Targeting the anti-apoptotic BCL-2 family members for the treatment of cancer

Most cells express a variety of both anti-apoptotic and pro-apoptotic Bcl-2 proteins and the interaction within this family dictates whether a cell survives or dies. The dysregulation of the anti-anti-apoptotic Bcl-2 family members is one of the defining features of cancer cells in comparison to normal cells, and significantly contributes to the resistance of cancer cells to current treatment modalities. This anti-apoptotic subfamily of proteins is now a major target in the development of new methods to improve treatment outcomes for cancer patients. Several drugs directed at inhibiting Bcl-2 and related anti-apoptotic proteins have been developed with some showing considerable promise in the clinic. This Review presents the current knowledge of the role of the anti-apoptotic Bcl-2 family in cancer cells, as well as current and future perspectives on targeting this subfamily of proteins for therapeutic intervention in human malignancies. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”

Temporal and spatial carbon dioxide concentration patterns in a small boreal lake in relation to ice-cover dynamics

Global carbon dioxide (CO2) emission estimates from inland waters commonly neglect the ice-cover season. To account for CO2 accumulation below ice and consequent emissions into the atmosphere at ice-melt we combined automatically-monitored and manually- sampled spatially-distributed CO2 concentration measurements from a small boreal ice-covered lake in Sweden. In early winter, CO2 accumulated continuously below ice, whereas, in late winter, CO2 concentrations remained rather constant. At ice-melt, two CO2 concentration peaks were recorded, the first one reflecting lateral CO2 transport within the upper water column, and the second one reflecting vertical CO2 transport from bottom waters. We estimated that 66%–85% of the total CO2 accumulated in the water below ice left the lake at ice-melt, while the remainder was stored in bottom waters. Our results imply that CO2 accumulation under ice and emissions at ice-melt are more dynamic than previously reported, and thus need to be more accurately integrated into annual CO2 emission estimates from inland waters

Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis

Glioblastoma (GBM) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is associated with intrinsic or acquired apoptosis resistance and the presence of a highly tumourigenic subpopulation of cancer cells called GBM stem cells. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising novel therapy for some treatment-resistant tumours but unfortunately GBM can be completely resistant to TRAIL monotherapy. In this study, we identified Mcl-1, an anti-apoptotic Bcl-2 family member, as a critical player involved in determining the sensitivity of GBM to TRAIL-induced apoptosis. Effective targeting of Mcl-1 in TRAIL resistant GBM cells, either by gene silencing technology or by treatment with R-roscovitine, a cyclin-dependent kinase inhibitor that targets Mcl-1, was demonstrated to augment sensitivity to TRAIL, both within GBM cells grown as monolayers and in a 3D tumour model. Finally, we highlight that two separate pathways are activated during the apoptotic death of GBM cells treated with a combination of TRAIL and R-roscovitine, one which leads to caspase-8 and caspase-3 activation and a second pathway, involving a Mcl-1:Noxa axis. In conclusion, our study demonstrates that R-roscovitine in combination with TRAIL presents a promising novel strategy to trigger cell death pathways in glioblastoma. Electronic supplementary material The online version of this article (doi:10.1007/s10495-013-0935-2) contains supplementary material, which is available to authorized users

Increased winter drownings in ice-covered regions with warmer winters

Winter activities on ice are culturally important for many countries, yet they constitute a high safety risk depending upon the stability of the ice. Because consistently cold periods are required to form stable and thick ice, warmer winters could degrade ice conditions and increase the likelihood of falling through the ice. This study provides the first large-scale assessment of winter drowning from 10 Northern Hemisphere countries. We documented over 4000 winter drowning events. Winter drownings increased exponentially in regions with warmer winters when air temperatures neared 0 ̊C. The largest number of drownings occurred when winter air temperatures were between -5 ̊C and 0 ̊C, when ice is less stable, and also in regions where indigenous traditions and livelihood require extended time on ice. Rates of drowning were greatest late in the winter season when ice stability declines. Children and adults up to the age of 39 were at the highest risk of winter drownings. Beyond temperature, differences in cultures, regulations, and human behaviours can be important additional risk factors. Our findings indicate the potential for increased human mortality with warmer winter air temperatures. Incorporating drowning prevention plans would improve adaptation strategies to a changing climate.Funding was provided to SS by the Ontario Ministry of Research, Innovation and Science Early Researcher Award and York University Research Chair programme. Funding support for BAD was provided by Kempestiftelserna. AL was supported by Estonian Research Council Grant PSG 32. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Funding was provided to SS by the Ontario Ministry of Research, Innovation and Science Early Researcher Award and York University Research Chair programme. Funding support for BAD was provided by Kempestiftelserna. AL was supported by Estonian Research Council Grant PSG 32. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Citizen science shows systematic changes in the temperature difference between air and inland waters with global warming

Citizen science projects have a long history in ecological studies. The research usefulness of such projects is dependent on applying simple and standardized methods. Here, we conducted a citizen science project that involved more than 3500 Swedish high school students to examine the temperature difference between surface water and the overlying air (Tw-Ta) as a proxy for sensible heat flux (QH). If QH is directed upward, corresponding to positive Tw-Ta, it can enhance CO2 and CH4 emissions from inland waters, thereby contributing to increased greenhouse gas concentrations in the atmosphere. The students found mostly negative Tw-Ta across small ponds, lakes, streams/rivers and the sea shore (i.e. downward QH), with Tw-Ta becoming increasingly negative with increasing Ta. Further examination of Tw-Ta using high-frequency temperature data from inland waters across the globe confirmed that Tw-Ta is linearly related to Ta. Using the longest available high-frequency temperature time series from Lake Erken, Sweden, we found a rapid increase in the occasions of negative Tw-Ta with increasing annual mean Ta since 1989. From these results, we can expect that ongoing and projected global warming will result in increasingly negative Tw-Ta, thereby reducing CO2 and CH4 transfer velocities from inland waters into the atmosphere

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes