BackgroundIrinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions.MethodsColon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity.ResultsBoth pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance.ConclusionsOur results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug-refractory cancers resulting from high expression of ABCG2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0362-9) contains supplementary material, which is available to authorized users.

During the emergence of regional hierarchy around the site of Uci in northwest Yucatan, Mexico, ordinary people affected power relations in at least two ways. First, in the Late Preclassic and Early Classic periods, Uci had the largest ceremonial center and the largest population within a 20 km radius. Uci also physically linked itself to smaller settlements, such as Kancab and Ucanha, by means of a broad stone causeway. Yet Kancab and Ucanha's quadripartite placement of causeways and central plaza suggests that its households created a sacred landscape that gave them a degree of ritual autonomy. Ordinary people impacted power relations a second way by participating in the development of the megalithic architectural style, which was used in the region's most authoritative buildings. The use of this style in domestic platforms illustrates the ability of modest households to make their own decisions and to act in ways that constituted society at large.

New Urbanists advocate for, among other things, spaces in cities where people of various backgrounds can interact. Yet not all interactions lead to the strong social bonds that make diverse communities more durable. The archaeological record provides rich examples of diverse communities that flourished. This article examines an ancient Maya city—Chunchucmil—where preservation of stone walls and pathways provides an unusual opportunity to reconstruct urban design in great detail. Analysis of neighborhood circulation patterns shows that people of very different wealth levels shared space on a daily basis. We present evidence that Chunchucmil’s diverse neighborhoods were also cohesive, and we identify a number of circumstances—worshipping together, working together, and maintaining local control over neighborhood affairs—that help interactions between different kinds of people develop into strong bonds. These circumstances are germane to contemporary contexts.

Despite the success of lidar in making ancient features visible in certain tropical environments, researchers often have difficulty using lidar to identify small, low, non-linear features. This study juxtaposes lidar data with data gathered from pedestrian survey along the Ucí-Cansahcab causeway, located in the Northern Maya lowlands, to assess the degree to which the invisibility of small buildings in lidar imagery affects demographic research. The juxtaposition shows that demographic research with lidar can move forward in some cases once pedestrian survey has been used as a baseline to establish correction factors for using lidar data on their own. Another current barrier to the use of lidar is cost. This paper provides examples of the kinds of questions that can be addressed by projects with smaller budgets and, therefore, smaller amounts of lidar coverage. These questions include site size comparisons and the degree to which settlement clustered around ancient features such as the Ucí-Cansahcab causeway.

A multiyear field project focused on long-distance causeways between Uci and Cansahcab in Yucatan, Mexico, supports their use for processions and pilgrimages, their role in the creation of multisite polities, and their involvement in the constitution of local authority. Yet details of the causeways’ construction suggest that people contested this authority. Work was central to these dynamics and comes in the form of labor as practice, investments in the maintenance of relations with other-than-human beings, and the ways that causeways produced embodied experiences that were ideal for their use in pilgrimages.