and a concise summary of the study participant characteristics. The REporting Recommendations for Tumor MARKer Prognostic Studies (REMARK) profile gives an overview of all analyses performed and the data used in them. REMARK primarily focuses on studies of single prognostic markers, but most of the recommendations apply equally to other types of prognostic studies, including studies of multiple markers, studies to develop prognostic models, and studies to predict response to treatment. Researchers preparing to publish results of prognostic marker studies will benefit from reviewing the REMARK recommendations to ensure that they have adequately reported all aspects of their work.

Ran is a small GTPase required for nuclear transport in eukaryotic cells [Gorlich, D. & Mattaj, I. W. (1996) Science 271, 1513-1518]. Mutants in Ran also show defects in mRNA processing, cell cycle regulation, and other aspects of nuclear function [Rush, M. G., Drivas, G. & D'Eustachio, P. (1996) BioEssays 18, 103-112; Sazer, S. (1996) Trends Cell Biol. 6, 81-85]. In an effort to understand the role of Ran in these diverse processes, we previously characterized 10 Ran interacting proteins (Rips) from Xenopus egg extracts. In this report, we present further characterization of a complex containing three of these Rips: p340RanBP2, p88, and p18. We have cloned the Xenopus homologue of RanGAP1, and we show here that p88 is a modified form of this protein. In RanGAP assays, the p340RanBP2-p88-p18 complex contains GTPase-activating protein activity, indicating that RanGAP1 is not inactivated by modification. Rather, modification of RanGAP1 appears to be linked to its association with p340RanBP2because we did not observe unmodified RanGAP1 in p340RanBP2immunoprecipitates. We have also characterized p18, and we found that it is the Xenopus homologue of Ubc9p, an E2 ubiquitin-conjugating enzyme that is required for cell cycle regulation [Seufert, W., Futcher, B. & Jentsch, S. (1995) Nature (London) 373, 78-81]. Using antibodies directed against Xenopus Ubc9p, we have confirmed that Ubc9p associates with p340RanBP2in Xenopus extracts. These results suggest Ubc9p's role in cell cycle regulation may involve either modification of nuclear transport substrates or the nuclear transport machinery.