Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34-negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.Peer reviewe

Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin

There is an urgent need to substitute the highly toxic arsenic compounds still in use for treatment of the encephalitic stage of African trypanosomiasis, a disease caused by infection with Trypanosoma brucei. We exploited the inability of trypanosomes to engage in de novo purine synthesis as a therapeutic target. Cordycepin was selected from a trypanocidal screen of a 2200-compound library. When administered together with the adenosine deaminase inhibitor deoxycoformycin, cordycepin cured mice inoculated with the human pathogenic subspecies T. brucei rhodesiense or T. brucei gambiense even after parasites had penetrated into the brain. Successful treatment was achieved by intraperitoneal, oral or subcutaneous administration of the compounds. Treatment with the doublet also diminished infection-induced cerebral inflammation. Cordycepin induced programmed cell death of the parasites. Although parasites grown in vitro with low doses of cordycepin gradually developed resistance, the resistant parasites lost virulence and showed no cross-resistance to trypanocidal drugs in clinical use. Our data strongly support testing cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT

Causes and Consequences of Local Government Efforts to Reduce Risk and Adapt to Extreme Weather Events: Municipal Organizational Robustness

This research article investigates the causes and consequences of municipal institutional arrangements for the provision of resilient critical infrastructure in municipalities. The study explains how the municipal organizational robustness and external institutional dynamics moderate the relation between capacities, leadership, and local government investment decisions. We examine hypotheses on moderating effects with regression methods, using data from 345 Chilean municipalities over a nine-year period, and analyzing the evidence with support of qualitative data. Our results reveal that municipal organizational robustness—operational rules, planning, managerial flexibility and integration, and accountability—is the most quantitatively outstanding moderating factor. The evidence leads us to deduce that efforts to support local governments in the emerging policy domain of resilient critical infrastructure require special attention to the robustness of municipal institutional arrangements. The results are valid for countries where the local governments have responsibilities to fulfill and their decisions have consequences for the adaptation. Since one of the objectives of the Special Issue “Bringing Governance Back Home—Lessons for Local Government Regarding Rapid Climate Action” is to explore how action is enabled or constrained by institutional relations in which the actors are embedded, this study contributes to achieving the goal

Decentralization can help reduce deforestation when user groups engage with local government

Policy makers around the world tout decentralization as an effective tool in the governance of natural resources. Despite the popularity of these reforms, there is limited scientific evidence on the environmental effects of decentralization, especially in tropical biomes. This study presents evidence on the institutional conditions under which decentralization is likely to be successful in sustaining forests. We draw on common-pool resource theory to argue that the environmental impact of decentralization hinges on the ability of reforms to engage local forest users in the governance of forests. Using matching techniques, we analyze longitudinal field observations on both social and biophysical characteristics in a large number of local government territories in Bolivia (a country with a decentralized forestry policy) and Peru (a country with a much more centralized forestry policy). We find that territories with a decentralized forest governance structure have more stable forest cover, but only when local forest user groups actively engage with the local government officials. We provide evidence in support of a possible causal process behind these results: When user groups engage with the decentralized units, it creates a more enabling environment for effective local governance of forests, including more local government-led forest governance activities, fora for the resolution of forest-related conflicts, intermunicipal cooperation in the forestry sector, and stronger technical capabilities of the local government staff

Decentralization can help reduce deforestation when user groups engage with local government

Policy makers around the world tout decentralization as an effective tool in the governance of natural resources. Despite the popularity of these reforms, there is limited scientific evidence on the environmental effects of decentralization, especially in tropical biomes. This study presents evidence on the institutional conditions under which decentralization is likely to be successful in sustaining forests. We draw on common-pool resource theory to argue that the environmental impact of decentralization hinges on the ability of reforms to engage local forest users in the governance of forests. Using matching techniques, we analyze longitudinal field observations on both social and biophysical characteristics in a large number of local government territories in Bolivia (a country with a decentralized forestry policy) and Peru (a country with a much more centralized forestry policy). We find that territories with a decentralized forest governance structure have more stable forest cover, but only when local forest user groups actively engage with the local government officials. We provide evidence in support of a possible causal process behind these results: When user groups engage with the decentralized units, it creates a more enabling environment for effective local governance of forests, including more local government-led forest governance activities, fora for the resolution of forest-related conflicts, intermunicipal cooperation in the forestry sector, and stronger technical capabilities of the local government staff

Place-based solutions for global social-ecological dilemmas: An analysis of locally grounded, diversified, and cross-scalar initiatives in the Amazon

The Amazon has a diverse array of social and environmental initiatives that adopt forest-based land-use practices to promote rural development and support local livelihoods. However, they are often insufficiently recognized as transformative pathways to sustainability and the factors that explain their success remain understudied. To address this gap, this paper proposes that local initiatives that pursue three particular pathways are more likely to generate improvements in social-ecological outcomes: (1) maintaining close connections with local grassroots, (2) pursuing diversity in productive activities performed and partnership choices, and (3) developing cross-scale collaborations. To test these ideas we collected and analyzed observations of 157 initiatives in Brazil and Peru, applying a combination of quantitative and qualitative analyses. Our results show that initiatives maintaining groundedness in representing the interests and concerns of local actors while partnering with other organizations at multiple scales are more likely to develop joint solutions to social-ecological problems. Partnerships and support from external organizations may strengthen and enhance local capabilities, providing a platform for negotiating interests and finding common ground. Such diversified pathways demonstrate the power of local actors to transcend their own territories and have broader impacts in sustainability objectives. Our findings highlight the need to make governmental and non-governmental support (e.g., financial, technical, political) available according to local needs to enable local initiatives' own ways of addressing global environmental change