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"Weber, Barbara"
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Synthetic lethality as an engine for cancer drug target discovery
The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes). Functional genomic screening based on the genetic concept of synthetic lethality provides an avenue to discover drug targets in all these areas. Although synthetic lethality is not a new idea, recent advances, including CRISPR-based gene editing, have made possible systematic screens for synthetic lethal drug targets in human cancers. Such approaches have broad potential to drive the discovery of the next wave of genetic cancer targets and ultimately the introduction of effective medicines that are still needed for most cancers.
Journal Article
Infrastructure as an Asset Class
Clear, comprehensive guidance toward the global infrastructure investment market
Infrastructure As An Asset Class is the leading infrastructure investment guide, with comprehensive coverage and in-depth expert insight. This new second edition has been fully updated to reflect the current state of the global infrastructure market, its sector and capital requirements, and provides a valuable overview of the knowledge base required to enter the market securely. Step-by-step guidance walks you through individual infrastructure assets, emphasizing project financing structures, risk analysis, instruments to help you understand the mechanics of this complex, but potentially rewarding, market. New chapters explore energy, renewable energy, transmission and sustainability, providing a close analysis of these increasingly lucrative areas. The risk profile of an asset varies depending on stage, sector and country, but the individual structure is most important in determining the risk/return profile. This book provides clear, detailed explanations and invaluable insight from a leading practitioner to give you a solid understanding of the global infrastructure market.
* Get up to date on the current global infrastructure market
* Investigate individual infrastructure assets step-by-step
* Examine illustrative real-world case studies
* Understand the factors that determine risk/return profiles
Infrastructure continues to be an area of global investment growth, both in the developed world and in emerging markets. Conditions continually change, markets shift and new considerations arise; only the most current reference can supply the right information practitioners need to be successful. Infrastructure As An Asset Class provides clear reference based on the current global infrastructure markets, with in-depth analysis and expert guidance toward effective infrastructure investment.
eBook
Womens work
Womens work was a magazine edited by Alison Knowles and Annea Lockwood that featured text-based and instructional performance scores by twenty-five women artists. In the original publication of Issue 1, Nye Ffarrabas appeared as Bici Forbes and Annea Lockwood appeared as Anna Lockwood. In the original publication of Issue 2, Ann Noël appeared as Ann Williams.
Book
An Interactive Method for Detection of Process Activity Executions from IoT Data
The increasing number of IoT devices equipped with sensors and actuators pervading every domain of everyday life allows for improved automated monitoring and analysis of processes executed in IoT-enabled environments. While sophisticated analysis methods exist to detect specific types of activities from low-level IoT data, a general approach for detecting activity executions that are part of more complex business processes does not exist. Moreover, dedicated information systems to orchestrate or monitor process executions are not available in typical IoT environments. As a consequence, the large corpus of existing process analysis and mining techniques to check and improve process executions cannot be applied. In this work, we develop an interactive method guiding the analysis of low-level IoT data with the goal of detecting higher-level process activity executions. The method is derived following the exploratory data analysis of an IoT data set from a smart factory. We propose analysis steps, sensor-actuator-activity patterns, and the novel concept of activity signatures that are applicable in many IoT domains. The method shows to be valuable for the early stages of IoT data analyses to build a ground truth based on domain knowledge and decisions of the process analyst, which can be used for automated activity detection in later stages.
Journal Article
Dwelling and Departure: Beginning Disputes between Arendt and Heidegger
In “Letter on Humanism,” Martin Heidegger juxtaposes the notion of homelessness (Heimlosigkeit) with home-coming (Heimholung), i.e. the reawakening to our original relationship to Being. This focus on dwelling in Being represents an interesting modification from his earlier study of “incipience” (Anfang), which emphasizes departure. We follow the critique of this shift in thinking in Hannah Arendt’s work, beginning with a short allegory titled “Heidegger the Fox” (1953). We suggest that reading this allegory in the light of Arendt’s decades-long debate with Heidegger illuminates the tense relationship between dwelling and incipience (or in her terms, “natality”). Though we do not attempt a complete analysis of Heidegger and Arendt’s works here, we aim to draw out specific movements of their thinking. We suggest that Arendt’s concept of natality, which, though partly influenced by Heidegger, ultimately challenges the authenticity of Heidegger’s solitary, silent thinker who dwells in the House of Being. In the back and forth between their thinking an unresolvable tension between dwelling and departure arises as the existential fissure.
Journal Article
Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies
Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP‐ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady‐state concentration (Css) at the approved dose was compared to the in vitro cell potency (half‐maximal inhibitory concentration (IC50)). Average steady‐state area under the plasma concentration‐time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer‐reviewed journal articles. The Css was remarkably similar to the IC50. The median Css/IC50 value was 1.2, and 76% of the values were within 3‐fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a Css/IC50 value > 25. Seven other therapies targeting the same 3 kinases had much lower Css/IC50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first‐in‐human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and Css exceeds a potency threshold. This potency‐guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.
Journal Article
MicroRNAs Exhibit High Frequency Genomic Alterations in Human Cancer
MicroRNAs (miRNAs) are endogenous noncoding RNAs, which negatively regulate gene expression. To determine genomewide miRNA DNA copy number abnormalities in cancer, 283 known human miRNA genes were analyzed by high-resolution arraybased comparative genomic hybridization in 227 human ovarian cancer, breast cancer, and melanoma specimens. A high proportion of genomic loci containing miRNA genes exhibited DNA copy number alterations in ovarian cancer (37.1%), breast cancer (72.8%), and melanoma (85.9%), where copy number alterations observed in >15% tumors were considered significant for each miRNA gene. We identified 41 miRNA genes with gene copy number changes that were shared among the three cancer types (26 with gains and 15 with losses) as well as miRNA genes with copy number changes that were unique to each tumor type. Importantly, we show that miRNA copy changes correlate with miRNA expression. Finally, we identified high frequency copy number abnormalities of Dicerl, Argonaute2, and other miRNA-associated genes in breast and ovarian cancer as well as melanoma. These findings support the notion that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.
Journal Article
Aging and Chronic Sun Exposure Cause Distinct Epigenetic Changes in Human Skin
Epigenetic changes are widely considered to play an important role in aging, but experimental evidence to support this hypothesis has been scarce. We have used array-based analysis to determine genome-scale DNA methylation patterns from human skin samples and to investigate the effects of aging, chronic sun exposure, and tissue variation. Our results reveal a high degree of tissue specificity in the methylation patterns and also showed very little interindividual variation within tissues. Data stratification by age revealed that DNA from older individuals was characterized by a specific hypermethylation pattern affecting less than 1% of the markers analyzed. Interestingly, stratification by sun exposure produced a fundamentally different pattern with a significant trend towards hypomethylation. Our results thus identify defined age-related DNA methylation changes and suggest that these alterations might contribute to the phenotypic changes associated with skin aging.
Journal Article