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"Chapman, Margaret"
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My very end of the universe : five novellas-in-flash and a study of the form
\"A celebration and study of an increasingly popular genre: the novella-in-flash, a novella built of standalone flash stories.\"--Back cover.
Book
Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer
Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo.
Resistance to therapy can be driven by intratumoral heterogeneity. Here, the authors show that drug tolerant persistent cell populations emerge during treatment, and these emergent populations arise through epigenetically mediated cell state transitions rather than sub population selection.
Journal Article
Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer
Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cancer cells to a drug-tolerant state, for example through epithelial-to-mesenchymal transition or transition to a cancer stem cell state. However, many breast tumors are a heterogeneous mixture of cell types with numerous epigenetic states in addition to stem-like and mesenchymal phenotypes, and the dynamic behavior of this heterogeneous mixture in response to drug treatment is not well-understood. Recently, we showed that plasticity between differentiation states, as identified with intracellular markers such as cytokeratins, is linked to resistance to specific targeted therapeutics. Understanding the dynamics of differentiation-state transitions in this context could facilitate the development of more effective treatments for cancers that exhibit phenotypic heterogeneity and plasticity. In this work, we develop computational models of a drug-treated, phenotypically heterogeneous triple-negative breast cancer (TNBC) cell line to elucidate the feasibility of differentiation-state transition as a mechanism for therapeutic escape in this tumor subtype. Specifically, we use modeling to predict the changes in differentiation-state transitions that underlie specific therapy-induced changes in differentiation-state marker expression that we recently observed in the HCC1143 cell line. We report several statistically significant therapy-induced changes in transition rates between basal, luminal, mesenchymal, and non-basal/non-luminal/non-mesenchymal differentiation states in HCC1143 cell populations. Moreover, we validate model predictions on cell division and cell death empirically, and we test our models on an independent data set. Overall, we demonstrate that changes in differentiation-state transition rates induced by targeted therapy can provoke distinct differentiation-state aggregations of drug-resistant cells, which may be fundamental to the design of improved therapeutic regimens for cancers with phenotypic heterogeneity.
Journal Article
Emergence and influence of sequence bias in evolutionarily malleable, mammalian tandem arrays
Background
The radiation of mammals at the extinction of the dinosaurs produced a plethora of new forms—as diverse as bats, dolphins, and elephants—in only 10–20 million years. Behind the scenes, adaptation to new niches is accompanied by extensive innovation in large families of genes that allow animals to contact the environment, including chemosensors, xenobiotic enzymes, and immune and barrier proteins. Genes in these “outward-looking” families are allelically diverse among humans and exhibit tissue-specific and sometimes stochastic expression.
Results
Here, we show that these tandem arrays of outward-looking genes occupy AT-biased isochores and comprise the “tissue-specific” gene class that lack CpG islands in their promoters. Models of mammalian genome evolution have not incorporated the sharply different functions and transcriptional patterns of genes in AT- versus GC-biased regions. To examine the relationship between gene family expansion, sequence content, and allelic diversity, we use population genetic data and comparative analysis. First, we find that AT bias can emerge during evolutionary expansion of gene families in cis. Second, human genes in AT-biased isochores or with GC-poor promoters experience relatively low rates of de novo point mutation today but are enriched for non-synonymous variants. Finally, we find that isochores containing gene clusters exhibit low rates of recombination.
Conclusions
Our analyses suggest that tolerance of non-synonymous variation and low recombination are two forces that have produced the depletion of GC bases in outward-facing gene arrays. In turn, high AT content exerts a profound effect on their chromatin organization and transcriptional regulation.
Journal Article
Correction: Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer
[This corrects the article DOI: 10.1371/journal.pcbi.1006840.].[This corrects the article DOI: 10.1371/journal.pcbi.1006840.].
Journal Article
Case 35-2021: A 50-Year-Old Woman with Pain in the Left Upper Quadrant and Hypoxemia
A 50-year-old woman with sarcoidosis presented with pain in the left upper quadrant and hypoxemia. The oxygen saturation was 85% while she was breathing ambient air, and crackles were present in both lungs. Chest radiography revealed consolidations in the middle and lower lobes with diffuse ground-glass opacities. A diagnostic test was performed.
Journal Article
Drug Smugglers on Drug Smuggling
Drug Smugglers on Drug Smugglingfeatures interviews with 34 convicted drug smugglers -- most of them once major operators -- detailing exactly how drugs are smuggled into the U.S. from Latin America. These sources provide tangible evidence of the risks, rewards, and organization of international drug smuggling.Quoting frequently from their interviews, Decker and Chapman explain how individuals are recruited into smuggling, why they stay in it, and how their roles change over time. They describe the specific strategies their interviewees employed to bring drugs into the country and how they previously escaped apprehension. Over-all, the authors find that drug smuggling is organized in a series of networks which are usually unconnected.This extraordinarily informative book will be of particular interest to law enforcement officials and policymakers, but it will appeal to anyone who wants to know how the drug business actually works.
eBook
Micro-Credit and Community Wildlife Management: Complementary Strategies to Improve Conservation Outcomes in Serengeti National Park, Tanzania
Community wildlife management programs in African protected areas aim to deliver livelihood and social benefits to local communities in order to bolster support for their conservation objectives. Most of these benefits are delivered at the community level. However, many local people are also seeking more individual or household-level livelihood benefits from community wildlife management programs because it is at this level that many of the costs of protected area conservation are borne. Because community wildlife management delivers few benefits at this level, support for their conservation objectives amongst local people often declines. The study investigated the implications of this for reducing poaching in Serengeti National Park, Tanzania. Three community wildlife management initiatives undertaken by Park management were compared with regard to their capacity to deliver the individual and household-level benefits sought by local people: community conservation services, wildlife management areas and community conservation banks. Interviews were carried out with poachers and local people from four villages in the Western Serengeti including members of village conservation banks, as well as a number of key informants. The results suggest that community conservation banks could, as a complementary strategy to existing community wildlife management programs, potentially provide a more effective means of reducing poaching in African protected areas than community wildlife management programs alone.
Journal Article
Excellence in innovative implementation of clinical guidelines - the empowerment of the consumer with chronic kidney disease
In October 2011, the Caring for Australasians Renal Impairment (CARI) Guidelines (Kelly et al., 2005) and the Kidney Disease Outcomes Quality Initiative (KDOQI) (Vascular Access Working Group, 2006) were reviewed and developed into a care pathway to facilitate the new model of case management for all patients with chronic kidney disease. It has then subsequently been embedded into clinical practice.
Journal Article