Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of next-generation sequencing. To address this, we developed a high-complexity barcode library, ClonTracer, which enables the high-resolution tracking of more than 1 million cancer cells under drug treatment. In two clinically relevant models, ClonTracer studies showed that the majority of resistant clones were part of small, pre-existing subpopulations that selectively escaped under therapeutic challenge. Moreover, the ClonTracer approach enabled quantitative assessment of the ability of combination treatments to suppress resistant clones. These findings suggest that resistant clones are present before treatment, which would make up-front therapeutic combinations that target non-overlapping resistance a preferred approach. Thus, ClonTracer barcoding may be a valuable tool for optimizing therapeutic regimens with the goal of curative combination therapies for cancer.

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Background UW Medicine was one of the first health systems to encounter and treat COVID-19 patients in the United States, starting in late February 2020. Objective Here we describe the rapid rollout of capabilities by UW Medicine Information Technology Services (ITS) to support our clinical response to the COVID-19 pandemic and provide recommendations for health systems to urgently consider, as they plan their own response to this and potentially other future pandemics. Methods Our recommendations include establishing a hospital incident command structure that includes tight integration with IT, creating automated dashboards for incident command, optimizing emergency communication to staff and patients, and preparing human resources, security, other policies, and equipment to support the transition of all nonessential staff to telework. We describe how UW Medicine quickly expanded telemedicine capabilities to include most primary care providers and increasing numbers of specialty providers. We look at how we managed expedited change control processes to quickly update electronic health records (EHR) with new COVID-19 laboratory and clinical workflows. We also examine the integration of new technology such as tele-intensive care (ICU) equipment and improved integration with teleconferencing software into our EHR. To

BackgroundMatched sequencing of both tumor and normal tissue is routinely used to classify variants of uncertain significance (VUS) into somatic vs. germline. However, assays used in molecular diagnostics focus on known somatic alterations in cancer genes and often only sequence tumors. Therefore, an algorithm that reliably classifies variants would be helpful for retrospective exploratory analyses. Contamination of tumor samples with normal cells results in differences in expected allelic fractions of germline and somatic variants, which can be exploited to accurately infer genotypes after adjusting for local copy number. However, existing algorithms for determining tumor purity, ploidy and copy number are not designed for unmatched short read sequencing data.ResultsWe describe a methodology and corresponding open source software for estimating tumor purity, copy number, loss of heterozygosity (LOH), and contamination, and for classification of single nucleotide variants (SNVs) by somatic status and clonality. This R package, PureCN, is optimized for targeted short read sequencing data, integrates well with standard somatic variant detection pipelines, and has support for matched and unmatched tumor samples. Accuracy is demonstrated on simulated data and on real whole exome sequencing data.ConclusionsOur algorithm provides accurate estimates of tumor purity and ploidy, even if matched normal samples are not available. This in turn allows accurate classification of SNVs. The software is provided as open source (Artistic License 2.0) R/Bioconductor package PureCN (http://bioconductor.org/packages/PureCN/).Electronic supplementary materialThe online version of this article (doi:10.1186/s13029-016-0060-z) contains supplementary material, which is available to authorized users.

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Identification of population-based factors should influence regional and national policy.

Results of lipase production by a soil microorganism, expressed in terms of lipolytic activities of the culture were modeled and optimized using artificial neural network (ANN) and genetic algorithm (GA) techniques, respectively. ANN model, developed based on back propagation algorithm, were highly accurate in predicting the system with coefficient of determination (R2) value being close to 0.99. Optimization using GA, based on the ANN model developed, resulted in the following values of the media constituents: 9.991 ml/l oil, 0.100 g/l MgSO4 and 0.009 g/l FeSO4. And a maximum value of 7.69 U/ml of lipolytic activity at 72 h of culture was obtained using the ANN-GA method, which was found to be 8.8% higher than the maximum values predicted by a statistical regression-based optimization technique-response surface methodology.