Large efforts dedicated to detect somatic alterations across tumor genomes/exomes are expected to produce significant improvements in precision cancer medicine. However, high inter-tumor ...heterogeneity is a major obstacle to developing and applying therapeutic targeted agents to treat most cancer patients. Here, we offer a comprehensive assessment of the scope of targeted therapeutic agents in a large pan-cancer cohort. We developed an in silico prescription strategy based on identification of the driver alterations in each tumor and their druggability options. Although relatively few tumors are tractable by approved agents following clinical guidelines (5.9%), up to 40.2% could benefit from different repurposing options, and up to 73.3% considering treatments currently under clinical investigation. We also identified 80 therapeutically targetable cancer genes.
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•Driver genes are comprehensively identified across a large pan-cancer cohort•In silico prescription links approved or experimental targeted therapies to patients•Up to 73.3% of patients could benefit from agents in clinical stages•80 therapeutically unexploited targetable cancer driver genes are identified
Using a large pan-cancer cohort, Rubio-Perez et al. develop an in silico drug prescription strategy based on driver alterations in each tumor and their druggability options and use it to identify druggable targets and promising repurposing opportunities.
Value of strong ties to disconnected others McFadyen, M. Ann; Semadeni, Matthew; Cannella, Albert A
Organization science (Providence, R.I.),
05/2009, Letnik:
20, Številka:
3
Journal Article
Recenzirano
Knowledge creation requires the combination and exchange of diverse and overlapping knowledge inputs as individuals interact with exchange partners to create new knowledge. In this study, we examine ...knowledge creation among university research scientists as a function of their professional (ego) networks—those others with whom they collaborate for the purpose of creating new knowledge. We propose that knowledge creation relies, in part, on two attributes of a researcher's professional network structure—average tie strength and ego network density—and we provide insights into how these attributes jointly affect knowledge creation. Our study of over 7,300 scientific publications by 177 research scientists working with more than 14,000 others over an 11-year period provides evidence that the relationship between a research scientist's professional network and knowledge creation depends on both ego network density and average tie strength. Our evidence suggests that both attributes affect knowledge creation. Moreover, average tie strength interacts with density to affect knowledge creation such that researchers who maintain mostly strong ties with research collaborators who themselves comprise a sparse network have the highest levels of new knowledge creation.
Diverse effects of nano- and microplastic (NMP) have been demonstrated in the laboratory. We provide a broad review of current knowledge on occurrence, measurement, modeling approaches, fate, ...exposure, effects, and effect thresholds as regard to microplastics in the aquatic environment. Using this information, we perform a 'proof of concept' risk assessment for NMP, accounting for the diversity of the material. New data is included showing how bioturbation affects exposure, and exposure is evaluated based on literature data and model analyses. We review exposure and effect data and provide a worst case risk characterization, by comparing HC
5
effect thresholds from 'all inclusive' Species Sensitivity Distributions (SSDs) with the highest environmental concentrations reported. HC
5
values show wide confidence intervals yet suggest that sensitive aquatic organisms in near-shore surface waters might be at risk.
Human exposure to microplastic is recognized as a global problem, but the uncertainty, variability, and lifetime accumulation are unresolved. We provide a probabilistic lifetime exposure model for ...children and adults, which accounts for intake via eight food types and inhalation, intestinal absorption, biliary excretion, and plastic-associated chemical exposure via a physiologically based pharmacokinetic submodel. The model probabilistically simulates microplastic concentrations in the gut, body tissue, and stool, the latter allowing validation against empirical data. Rescaling methods were used to ensure comparability between microplastic abundance data. Microplastic (1-5000 μm) median intake rates are 553 particles/capita/day (184 ng/capita/day) and 883 particles/capita/day (583 ng/capita/day) for children and adults, respectively. This intake can irreversibly accumulate to 8.32 × 10
(90% CI, 7.08 × 10
-1.91 × 10
) particles/capita or 6.4 (90% CI, 0.1-2.31 × 10
) ng/capita for children until age 18, and up to 5.01 × 10
(90% CI, 5.25 × 10
-9.33 × 10
) particles/capita or 40.7 (90% CI, 0.8-9.85 × 10
) ng/capita for adults until age 70 in the body tissue for 1-10 μm particles. Simulated microplastic concentrations in stool agree with empirical data. Chemical absorption from food and ingested microplastic of the nine intake media based on biphasic, reversible, and size-specific sorption kinetics, reveals that the contribution of microplastics to total chemical intake is small. The as-yet-unknown contributions of other food types are discussed in light of future research needs.
