Accepted for publication September 26, 2012. Supported by a Team Grant from the Vancouver Coastal Health Research Institute. Study received human ethics committee approval. * Nothing to disclose. † Financial interest and/or other relationship with Sanofi and Abbott. ‡ Financial interest and/or other relationship with Ultrasonix Inc., Cook Inc. and Boston Scientific Corp. § Correspondence: Department of Urological Sciences, University of British Columbia, Level 6, 2775 Laurel St., Vancouver, British Columbia V5Z 1M9, Canada (e-mail: pblack@mail.ubc.ca).
Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank of transplantable patient-derived prostate cancer xenografts that capture the biologic and molecular heterogeneity currently confounding prognostication and therapy development. Xenografts preserved the histopathology, genome architecture, and global gene expression of donor tumors. Moreover, their aggressiveness matched patient observations, and their response to androgen withdrawal correlated with tumor subtype. The panel includes the first xenografts generated from needle biopsy tissue obtained at diagnosis. This advance was exploited to generate independent xenografts from different sites of a primary site, enabling functional dissection of tumor heterogeneity. Prolonged exposure of adenocarcinoma xenografts to androgen withdrawal led to castration-resistant prostate cancer, including the first-in-field model of complete transdifferentiation into lethal neuroendocrine prostate cancer. Further analysis of this model supports the hypothesis that neuroendocrine prostate cancer can evolve directly from adenocarcinoma via an adaptive response and yielded a set of genes potentially involved in neuroendocrine transdifferentiation. We predict that these next-generation models will be transformative for advancing mechanistic understanding of disease progression, response to therapy, and personalized oncology.
EUROPEAN COURT OF JUSTICE CLARIFIES SCOPE OF GUN JUMPING PROHIBITION* Over the last year, we have noted an increased crackdown by competition agencies on so-called “gun jumping” – that is, the…
Abstract Folly, as Johnson said of comedy, has been “particularly unpropitious to definers,” struggling to conceive a notoriously indeterminate term. “Folly” is usually derogatory, pinned on any disbeliever or adversary, telling us as much about the judge as the judged, or ironically laudatory. While “folly” flaunts its maddening elusiveness, fools will rush in where wise men fear to tread. This essay explores the concept of folly, investigates its pertinence for literary criticism, and tests its usefulness in a consideration of literature's greatest fool, Falstaff. The fool's cross-eyed vision always threatens to become a revelation; what starts as impish play may end as prophecy. Fools divide and confuse us, so that we either scant or privilege folly by reducing it to diverting babble or magnifying it into encoded prophecy. A great fool has amazing powers of disorientation: he is an avatar of disequilibrium. Disabled yet enabled, invincible yet particularly vulnerable, the fool is always double, both lightning bolt and lightning rod: his bad luck might bring me good luck, so we make room for fools but keep our distance: there with/but for the grace of God go I. The Fool has a strange duality, like the medieval monarch, two separate “bodies,” one enduring, potent, capable of revival, personifying survival and adaptability; the other marginal, susceptible, provisional, easily hurt. Shakespeare's most majestic fool dramatizes folly's powers, perils, and paradoxes. Foolishly immersed in the “lower bodily element,” Falstaff imagines himself somehow freed from natural law; simultaneously Caliban and Ariel, he is enmired yet aloft, immanent yet transcendent, that quality wonderfully characterized by Bradley as Falstaff 's “inexplicable touch of infinity.” When “Falstaff riseth up” from playing possum, his comic resurrection seems the definitive triumph, “the true and perfect image of life indeed.” This “great fool” not only affirms life but outrageously redeems it with “counterfeit” or bogus scriptural idiom. Falstaff robustly embodies the power of folly and dimly, occasionally perceives its limits. In 2 Henry IV , Falstaff, obviously enfeebled, becomes more the object than the source of humor. The banishment of Falstaff is not humorous and it hurts. As a seemingly imperishable fool, exuberantly enacting folly, Falstaff liberates life from fact, in defiance of reason and pursuit of joy. Falstaff's force draws us all into the field of folly, so that the great fool is our double whose loss we deplore.
ELECTRO RENT APPEALS FIRST EVER CMA FINE FOR GUN JUMPING.* Introduction and Summary An appeal has been launched against the UK competition regulator, the Competition and Markets Authority's…
Abstract Motivation Next-Generation Sequencing has led to the availability of massive genomic datasets whose processing raises many challenges, including the handling of sequencing errors. This is especially pertinent in cancer genomics, e.g. for detecting low allele frequency variations from circulating tumor DNA. Barcode tagging of DNA molecules with unique molecular identifiers (UMI) attempts to mitigate sequencing errors; UMI tagged molecules are polymerase chain reaction (PCR) amplified, and the PCR copies of UMI tagged molecules are sequenced independently. However, the PCR and sequencing steps can generate errors in the sequenced reads that can be located in the barcode and/or the DNA sequence. Analyzing UMI tagged sequencing data requires an initial clustering step, with the aim of grouping reads sequenced from PCR duplicates of the same UMI tagged molecule into a single cluster, and the size of the current datasets requires this clustering process to be resource-efficient. Results We introduce Calib, a computational tool that clusters paired-end reads from UMI tagged sequencing experiments generated by substitution-error-dominant sequencing platforms such as Illumina. Calib clusters are defined as connected components of a graph whose edges are defined in terms of both barcode similarity and read sequence similarity. The graph is constructed efficiently using locality sensitive hashing and MinHashing techniques. Calib’s default clustering parameters are optimized empirically, for different UMI and read lengths, using a simulation module that is packaged with Calib. Compared to other tools, Calib has the best accuracy on simulated data, while maintaining reasonable runtime and memory footprint. On a real dataset, Calib runs with far less resources than alignment-based methods, and its clusters reduce the number of tentative false positive in downstream variation calling. Availability and implementation Calib is implemented in C++ and its simulation module is implemented in Python. Calib is available at https://github.com/vpc-ccg/calib. Supplementary information Supplementary data are available at Bioinformatics online.
The direct current arc is perhaps one of the most simple and versatile of the sources of excitation for spectrographic analysis. Much has been written of its erratic behavior and general unstable character for quantitative work, but nonetheless many satisfactory analyses are routinely performed with this source.
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