Christine D. Wilson

Bio: Christine D. Wilson is an academic researcher from McMaster University. The author has contributed to research in topics: Galaxy & Star formation. The author has an hindex of 90, co-authored 528 publications receiving 39198 citations. Previous affiliations of Christine D. Wilson include Purdue University & Norwegian Water Resources and Energy Directorate.

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

Abstract: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.

The Herschel-SPIRE instrument and its in-flight performance

Abstract: The Spectral and Photometric Imaging REceiver (SPIRE), is the Herschel Space Observatory`s submillimetre camera and spectrometer It contains a three-band imaging photometer operating at 250, 350 and 500 mu m, and an imaging Fourier-transform spectrometer (FTS) which covers simultaneously its whole operating range of 194-671 mu m (447-1550 GHz) The SPIRE detectors are arrays of feedhorn-coupled bolometers cooled to 03 K The photometer has a field of view of 4' x 8', observed simultaneously in the three spectral bands Its main operating mode is scan-mapping, whereby the field of view is scanned across the sky to achieve full spatial sampling and to cover large areas if desired The spectrometer has an approximately circular field of view with a diameter of 26' The spectral resolution can be adjusted between 12 and 25 GHz by changing the stroke length of the FTS scan mirror Its main operating mode involves a fixed telescope pointing with multiple scans of the FTS mirror to acquire spectral data For extended source measurements, multiple position offsets are implemented by means of an internal beam steering mirror to achieve the desired spatial sampling and by rastering of the telescope pointing to map areas larger than the field of view The SPIRE instrument consists of a cold focal plane unit located inside the Herschel cryostat and warm electronics units, located on the spacecraft Service Module, for instrument control and data handling Science data are transmitted to Earth with no on-board data compression, and processed by automatic pipelines to produce calibrated science products The in-flight performance of the instrument matches or exceeds predictions based on pre-launch testing and modelling: the photometer sensitivity is comparable to or slightly better than estimated pre-launch, and the spectrometer sensitivity is also better by a factor of 15-2

Search-and-replace genome editing without double-strand breaks or donor DNA

Abstract: Most genetic variants that contribute to disease1 are challenging to correct efficiently and without excess byproducts2-5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 edits in human cells, including targeted insertions, deletions, and all 12 types of point mutation, without requiring double-strand breaks or donor DNA templates. We used prime editing in human cells to correct, efficiently and with few byproducts, the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay-Sachs disease (requiring a deletion in HEXA); to install a protective transversion in PRNP; and to insert various tags and epitopes precisely into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, has complementary strengths and weaknesses compared to base editing, and induces much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases.

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Abstract: The stability of the Wnt pathway transcription factor -catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits -catenin-mediated transcription. XAV939 stimulates -catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal

Abstract: The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

Abstract: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

Star formation in galaxies along the hubble sequence

Abstract: Observations of star formation rates (SFRs) in galaxies provide vital clues to the physical nature of the Hubble sequence and are key probes of the evolutionary histories of galaxies. The focus of this review is on the broad patterns in the star formation properties of galaxies along the Hubble sequence and their implications for understanding galaxy evolution and the physical processes that drive the evolution. Star formation in the disks and nuclear regions of galaxies are reviewed separately, then discussed within a common interpretive framework. The diagnostic methods used to measure SFRs are also reviewed, and a self-consistent set of SFR calibrations is presented as an aid to workers in the field. One of the most recognizable features of galaxies along the Hubble sequence is the wide range in young stellar content and star formation activity. This variation in stellar content is part of the basis of the Hubble classification itself (Hubble 1926), and understanding its physical nature and origins is fundamental to understanding galaxy evolution in its broader context. This review deals with the global star formation properties of galaxies, the systematics of those properties along the Hubble sequence, and their implications for galactic evolution. I interpret “Hubble sequence” in this context very loosely, to encompass not only morphological type but other properties such as gas content, mass, bar structure, and dynamical environment, which can strongly influence the largescale star formation rate (SFR).

The Molecular Signatures Database Hallmark Gene Set Collection

Abstract: The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of “hallmark” gene sets as part of MSigDB. Each hallmark in this collection consists of a “refined” gene set, derived from multiple “founder” sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the original founder sets and, by reducing both variation and redundancy, provide more refined and concise inputs for gene set enrichment analysis.

The Global Schmidt law in star forming galaxies

Abstract: Measurements of Hα, H I, and CO distributions in 61 normal spiral galaxies are combined with published far-infrared and CO observations of 36 infrared-selected starburst galaxies, in order to study the form of the global star formation law over the full range of gas densities and star formation rates (SFRs) observed in galaxies. The disk-averaged SFRs and gas densities for the combined sample are well represented by a Schmidt law with index N = 1.4 ± 0.15. The Schmidt law provides a surprisingly tight parametrization of the global star formation law, extending over several orders of magnitude in SFR and gas density. An alternative formulation of the star formation law, in which the SFR is presumed to scale with the ratio of the gas density to the average orbital timescale, also fits the data very well. Both descriptions provide potentially useful "recipes" for modeling the SFR in numerical simulations of galaxy formation and evolution.