Summary Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.

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Abstract. Glacial lake outburst floods (GLOFs) are among the most concerning consequences of retreating glaciers in mountain ranges worldwide. GLOFs have attracted significant attention amongst scientists and practitioners in the past 2 decades, with particular interest in the physical drivers and mechanisms of GLOF hazard and in socioeconomic and other human-related developments that affect vulnerabilities to GLOF events. This increased research focus on GLOFs is reflected in the gradually increasing number of papers published annually. This study offers an overview of recent GLOF research by analysing 594 peer-reviewed GLOF studies published between 2017 and 2021 (Web of Science and Scopus databases), reviewing the content and geographical focus as well as other characteristics of GLOF studies. This review is complemented with perspectives from the first GLOF conference (7–9 July 2021, online) where a global GLOF research community of major mountain regions gathered to discuss the current state of the art of integrated GLOF research. Therefore, representatives from 17 countries identified and elaborated trends and challenges and proposed possible ways forward to navigate future GLOF research, in four thematic areas: (i) understanding GLOFs – timing and processes; (ii) modelling GLOFs and GLOF process chains; (iii) GLOF risk management, prevention and warning; and (iv) human dimensions of GLOFs and GLOF attribution to climate change.

The fundamental nature of Dark Matter is a central theme of the Snowmass 2021 process, extending across all frontiers. In the last decade, advances in detector technology, analysis techniques and theoretical modeling have enabled a new generation of experiments and searches while broadening the types of candidates we can pursue. Over the next decade, there is great potential for discoveries that would transform our understanding of dark matter. In the following, we outline a road map for discovery developed in collaboration among the frontiers. A strong portfolio of experiments that delves deep, searches wide, and harnesses the complementarity between techniques is key to tackling this complicated problem, requiring expertise, results, and planning from all Frontiers of the Snowmass 2021 process. Note from the authors: This is the first version of the Cross-Frontier Complementarity report. We welcome feedback or changes (including constructive criticism) that you'd like us to take into account in the next version, on this google document.

Abstract. Glacial lake outburst floods (GLOFs) are among the most concerning consequences of retreating glaciers in mountain ranges worldwide. GLOFs have attracted significant attention amongst scientists and practitioners in the past few decades, with particular interests in the physical drivers and mechanisms of GLOF hazard, and socioeconomic and other human-related developments that affect vulnerability to GLOF events. This increased research focus on GLOFs is reflected in the gradually increasing number of papers published annually. This study offers an overview of recent GLOF research by analysing 570 peer-reviewed GLOF studies published between 2017 and 2021 (Web of Science and Scopus databases), reviewing the content, geographical focus as well as other characteristics of GLOF studies. This review is complemented with perspectives from the first GLOF conference (7–9 July 2021, online) where a global GLOF research community from major mountain regions gathered to discuss the current state of the art of integrated GLOF research. Therefore, representatives from 17 countries identified and elaborated trends and challenges and proposed possible ways forward to navigate future GLOF research, in four thematic areas: (i) understanding GLOFs – timing and processes; (ii) modelling GLOFs and GLOF process chains; (iii) GLOF risk management, prevention and warning; (iv) human dimensions of GLOFs and GLOF attribution to climate change.