Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30% response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results: We found that the resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions: Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan

The Arctic in the twenty-first century: changing biogeochemical linkages across a paraglacial landscape of Greenland

The Kangerlussuaq area of southwest Greenland encompasses diverse ecological, geomorphic, and climate gradients that function over a range of spatial and temporal scales. Ecosystems range from the microbial communities on the ice sheet and moisture-stressed terrestrial vegetation (and their associated herbivores) to freshwater and oligosaline lakes. These ecosystems are linked by a dynamic glacio-fluvial-aeolian geomorphic system that transports water, geological material, organic carbon and nutrients from the glacier surface to adjacent terrestrial and aquatic systems. This paraglacial system is now subject to substantial change because of rapid regional warming since 2000. Here, we describe changes in the eco- and geomorphic systems at a range of timescales and explore rapid future change in the links that integrate these systems. We highlight the importance of cross-system subsidies at the landscape scale and, importantly, how these might change in the near future as the Arctic is expected to continue to warm

Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs

Analysis of Epithelial and Mesenchymal Markers in Ovarian Cancer Reveals Phenotypic Heterogeneity and Plasticity

Peer reviewe

Longitudinal zonation of macroinvertebrates in an Ecuadorian glacier-fed stream : do tropical glacial systems fit the temperate model ?

1. The ecology of glacier-fed streams at temperate latitudes has been intensely studied in recent years, leading to the development of a well-validated conceptual model on the longitudinal distribution of macroinvertebrate communities downstream of the glacier margin (Freshwater Biology, 2001a; 46, 1833). However, to our knowledge, the ecology of tropical glacier-fed streams has not yet been studied. 2. We sampled benthic macroinvertebrates and measured environmental variables at nine sites between 4730 and 4225 m altitude along a 4.3 km stretch of a glacier-fed stream 40 km south of the equator in the Ecuadorian Andes. Our goal was to study the longitudinal distribution of the fauna in relation to environmental factors and to compare this with the conceptual model based on temperate-arctic glacier-fed streams. 3. Total density of invertebrates differed considerably at the two highest altitude sites; 4600 m-2 at a pro-glacial lake outlet and only 4 m-2 at a site originating directly from the glacier snout. Otherwise, there was a downstream decrease in density to about 825 m-2 at the three lowest sites. Taxon richness increased with distance from the glacier, very similar to the pattern predicted. A total of 28 taxa were collected; two at the glacier snout, seven at the nearby pro-glacial lake outlet, 13 at site 2 (< 400 m from the glacier) and 20 at the lowest sites. 4. The numerical percentage of Chironomidae (Diptera) decreased downstream from 100 to 44%. The subfamily Podonominae was numerous at the highest sites but became much less important further downstream. The Orthocladiinae were important both in numbers and species at all sites, while Diamesinae were numerous only in the middle of the reach studied and were completely absent from the upper three sites. The limited importance of the Diamesinae, and its replacement by Podonominae, is different from the pattern typically observed in north-temperate glacier-fed streams. This could be because of the fact that the genus Diamesa is missing from the Neotropics. 5. Stream temperature and channel stability explained most of the variability in faunal composition and richness, supporting the model. Stability increased systematically downstream while temperature did not. Surprisingly, no classical kryal zone (T-max < 4 degrees C) was found, as even the site closest to the glacier snout (50 m) had a T-max of 15 degrees C and no site had T-max < 8 degrees C. We propose that this might be a general feature of equatorial glacial streams

Changes in food web dynamics of low Arctic ponds with varying content of dissolved organic carbon

An influx of terrestrial dissolved organic carbon (DOC) into freshwater habitats can regulate a range of ecosystem characteristics, from water clarity to productivity. To understand the extent to which DOC can regulate ecosystem functioning, we conducted a survey to determine the source of DOC in low Arctic ponds close to the Arctic Circle (Kangerlussuaq, Greenland), including its role in food web dynamics. We used a multiple element (carbon, nitrogen, and hydrogen) stable isotope approach to examine the proportional contribution of different sources to aquatic consumers in nine arctic ponds that spanned a broad gradient of DOC (6.6–60.1 mgL-1). Our results show that benthic and pelagic primary production decreased along a gradient of increasing DOC content. Additionally, the changes in the organic matter pool with increasing DOC translated into changes in consumer resource use. We found significant differences in resource use between species. All consumers relied on benthic autotrophic material when DOC was low; but when DOC was high some consumers changed their diet. Collectively, our findings demonstrate how the concentration of DOC influences aquatic production and our study can be used as a baseline to predict how the aquatic food web may respond to regionally changing DOC concentrations

Acricotopus indet. morphotype incurvatus: description and genetics of a new Orthocladiinae (Diptera: Chironomidae) larval morphotype from the Tibetan Plateau

High mountain ranges such as the Tibetan Plateau with an average altitude above 4500 m are topographically complex formations. Elevational gradients, physiographic diversity and climatic heterogeneity have led to highly biodiverse ecosystems in these regions. Mountain ranges can be seen as cradles of evolution and harbour, due to their unique characteristics, a high number of highly adapted species. At the same time these areas are hard to access and therefore taxonomic information is limited. Here we describe a new Acricotopus (Diptera: Chironomidae: Orthocladiinae) larval morphotype occurring in lakes and ponds of differing salinity and water depths located on the Southern and Central Tibetan Plateau. The description is based on larvae and their genetics (ribosomal 18S, 28S and mitochondrial COI sequences) collected from a shallow pond in close proximity to the large saline lake Selin Co. Larvae of Acricotopus indet. morphotype incurvatus are characterized by a mentum with a cluster of lateral teeth, partially folded inwards, a mandible with a toothed lobe in addition to four inner teeth and a sclerotized plate positioned behind the mentum. Up to now, these morphological features have only been found in early instars of other Acricotopus species. The proposed morphotype name is inspired by the peculiar form of the mentu