Biology subjects

Drake, J. M.

Publications and source records attributed to Drake, J. M..

25 records · Page 2Linked to original sources

bioRxiv2019

Targeting RET Kinase in Neuroendocrine Prostate Cancer

Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression and may be a novel treatment option.\n\nStatement of SignificanceThere are limited treatment options for patients with metastatic aggressive variant prostate cancer and none are curative. Here we identified aberrantly activated RET kinase signaling in multiple models of NEPC. Inhibiting RET restricted tumor growth, providing a novel approach for treating NEPC.

cancer biology↗

bioRxiv2019

Microclimate and larval habitat density predict adult Aedes albopictus abundance in urban areas

The Asian tiger mosquito, Aedes albopictus, transmits several arboviruses of public health importance, including chikungunya and Zika. Since its introduction to the United States in 1985, the species has invaded over forty states, including temperate areas not previously at risk of Aedes-transmitted arboviruses. Mathematical models incorporate climatic variables in predictions of site-specific Ae. albopictus abundances to identify human populations at risk of disease. However, these models rely on coarse resolutions of environmental data that may not accurately represent the climatic profile experienced by mosquitoes in the field, particularly in climatically-heterogeneous urban areas. In this study, we pair field surveys of larval and adult Ae. albopictus mosquitoes with site-specific microclimate data across a range of land use types to investigate the relationships between microclimate, density of larval habitat, and adult mosquito abundance and determine whether these relationships change across an urban gradient. We find no evidence for a difference in larval habitat density or adult abundance between rural, suburban, and urban land classes. Adult abundance increases with increasing larval habitat density, which itself is dependent on microclimate. Adult abundance is strongly explained by microclimate variables, demonstrating that theoretically derived, lab-parameterized relationships in ectotherm physiology apply to the field. Our results provide support for the continued use of temperature-dependent models to predict Ae. albopictus abundance in urban areas.

ecology↗

bioRxiv2019

Do Synthesis Centers Synthesize? A Semantic Analysis of Diversity and Performance

Synthesis centers are a recently-developed form of scientific organization that catalyzes and supports a form of interdisciplinary research that integrates diverse theories, methods and data across spatial or temporal scales, scientific phenomena, and forms of expertise to increase the generality, parsimony, applicability, or empirical soundness of scientific explanations. Research has shown the synthesis working group to be a distinctive form of scientific collaboration that reliably produces consequential, high-impact publications, but no one has asked: do synthesis working groups produce publications that are substantially more diverse than those produced outside of synthesis centers, and if so, how and with what effects? We have investigated these questions through a novel textual analysis. We found that if diversity is measured solely by mean difference in the Rao-Stirling (aggregate) measure of diversity, then the answer is no. But synthesis center papers have significantly greater variety and balance, but significantly lower disparity, than papers in the reference corpus. Synthesis center influence is mediated by the greater size of synthesis center collaborations (numbers of authors, distinct institutions, and references) but even when taking size into account, there is a persistent direct effect: synthesis center papers have significantly greater variety and balance, but less disparity, than papers in the reference corpus. We conclude by inviting further exploration of what this novel textual analysis approach might reveal about interdisciplinary research and by offering some practical implications of our results.

scientific communication and education↗

bioRxiv2018

Estimating the distance to an epidemic threshold

The epidemic threshold of the susceptible-infected-recovered (SIR) model is a boundary separating parameters that can permit epidemics from those that cannot. This threshold corresponds to points where the stability of the systems equilibrium reaches zero. Consequently, we use the average rate at which deviations from the equilibrium shrink to define a distance to this threshold. However, the vital dynamics of the host population may occur slowly even when transmission is far from threshold levels. Here we show analytically how such slow dynamics can prevent estimation of the distance to the threshold for some individual variables of the model. Although these results are exact only in the limit of long-term observation of a large system, we find that they still provide useful insight into the behaviour of estimates from simulations with a range of population sizes, environmental noise, and observation schemes. Having established some guidelines about when estimates are accurate, we then illustrate how multiple distance estimates can be used to estimate the rate of approach to the threshold. The estimation approach is general and may be applicable to zoonotic pathogens such as MERS-CoV as well as vaccine-preventable diseases such as measles.

epidemiology↗

bioRxiv2017

Disentangling reporting and disease transmission using second order statistics

Second order statistics such as the variance and autocorrelation can be useful indicators of the stability of randomly perturbed systems, in some cases providing early warning of an impending, dramatic change in the systems dynamics. One specific application area of interest is the surveillance of infectious diseases. In the context of disease (re-)emergence, a goal could be to have an indicator that is informative of whether the system is approaching the epidemic threshold, a point beyond which a major outbreak becomes possible. Prior work in this area has provided some proof of this principle but has not analytically treated the effect of imperfect observation on the behavior of indicators. This work provides expected values for several moments of the number of reported cases, where reported cases follow a binomial or negative binomial distribution with a mean based on the number of deaths in a birth-death-immigration process over some reporting interval. The normalized second factorial moment and the decay time of the number of case reports are two indicators that are insensitive to the reporting probability. Simulation is used to show how this insensitivity could be used to distinguish a trend of increased reporting from a trend of increased transmission. The simulation study also illustrates both the high variance of estimates and the possibility of reducing the variance by avE. ODea eraging over an ensemble of estimates from multiple time series.

epidemiology↗

bioRxiv2017

Carry-over effects of larval microclimate on the transmission potential of a mosquito-borne pathogen

Climate shapes the transmission of mosquito-borne pathogens through impacts on both the vector and the pathogen. In addition to direct effects of the environment, carry-over effects from previous life history stages can influence mosquito traits relevant to disease transmission. While this has been explored in a laboratory setting, the net effect of temperature-mediated carry-over effects due to relevant environmental variation in the larval stage is ambiguous. Here, we use data collected from a semi-field experiment investigating dengue dynamics in Aedes albopictus across a natural environmental gradient to parameterize a dengue transmission model. We reared Ae. albopictus across three different land classes characterized by their proportion of impervious surface. Emerged females were offered a dengue infectious bloodmeal, kept at a constant 27 {degrees}C, and assayed for infection, dissemination, and infectiousness 21 days post infection. Incorporating carry-over effects of larval environment on measures of vector competence resulted in lower predicted dengue transmission potential across land class and season, however a strong positive relationship with larval environmental temperature remained. Given the significant impact of carry-over effects, future mechanistic models of disease transmission should include both direct and carry-over effects of environmental temperature.

ecology↗

bioRxiv2017

Anticipating Emerging Arboviruses: What Comes After Zika?

New vector-borne diseases have emerged on multiple occasions over the last several decades, raising fears that they may become established within the United States. Here, we provide a watchlist of flaviviruses with high potential to emerge in the US, identified using new statistical techniques for mining the associations in partially observed data, to allow the public health community to better target surveillance.

ecology↗