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- Das, A., et al.
(author)
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
- 2022
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
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Journal article (peer-reviewed)abstract
- Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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- Shapiro, M, et al.
(author)
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An Earth-system prediction initiative for the twenty-first century: An international interdisciplinary initiative to accelerate advances in knowledge, prediction, use and value of weather, climate and Earth-system information
- 2010
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In: BULLETIN OF THE AMERICAN METEOROLOGICAL SOCIETY. - 0003-0007. ; 91:10, s. 1377-1388
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Journal article (peer-reviewed)abstract
- The necessity and benefits for establishing the international Earth-system Prediction Initiative (EPI) are discussed by scientists associated with the World Meteorological Organization (WMO) World Weather Research Programme (WWRP), World Climate Research Programme (WCRP), International Geosphere–Biosphere Programme (IGBP), Global Climate Observing System (GCOS), and natural-hazards and socioeconomic communities. The proposed initiative will provide research and services to accelerate advances in weather, climate, and Earth system prediction and the use of this information by global societies. It will build upon the WMO, the Group on Earth Observations (GEO), the Global Earth Observation System of Systems (GEOSS) and the International Council for Science (ICSU) to coordinate the effort across the weather, climate, Earth system, natural-hazards, and socioeconomic disciplines. It will require (i) advanced high-performance computing facilities, supporting a worldwide network of research and operational modeling centers, and early warning systems; (ii) science, technology, and education projects to enhance knowledge, awareness, and utilization of weather, climate, environmental, and socioeconomic information; (iii) investments in maintaining existing and developing new observational capabilities; and (iv) infrastructure to transition achievements into operational products and services.
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- Lapola, David M., et al.
(author)
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Limiting the high impacts of Amazon forest dieback with no-regrets science and policy action
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:46, s. 11671-11679
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Journal article (peer-reviewed)abstract
- Large uncertainties still dominate the hypothesis of an abrupt large-scale shift of the Amazon forest caused by climate change [Amazonian forest dieback (AFD)] even though observational evidence shows the forest and regional climate changing. Here, we assess whether mitigation or adaptation action should be taken now, later, or not at all in light of such uncertainties. No action/later action would result in major social impacts that may influence migration to large Amazonian cities through a causal chain of climate change and forest degradation leading to lower river-water levels that affect transportation, food security, and health. Net-present value socioeconomic damage over a 30-year period after AFD is estimated between US dollar (USD) $957 billion (x10(9)) and $3,589 billion (compared with Gross Brazilian Amazon Product of USD $150 billion per year), arising primarily from changes in the provision of ecosystem services. Costs of acting now would be one to two orders of magnitude lower than economic damages. However, while AFD mitigation alternatives-e.g., curbing deforestation-are attainable (USD $64 billion), their efficacy in achieving a forest resilience that prevents AFD is uncertain. Concurrently, a proposed set of 20 adaptation measures is also attainable (USD $122 billion) and could bring benefits even if AFD never occurs. An interdisciplinary research agenda to fill lingering knowledge gaps and constrain the risk of AFD should focus on developing sound experimental and modeling evidence regarding its likelihood, integrated with socioeconomic assessments to anticipate its impacts and evaluate the feasibility and efficacy of mitigation/adaptation options.
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