Reuniting philosophy and science to advance cancer research

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.     

20世纪90年代上海市热环境变化及其社会经济驱动力

城市化过程导致地表水分蒸腾减少、径流加速、显热的存储和传输增加以及水质降低等一系列生态环境效应,其中最典型的特征就是城市热岛的出现。城市热环境动态主要驱动力可以概括为两大方面:地表覆被的变化与人类社会经济活动。论文采用Landsat的TM/ETM+为基本数据源,先定量反演了每个像元内的陆地表面温度,以此探讨了20世纪90年代上海市主城区热环境的动态演化和社会经济驱动力。研究结果揭示,20世纪90年代上海市主城区热岛范围显著扩大,但中心城区的热岛强度在下降,空间格局也趋于复杂;通过分析,城市热环境空间格局动态演变是不同尺度上、相互嵌套、相互影响的多种驱动力的综合作用结果。其中,城市建成区的快速扩展是热岛范围不断扩展的最显性驱动力;中心城区人口密度显著下降是热岛中心强度降低的一个综合性驱动因子,而以重化工业为代表的能耗布局改变则是中心城区热岛强度降低的一个主要驱动力;通过增加绿化面积布局等人为措施改变热辐射和存储模式,对缓解城市热环境来说是最有意义的因素。由于多种驱动力相互嵌套、交互作用,因此建立城市热环境演变驱动机制的定量模型还十分困难,但是研究结果对于制定城市热环境改善政策和编制合理的城市规划等都具有一定的借鉴意义。     

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer

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Accumulation of soil carbon under elevated CO2 unaffected by warming and drought

Elevated atmospheric CO₂ concentration and climate change may substantially alter soil carbon (C) dynamics, which in turn may impact future climate through feedback cycles. However, only very few field experiments worldwide have combined elevated CO₂ (eCO₂) with both warming and changes in precipitation in order to study the potential combined effects of changes in these fundamental drivers of C cycling in ecosystems. We exposed a temperate heath/grassland to eCO₂, warming, and drought, in all combinations for 8 years. At the end of the study, soil C stocks were on average 0.927 kg C/m² higher across all treatment combinations with eCO₂ compared to ambient CO₂ treatments (equal to an increase of 0.120 ± 0.043 kg C m^?2 year^?1), and showed no sign of slowed accumulation over time. However, if observed pretreatment differences in soil C are taken into account, the annual rate of increase caused by eCO₂ may be as high as 0.177 ± 0.070 kg C m^?2 year^?1. Furthermore, the response to eCO₂ was not affected by simultaneous exposure to warming and drought. The robust increase in soil C under eCO₂ observed here, even when combined with other climate change factors, suggests that there is continued and strong potential for enhanced soil carbon sequestration in some ecosystems to mitigate increasing atmospheric CO₂ concentrations under future climate conditions. The feedback between land C and climate remains one of the largest sources of uncertainty in future climate projections, yet experimental data under simulated future climate, and especially including combined changes, are still scarce. Globally coordinated and distributed experiments with long‐term measurements of changes in soil C in response to the three major climate change‐related global changes, eCO₂, warming, and changes in precipitation patterns, are, therefore, urgently needed.     

A general framework to quantify and compare ecological impacts under temporal dynamics

Biodiversity is diminishing at alarming rates due to multiple anthropogenic drivers. To mitigate these drivers, their impacts must be quantified accurately and comparably across drivers. To enable that, we present a generally applicable framework introducing fundamental principles of ecological impact quantification, including the quantification of interactions between multiple drivers. The framework contrasts biodiversity variables in impacted against those in unimpacted or other reference situations while accounting for their temporal dynamics through modelling. Properly accounting for temporal dynamics reduces biases in impact quantification and comparison. The framework addresses key questions around ecological impacts in global change science, namely, how to compare impacts under temporal dynamics across stressors, how to account for stressor interactions in such comparisons, and how to compare the success of management actions over time.     

Reprogramming strategies for the establishment of novel human cancer models

Cancer comprises heterogeneous cells, ranging from highly proliferative immature precursors to more differentiated cell lineages. The emergence of the “cancer stem cell” (CSC) hypothesis that they are the cells responsible for resistance, metastasis and secondary tumor appearance identifies these populations as novel obligatory targets for the treatment of cancer. CSCs, like their normal tissue-specific stem cell counterparts, are multipotent, partially differentiated, self-sustaining, yet transformed cells. To date, most studies on CSC biology have relied on the use of murine models and primary human material. In spite of much progress, the use of primary material presents several limitations that limit our understanding of the mechanisms underlying CSC formation, the similarities between normal stem cells and CSCs and ultimately, the possibility for developing targeted therapies. Recently, different strategies for controlling cell fate have been applied to the modeling of human cancer initiation and for the generation of human CSC models. Here we will summarize recent developments in the establishment and application of reprogramming strategies for the modeling of human cancer initiation and CSC formation.     

Global change biology: A primer

Because of human action, the Earth has entered an era where profound changes in the global environment are creating novel conditions that will be discernable far into the future. One consequence may be a large reduction of the Earth's biodiversity, potentially representing a sixth mass extinction. With effective stewardship, the global change drivers that threaten the Earth's biota could be alleviated, but this requires clear understanding of the drivers, their interactions, and how they impact ecological communities. This review identifies 10 anthropogenic global change drivers and discusses how six of the drivers (atmospheric CO₂ enrichment, climate change, land transformation, species exploitation, exotic species invasions, eutrophication) impact Earth's biodiversity. Driver impacts on a particular species could be positive or negative. In either case, they initiate secondary responses that cascade along ecological lines of connection and in doing so magnify the initial impact. The unique nature of the threat to the Earth's biodiversity is not simply due to the magnitude of each driver, but due to the speed of change, the novelty of the drivers, and their interactions. Emphasizing one driver, notably climate change, is problematic because the other global change drivers also degrade biodiversity and together threaten the stability of the biosphere. As the main academic journal addressing global change effects on living systems, GCB is well positioned to provide leadership in solving the global change challenge. If humanity cannot meet the challenge, then GCB is positioned to serve as a leading chronicle of the sixth mass extinction to occur on planet Earth.     

Co-survival of the fittest few: mosaic amplification of receptor tyrosine kinases in glioblastoma

Mosaic amplification of receptor tyrosine kinases in glioblastoma suggests that tumor cells with different progression driver mutations may coevolve rather than compete during clonal evolution.     

An Evaluation of Risk Drivers from a Sample of Risk Assessments Conducted for the U.S. Army

We evaluate risk drivers at selected U.S. Army installations by developing a database containing contaminant-pathway-receptor combinations that exceed regulatory thresholds for ecological (toxicity quotient greater than one), human health cancer risk (predicted incremental lifetime cancer risk greater than one in ten thousand), and noncancer human health (hazard index greater than one). We compare the risk drivers from the database to reported corrective action objectives from available decision documents. For noncancer hazards, explosives (particularly in ground water) dominate the reported exceedances of regulatory thresholds in the database. PAHs in home-grown produce show the highest number of exceedances of regulatory thresholds for cancer risk. For ecological risks, PAHs in both terrestrial and aquatic environments dominate the exceedances of regulatory thresholds. All available cleanup levels were derived based on human health exposures rather than ecological exposures, except for one site. In general, ecological risks were considered to be “more uncertain,” and that was used as a basis for not relying on backcalculated target levels on the basis of ecological risk. The reverse was true for human health risks: the “conservative” assumptions incorporated into the modeling provided the justification for backcalculating health-protective target levels.