Organizing knowledge to enable personalization of medicine in cancer

Interpretation of the clinical significance of genomic alterations remains the most severe bottleneck preventing the realization of personalized medicine in cancer. We propose a knowledge commons to facilitate collaborative contributions and open discussion of clinical decision-making based on genomic events in cancer.     

Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy

Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10^-7). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10^-7. Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.     

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

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Collaborating with recreational fishers to inform fisheries management: Estimating population abundance for an iconic freshwater crayfish

Can the abundance of fish populations be effectively determined by the collection of scientific research with support from recreational fishers? Collecting and analysing fishing data from recreational fishers to aid management are not new; however, engaging fishers in a scientific survey design to produce specific population estimates is rarely undertaken. We engaged recreational fishers to assist with field sampling to provide an estimate Murray Crayfish (Euastacus armatus von Martens, 1866) abundance at three sites on the Edward River which were recently impacted by an extreme blackwater disturbance. Employing mark‐resight models, fishers undertook crayfish surveys and produced research data which estimated adult population sizes of Murray Crayfish in the studied reaches ranging between 94.27 ± 24.72 individuals (Below Stevens) and 450.01 ± 175.30 individuals (Twin Rivers). Both the effective undertaking of the mark‐resight designs in collaboration with fishers and acquiring population abundance estimates for Murray Crayfish in a river reach are concepts which have not previously been published and are important attributes for the management of aquatic species.     

Asymptotic Relative Risk Results from a Simplified Armitage and Doll Model of Carcinogenesis

We examine basic asymptotic properties of relative risk for two families of generalized Erlang processes (where each one is based off of a simplified Armitage and Doll multistage model) in order to predict relative risk data from cancer. The main theorems that we are able to prove are all corroborated by large clinical studies involving relative risk for former smokers and transplant recipients. We then show that at least some of these theorems do not extend to other Armitage and Doll multistage models. We conclude with suggestions for lifelong increased cancer screening for both former smoker and transplant recipient subpopulations of individuals and possible future directions of research.     

Revisiting Beverton–Holt recruitment in the presence of variation in food availability

Understanding density-dependent changes in juvenile survival and growth rates is of great importance because these rates determine recovery rates for imperiled populations and/or sustainable harvest rates. Unfortunately, the mechanisms leading to density dependent survival and growth are among the least understood process in biology and fisheries. Previous work has shown that small fish may vary foraging times to achieve a target growth rate, resulting in the well-known Beverton–Holt recruitment function with variation in food availability affected the initial slope of the recruitment curve. We amend their derivation to show that incorporating fish growth under a variety of evolutionary strategies for balancing foraging time and predation risk still leads to recruitment approximately as expected under the Beverton–Holt recruitment model but that changing food availability affects both the initial slope and maximum recruitment level. We demonstrate that when food availability is known to vary over time, these models often result in a more parsimonious alternative than the standard Beverton–Holt function. Further, Beverton–Holt recruitment is expected when foraging times are adjusted to balance fitness gains from growth against mortality risk. Finally, linking recruitment success to food availability warns that species with high scope for density dependent survival (high compensation ratio or steepness) may be extremely sensitive to changes in available food densities. This work emphasizes the sensitivity of stock-recruitment parameters to food availability and strongly suggests a need to carefully monitor lower trophic levels to better understand and predict dramatic changes in juvenile recruitment and carrying capacity.     

COSTS AND BENEFITS OF A PREDATOR-INDUCED POLYPHENISM IN THE GRAY TREEFROG HYLA CHRYSOSCELIS

The phenotypes of gray treefrog (Hyla chrysoscelis) tadpoles vary depending on whether predators are present in the pond. Tadpoles reared in ponds with predatory dragonfly larvae are relatively inactive compared with tadpoles in predator-free ponds, and have relatively large, brightly colored tailfins with dark spots along the margins. Models for the evolution of plasticity predict that induced phenotypes such as this should confer high fitness relative to the typical phenotype when in the presence of predators, but should be costly when the predator is absent. Our study tested for the predicted fitness trade-off in H. chrysoscelis by first rearing tadpoles in mesocosms under conditions that induce the alternate phenotypes, and then comparing the performance of both phenotypes in both environments. We generated the two phenotypes by rearing tadpoles in 600-liter outdoor artificial ponds that contained either two caged dragonflies (Anax junius) or an empty cage. Tadpoles from the two environments showed significantly different behavior, tail shape, and tail color within two weeks of exposure. We compared the growth and survival of both phenotypes over four weeks in ponds where there was no actual risk of predation. Under these conditions, both phenotypes grew at the same rate, but the predator-induced phenotype had significantly lower survival than the typical phenotype, indicating that induced tadpoles suffered greater mortality from causes other than odonate predation. We tested the susceptibility of both phenotypes to predation by exposing them to dragonflies in 24-h predation trials. The predator-induced phenotype showed a significant survival advantage in these trials. These results confirm that the predator-induced phenotype in H. chrysoscelis larvae is associated with fitness costs and benefits that explain why the defensive phenotype is induced rather than constitutive.     

Large‐scale pest control in New Zealand beech forests

In 2014, baits laced with the poison sodium fluoroacetate (1080) were sown over 694 000 ha of mostly native beech forests in New Zealand to control rats, stoats and possums – a landscape‐scale pest control programme called ‘Battle for our Birds’. This large pest control operation was necessitated by the mast seeding of beech trees which led to irruptions of rodent and stoats which were predicted to lead to decreases in vulnerable native wildlife. In this article, we describe why and how this extensive pest control programme was developed and implemented. We describe the seedfall monitoring that was used to determine the need for large‐scale rodent and stoat control and the response of these predators to this control. We also provide a summary of the bird monitoring that was undertaken to demonstrate the effectiveness or otherwise of the programme.     

Impacts of management practices on bioenergy feedstock yield and economic feasibility on Conservation Reserve Program grasslands

Perennial grass mixtures planted on Conservation Reserve Program (CRP) land are a potential source of dedicated bioenergy feedstock. Long‐term nitrogen (N) and harvest management are critical factors for maximizing biomass yield while maintaining the longevity of grass stands. A six‐year farm‐scale study was conducted to understand the impact of weather variability on biomass yield, determine optimal N fertilization and harvest timing management practices for sustainable biomass production, and estimate economic viability at six CRP sites in the United States. Precipitation during the growing season was a critical factor for annual biomass production across all regions, and annual biomass production was severely reduced when growing season precipitation was below 50% of average. The N rate of 112 kg ha^?1 produced the highest biomass yield at each location. Harvest timing resulting in the highest biomass yield was site‐specific and was a factor of predominant grass type, seasonal precipitation, and the number of harvests taken per year. The use of N fertilizer for yield enhancement unambiguously increased the cost of biomass regardless of the harvest timing for all six sites. The breakeven price of biomass at the farmgate ranged from $37 to $311 Mg^?1 depending on the rate of N application, timing of harvesting, and location when foregone opportunity costs were not considered. Breakeven prices ranged from $69 to $526 Mg^?1 when the loss of CRP land rental payments was included as an opportunity cost. Annual cost of the CRP to the federal government could be reduced by over 8% in the states included in this study; however, this would require the biomass price to be much higher than in the case where the landowner receives the CRP land rent. This field research demonstrated the importance of long‐term, farm‐scale research for accurate estimation of biomass feedstock production and economic viability from perennial grasslands.