Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides

Apurinic/apyrimidinic endonuclease (APE) is a key enzyme involved in DNA base excision repair (BER) that is often expressed at elevated levels in human cancers. Pancreatic cancer cells treated with the nucleoside analogue gemcitabine (2′, 2′-difluoro-2′deoxycytidine) showed increases in APE/redox effector factor (ref-1) protein levels (approximately two-fold for Panc-1 and six-fold for MiaPaCa-2), with corresponding increases in endonuclease activity. These results suggested that the activation of APE/ref-1 might be an adaptive response that contributes to gemcitabine resistance by facilitating BER. To test this hypothesis, we examined the effects of disrupting APE/ref-1 using antisense on gemcitabine toxicity. Antisense oligonucleotides decreased protein levels three-fold in MiaPaCa-2 and five-fold in Panc-1 in comparison to controls, associated with reduced endonuclease activity. Combination treatments with antisense oligonucleotides and gemcitabine partially suppressed the increase in APE/ref-1 activity seen in cells exposed to gemcitabine alone. While clonogenic assays showed only slight decreases in colony formation in cells treated with either antisense oligonucleotides or gemcitabine alone, the combination with APE/ref-1 antisense resulted in a 2-log enhancement of gemcitabine toxicity in Panc-1 cells. Overall these findings suggest that APE/ref-1 plays a significant role in gemcitabine resistance in some pancreatic cancer cells, and support the further investigation of novel treatments that target this protein

Building capacity in biodiversity monitoring at the global scale

Human-driven global change is causing ongoing declines in biodiversity worldwide. In order to address these declines, decision-makers need accurate assessments of the status of and pressures on biodiversity. However, these are heavily constrained by incomplete and uneven spatial, temporal and taxonomic coverage. For instance, data from regions such as Europe and North America are currently used overwhelmingly for large-scale biodiversity assessments due to lesser availability of suitable data from other, more biodiversity-rich, regions. These data-poor regions are often those experiencing the strongest threats to biodiversity, however. There is therefore an urgent need to fill the existing gaps in global biodiversity monitoring. Here, we review current knowledge on best practice in capacity building for biodiversity monitoring and provide an overview of existing means to improve biodiversity data collection considering the different types of biodiversity monitoring data. Our review comprises insights from work in Africa, South America, Polar Regions and Europe; in government-funded, volunteer and citizen-based monitoring in terrestrial, freshwater and marine ecosystems. The key steps to effectively building capacity in biodiversity monitoring are: identifying monitoring questions and aims; identifying the key components, functions, and processes to monitor; identifying the most suitable monitoring methods for these elements, carrying out monitoring activities; managing the resultant data; and interpreting monitoring data. Additionally, biodiversity monitoring should use multiple approaches including extensive and intensive monitoring through volunteers and professional scientists but also harnessing new technologies. Finally, we call on the scientific community to share biodiversity monitoring data, knowledge and tools to ensure the accessibility, interoperability, and reporting of biodiversity data at a global scale

Projected Scenarios for Coastal First Nations' Fisheries Catch Potential under Climate Change: Management Challenges and Opportunities.

Studies have demonstrated ways in which climate-related shifts in the distributions and relative abundances of marine species are expected to alter the dynamics and catch potential of global fisheries. While these studies assess impacts on large-scale commercial fisheries, few efforts have been made to quantitatively project impacts on small-scale subsistence and commercial fisheries that are economically, socially and culturally important to many coastal communities. This study uses a dynamic bioclimate envelope model to project scenarios of climate-related changes in the relative abundance, distribution and richness of 98 exploited marine fishes and invertebrates of commercial and cultural importance to First Nations in coastal British Columbia, Canada. Declines in abundance are projected for most of the sampled species under both the lower (Representative Concentration Pathway [RCP] 2.6) and higher (RCP 8.5) emission scenarios (-15.0% to -20.8%, respectively), with poleward range shifts occurring at a median rate of 10.3 to 18.0 km decade(-1) by 2050 relative to 2000. While a cumulative decline in catch potential is projected coastwide (-4.5 to -10.7%), estimates suggest a strong positive correlation between the change in relative catch potential and latitude, with First Nations' territories along the northern and central coasts of British Columbia likely to experience less severe declines than those to the south. Furthermore, a strong negative correlation is projected between latitude and the number of species exhibiting declining abundance. These trends are shown to be robust to alternative species distribution models. This study concludes by discussing corresponding management challenges that are likely to be encountered under climate change, and by highlighting the value of joint-management frameworks and traditional fisheries management approaches that could aid in offsetting impacts and developing site-specific mitigation and adaptation strategies derived from local fishers' knowledge

Sample of First Nations included in this study and their respective regions and treaty groups.

<p>Sample of First Nations included in this study and their respective regions and treaty groups.</p

Multi-model ensemble examining the variability of projected latitudinal range shifts by species (Table B in S2 Text).

<p>Multi-model ensemble examining the variability of projected latitudinal range shifts by species (Table B in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145285#pone.0145285.s003" target="_blank">S2 Text</a>).</p

Projected median latitudinal range shifts (km decade^-1) by taxonomic group or species.

<p>Projections used an average 20-year latitudinal centroid centred on 2050 relative to that centred on 2000 under the lower (blue; RCP 2.6) and upper (red; RCP 8.5) scenarios of climate change. Where applicable, black dots represent the results for each species that were used to determine the aggregated median values.</p

Correlation between latitude and (a) the number of species exhibiting declines in catch potential by 2050 (yellow) and (b) the percentage of the total number of surveyed species in the respective domestic fishing area exhibiting declining abundance by 2050 (blue).

<p>Declines are exhibited under both the lower (RCP 2.6) and upper (RCP 8.5) scenarios of climate change. Shaded bars represent 95% confidence intervals (data available in Table B in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145285#pone.0145285.s002" target="_blank">S1 Text</a>). </p

Relationship between latitude and cumulative change in catch potential (%) by 2050 from the baseline (0%) under the lower (RCP 2.6; blue) and upper (RCP 8.5; red) scenarios of climate change.

<p>Shaded bars represent 95% confidence intervals (data available in Table A in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145285#pone.0145285.s002" target="_blank">S1 Text</a>).</p

Sample of species harvested by First Nations for food, social and ceremonial (FSC) purposes, ordered alphabetically [30,62–69].

<p>Sample of species harvested by First Nations for food, social and ceremonial (FSC) purposes, ordered alphabetically [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145285#pone.0145285.ref030" target="_blank">30</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145285#pone.0145285.ref062" target="_blank">62</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145285#pone.0145285.ref069" target="_blank">69</a>].</p

Projected change in relative catch potential by commercial fishery with known First Nation participation.

<p>Changes were calculated using 20-year average catch potential for 2050 relative to 2000 within British Columbia’s marine environment. Projections reflected the lower (blue; RCP 2.6) and upper (red; RCP 8.5) ranges of climate change. Values on the right reflect conservative cumulative estimates of impacts on First Nations’ commercial fisheries revenue (median values for 2001–2010 in CAD). Letters represent the type of commercial fishery: [a] seine, [b] hand, [c] trap, [d] trawl, [e] hook and line, [f] longline, [g] dive, [h] troll, [i] gill net, [j] roe herring, [k] spawn on kelp, and [l] bait (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145285#pone.0145285.s005" target="_blank">S2 Table</a>).</p