Emergence of anti-cancer drug resistance: Exploring the importance of the microenvironmental niche via a spatial model.

Practically, all chemotherapeutic agents lead to drug resistance. Clinically, it is a challenge to determine whether resistance arises prior to, or as a result of, cancer therapy. Further, a number of different intracellular and microenvironmental factors have been correlated with the emergence of drug resistance. With the goal of better understanding drug resistance and its connection with the tumor microenvironment, we have developed a hybrid discrete-continuous mathematical model. In this model, cancer cells described through a particle-spring approach respond to dynamically changing oxygen and DNA damaging drug concentrations described through partial differential equations. We thoroughly explored the behavior of our self-calibrated model under the following common conditions: a fixed layout of the vasculature, an identical initial configuration of cancer cells, the same mechanism of drug action, and one mechanism of cellular response to the drug. We considered one set of simulations in which drug resistance existed prior to the start of treatment, and another set in which drug resistance is acquired in response to treatment. This allows us to compare how both kinds of resistance influence the spatial and temporal dynamics of the developing tumor, and its clonal diversity. We show that both pre-existing and acquired resistance can give rise to three biologically distinct parameter regimes: successful tumor eradication, reduced effectiveness of drug during the course of treatment (resistance), and complete treatment failure. When a drug resistant tumor population forms from cells that acquire resistance, we find that the spatial component of our model (the microenvironment) has a significant impact on the transient and long-term tumor behavior. On the other hand, when a resistant tumor population forms from pre-existing resistant cells, the microenvironment only has a minimal transient impact on treatment response. Finally, we present evidence that the microenvironmental niches of low drug/sufficient oxygen and low drug/low oxygen play an important role in tumor cell survival and tumor expansion. This may play role in designing new therapeutic agents or new drug combination schedules

Zonação de comunidade bêntica do entremarés em molhes sob diferente hidrodinamismo na costa norte do estado do Rio de Janeiro, Brasil Zonation of intertidal benthic communities on breakwaters of different hydrodynamics in the north coast of the state of Rio de Janeiro, Brazil

O presente estudo pretende comparar a distribuição vertical da comunidade bêntica na zona entremarés em dois locais compostos por matacões graníticos caracterizados por hidrodinâmica distinta, reflexo da diferença na orientação dos molhes nas praias do Farol de São Tomé (Píer) e na Barra do Furado (Barra), norte do Estado do Rio de Janeiro. Quadrados de 400 cm² foram sobrepostos ao longo de três perfis verticais de ambos os sítios e amostrados através do método de fotoquadrats, desde o nível 0,2 m da maré até o limite superior de Littorina spp. O limite superior dos organismos marinhos foi ampliado na Barra (3,8 m) em relação ao Píer (2,2 m). Quanto à composição taxonômica, nove espécies foram comuns. Chaetomorpha sp., Chondracanthus teedii (Mertens ex Roth) Fredericq e Grateloupia sp. foram exclusivas na Barra, enquanto Tetraclita stalactifera (Lamarck, 1818), Fissurella clench, Gracilaria domingensis (Kützing) Sonder ex Dickie e Hypnea musciformis (Wulfen in Jacqu.) Lamouroux ocorreram somente no Píer. Em ambos os locais, a riqueza e a diversidade de espécies foram superiores nos quadrados intermediários. Os maiores valores foram registrados na Barra. As maiores diferenças nos agrupamentos entre faixas equivalentes de locais distintos ocorreram na faixa eulitorânea superior, seguida pela faixa eulitorânea inferior e franja sublitorânea. Apenas a orla litorânea não revelou diferença significativa entre os locais, mas uma maior extensão desta franja e da faixa eulitorânea superior era bastante evidente. As demais faixas na Barra do Furado foram caracterizadas em grande parte por espécies típicas de ambientes mais expostos como Chaetomorpha sp. na faixa eulitorânea superior e Perna perna (Linnaeus, 1758) na eulitorânea inferior, além de C. teedii e Ulva fasciata Delile, 1813 na franja sublitorânea. No Píer, as diferentes faixas apresentavam distribuição eqüitativa, refletindo um ambiente menos estressante. As diferenças observadas na distribuição vertical dos organismos bênticos, principalmente na extensão das faixas superiores, evidenciam condições de exposição a ondas variáveis.<br>The present study aims to compare the vertical distribution of intertidal benthic communities in two sites composed by granitic boulders with distint hydrodynamics due to different wave swells at Farol de São Tomé (Pier) and Barra do Furado beaches (Barra), both in northern state of Rio de Janeiro. Quadrats of 400 cm² were overlapped along three vertical profiles on each site and were sampled by the photoquadrat method from 0.2 m of the tide level to the upper limit of Littorina spp. The upper limit of the marine organisms was higher at Barra site (3.8 m) than at Píer site (2.2 m). Nine species were common to both sites. Chaetomorpha sp., Chondracanthus teedii (Mertens ex Roth) Fredericq, and Grateloupia sp. were unique to Barra, whereas Tetraclita stalactifera (Lamarck, 1818), Fissurella clench, Gracilaria domingensis (Kützing) Sonder ex Dickie, and Hypnea musciformis (Wulfen in Jacqu.) Lamouroux occurred only at Píer boulders. On both sites species richness and diversity were superior at the intermediate quadrats of the intertidal zone. The highest values were recorded at Barra. The most pronounced assemblage differences between equivalent areas of either site occurred on the lower upper eulittoral band followed by the lower eulittoral and the sub-littoral fringe, respectively. The littoral fringe assemblage was the only one that did not show significant differences among the studied sites, yet a larger range of this fringe and the upper eulittoral band at Barra was quite evident. This site was mostly characterized by species of more exposed areas, such as Chaetomorpha sp. and Perna perna (Linnaeus, 1758) on upper and lower eulittoral bands, and by C. teedii and Ulva fasciata Delile, 1813 on the sub-littoral fringe. At Píer, the intertidal zone showed an even distribution, reflecting a less stressful environment. The differences on vertical distribution of the local benthic, particularly in the extent of the upper bands, indicate the variable conditions of wave exposure