Epidemiological and evolutionary consequences of periodicity in treatment coverage

Host heterogeneity is a key driver of host–pathogen dynamics. In particular, the use of treatments against infectious diseases creates variation in quality among hosts, which can have both epidemiological and evolutionary consequences. We present a general theoretical model to highlight the consequences of different imperfect treatments on pathogen prevalence and evolution. These treatments differ in their action on host and pathogen traits. In contrast with previous studies, we assume that treatment coverage can vary in time, as in seasonal or pulsed treatment strategies. We show that periodic treatment strategies can limit both disease spread and virulence evolution, depending on the type of treatment. We also introduce a new method to analytically calculate the selection gradient in periodic environments, which allows our predictions to be interpreted using the concept of reproductive value, and can be applied more generally to analyse eco-evolutionary dynamics in class-structured populations and fluctuating environments.

Generation and characterization of a mitotane-resistant adrenocortical cell line

Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines. After long-term pulsed treatment of HAC-15 human adrenocortical carcinoma cells with 70 µM mitotane, we isolated monoclonal cell populations of treated cells and controls and assessed their respective mitotane sensitivities by MTT assay. We performed exome sequencing and electron microscopy, conducted gene expression microarray analysis and determined intracellular lipid concentrations in the presence and absence of mitotane. Clonal cell lines established after pulsed treatment were resistant to mitotane (IC50 of 102.2 ± 7.3 µM (n = 12) vs 39.4 ± 6.2 µM (n = 6) in controls (biological replicates, mean ± s.d., P = 0.0001)). Unlike nonresistant clones, resistant clones maintained normal mitochondrial and nucleolar morphology during mitotane treatment. Resistant clones largely shared structural and single nucleotide variants, suggesting a common cell of origin. Resistance depended, in part, on extracellular lipoproteins and was associated with alterations in intracellular lipid homeostasis, including levels of free cholesterol, as well as decreased steroid production. By gene expression analysis, resistant cells showed profound alterations in pathways including steroid metabolism and transport, apoptosis, cell growth and Wnt signaling. These studies establish an in vitro model of mitotane resistance in ACC and point to underlying molecular mechanisms. They may enable future studies to overcome resistance in vitro and improve ACC treatment in vivo.

Chronic myeloid leukemia model with periodic pulsed treatment

In this work we develop a mathematical model of chronic myeloid leukemia including treatment with instantaneous effects. Our analysis focuses on the values of growth rate γ which give either stability or instability of the disease free equilibrium. If the growth rate γ of sensitive leukemic stem cells is less than some threshold γ * , we obtain the stability of disease free equilibrium which means that the disease is eradicated for any period of treatment τ 0. Otherwise, for γ great than γ * , the period of treatment must be less than some specific value τ * 0. In the critical case when the period of treatment is equal to τ * 0 , we observe a persistence of the tumor, which means that the disease is viable. Dans ce travail, nous développons un modèle mathématique de la leucémie myéloïde chronique avec un traitement à effets instantanés. Notre analyse se focalise sur les valeurs du taux de croissance γ pour avoir la stabilité ou l'instabilité de l'équilibre sans maladie. Si le taux de croissance γ des cellules souches leucémiques sensibles est inférieur à un seuil γ * , nous obtenons la stabilité d'un équilibre sans maladie, ce qui signifie que la maladie sera éradiquée pour toute période de traitement τ 0. Sinon, pour γ supérieur à γ * , la durée du traitement doit être inférieure à une valeur spécifique τ * 0. Dans le cas critique où la période de traitement est égale à τ * 0 , nous observons une persistance de la tumeur, ce qui signifie que la maladie est viable.

Responses to nitrate pollution, warming and density in common frog tadpoles (Rana temporaria)

Amphibians face a variety of anthropogenic environmental perturbations that could act alone or in combination to influence population size. We investigated interactive effects of warming conditions, a moderate pulse of nitrogen pollution, and conspecific density on larvae of the common frog, Rana temporaria. The 16-day experiment had a 2 × 2 × 2 factorial design implemented in 80-l outdoor mesocosms. High density and warm temperature both resulted in reduced activity and visibility; tadpoles grew and developed more quickly at low density and high temperature. The high-nitrogen treatment did not influence behavior, growth, or development rate. We attribute this to several realistic features of our study, including a pulsed treatment application and natural denitrification within the mesocosms. There was only a single interaction among the three factors: higher temperature exacerbated density-dependence in growth rate. These results illustrate that climate warming may benefit temperate amphibians, although the benefits may be counteracted by enhanced larval crowding.