Because of their diverse sizes, shapes, and densities, environmental microplastics are often perceived as complex. Many studies struggle with this complexity and either address only a part of this ...diversity or present data using discrete classifications for sizes, shapes, and densities. We argue that such classifications will never be fully satisfactory, as any definition using classes does not capture the essentially continuous nature of environmental microplastic. Therefore, we propose to simplify microplastics by fully defining them through a three-dimensional (3D) probability distribution, with size, shape, and density as dimensions. In addition to introducing the concept, we parametrize these probability distributions, using empirical data. This parametrization results in an approximate yet realistic representation of “true” environmental microplastic. This approach to simplifying microplastic could be applicable to exposure measurements, effect studies, and fate modeling. Furthermore, it allows for easy comparison between studies, irrespective of sampling or laboratory setup. We demonstrate how the 3D probability distribution of environmental versus ingested microplastic can be helpful in understanding the bioavailability of and exposure to microplastic. We argue that the concept of simplified microplastic will also be helpful in probabilistic risk modeling, which would greatly enhance our understanding of the risk that microplastics pose to the environment.
CEO Duality Krause, Ryan; Semadeni, Matthew; Cannella, Albert A.
Journal of management,
01/2014, Letnik:
40, Številka:
1
Journal Article
Recenzirano
CEO duality—the practice of a single individual serving as both CEO and board chair—has been the subject of academic interest for more than 20 years. In that time, boards’ use of CEO duality has ...fluctuated and the scholarly conceptualizations of the phenomenon have become more complex. As such, the need to understand CEO duality has only increased with time. We review and integrate the disparate literature on this topic so that future attempts to study it will benefit from a more complete understanding of the knowledge already produced. We review the demonstrated antecedents and consequences of CEO duality, pointing out that while much work has been done in this area, much remains that we do not understand. Finally, we offer new theoretical, methodological, and contextual directions that researchers could explore to extend knowledge about CEO duality.
The hypothesis that ‘microplastic will transfer hazardous hydrophobic organic chemicals (HOC) to marine animals’ has been central to the perceived hazard and risk of plastic in the marine ...environment. The hypothesis is often cited and has gained momentum, turning it into paradigm status. We provide a critical evaluation of the scientific literature regarding this hypothesis. Using new calculations based on published studies, we explain the sometimes contrasting views and unify them in one interpretive framework. One explanation for the contrasting views among studies is that they test different hypotheses. When reframed in the context of the above hypothesis, the available data become consistent. We show that HOC microplastic-water partitioning can be assumed to be at equilibrium for most microplastic residing in the oceans. We calculate the fraction of total HOC sorbed by plastics to be small compared to that sorbed by other media in the ocean. We further demonstrate consistency among (a) measured HOC transfer from microplastic to organisms in the laboratory, (b) measured HOC desorption rates for polymers in artificial gut fluids (c) simulations by plastic-inclusive bioaccumulation models and (d) HOC desorption rates for polymers inferred from first principles. We conclude that overall the flux of HOCs bioaccumulated from natural prey overwhelms the flux from ingested microplastic for most habitats, which implies that microplastic ingestion is not likely to increase the exposure to and thus risks of HOCs in the marine environment.
Prior findings on the association between top management team (TMT) functional diversity and firm performance have been inconsistent. We consider the moderating effects of internal context ...(colocation of TMT members) and external context (environmental uncertainty) on the TMT diversity--firm performance relationship. Additionally, we consider both dominant and intrapersonal functional diversity. In our results from 207 U.S. firms in 11 industries, the effects of TMT functional diversity on firm performance become more positive as the proportion of TMT members with offices in the same location increases. The effects of intrapersonal functional diversity also become more positive as environmental uncertainty increases.
Recent studies suggest size-selective removal of small plastic particles from the ocean surface, an observation that remains unexplained. We studied one of the hypotheses regarding this ...size-selective removal: the formation of a biofilm on the microplastics (biofouling). We developed the first theoretical model that is capable of simulating the effect of biofouling on the fate of microplastic. The model is based on settling, biofilm growth, and ocean depth profiles for light, water density, temperature, salinity, and viscosity. Using realistic parameters, the model simulates the vertical transport of small microplastic particles over time, and predicts that the particles either float, sink to the ocean floor, or oscillate vertically, depending on the size and density of the particle. The predicted size-dependent vertical movement of microplastic particles results in a maximum concentration at intermediate depths. Consequently, relatively low abundances of small particles are predicted at the ocean surface, while at the same time these small particles may never reach the ocean floor. Our results hint at the fate of “lost” plastic in the ocean, and provide a start for predicting risks of exposure to microplastics for potentially vulnerable species living at these depths.
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