Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe

Underground energy-related product storage and sequestration: site characterization, risk analysis, and monitoring

This paper presents a high-level overview of site characterization, risk analysis, and monitoring priorities for underground energy-related product storage or sequestration facilities. The siting of an underground energy-related product storage or sequestration facility depends on several important factors beginning with the area of review. Collection of all existing and available records and data from within the rock volume, including potential vulnerabilities such as prior containment issues, proximity to infrastructure and/or population centers, must be evaluated. Baselining of natural processes before storage or sequestration operations begin provides the basis for assessing the effects of storage or sequestration on the surroundings. These initial investigations include geological, geophysical, and geochemical analyses of the suitability of the geological host rock and environs for storage or sequestration. A risk analysis identifies and evaluates threats and hazards, the potential impact should they develop into unwanted circumstances or events, and the consequences to the facility should any of them occur. This forms the basis for framing effective mitigation measures. combines the identified threats (unactualized hazards) and hazards, their potential magnitudes, and the consequences to the facility should any of them occur. This forms the basis for framing effective mitigation measures. Risk analyses produce deterministic and/or probabilistic predictions whose utility depends on the quality of threat, hazard, and consequence characterization. A comprehensive monitoring program that may include downhole well surveillance, observation wells, geochemical sampling, and well testing ensures that the facility operates as designed and that unforeseen issues, such as product migration or loss of integrity, can be identified and mitigated. In addition to these technical issues, human factors and public perception of a project are a critical part of the site characterization, construction, and operational phases of a project. Despite differences between underground storage and sequestration, sets of characterization, risk analysis, and monitoring approaches that were developed for underground natural gas storage or for carbon dioxide sequestration could be used for underground storage or sequestration of any type of energy-related product. Recommendations from this work include: (1) develop an industry-standard evaluation protocol (workflow) for the evaluation of salt beds, aquifers, depleted reservoirs, underground mines and cased wellbores for potential underground storage or sequestration development beyond those in use today; and (2) develop an industry-wide collaborative process whereby incident and near-miss data related to underground storage or sequestration operations can be reported, documented, and shared for use in refining risk analysis modeling.ISSN:0375-6440ISSN:0305-8719ISSN:2041-492

An overview of underground energy-related product storage and sequestration

Storage of energy-related products in the geologic subsurface provides reserve capacity, resilience, and security to the energy supply chain. Sequestration of energy-related products ensures long-term isolation from the environment and, for CO2, a reduction in atmospheric emissions. Both porous-rock media and engineered caverns can provide the large storage volumes needed today and in the future. Methods for site characterization and modeling, monitoring, and inventory verification have been developed and deployed to identify and mitigate geologic threats and hazards such as induced seismicity and loss of containment. Broader considerations such as life-cycle analysis; environment, social and governance (ESG) impact; and effective engagement with stakeholders can reduce project uncertainty and cost while promoting sustainability during the ongoing energy transition toward net-zero or low-carbon economies

An overview of underground energy-related product storage and sequestration

Storage of energy-related products in the geologic subsurface provides reserve capacity, resilience, and security to the energy supply chain. Sequestration of energy-related products ensures long-term isolation from the environment and, for CO2, a reduction in atmospheric emissions. Both porous-rock media and engineered caverns can provide the large storage volumes needed today and in the future. Methods for site characterization and modeling, monitoring, and inventory verification have been developed and deployed to identify and mitigate geologic threats and hazards such as induced seismicity and loss of containment. Broader considerations such as life-cycle analysis; environment, social and governance (ESG) impact; and effective engagement with stakeholders can reduce project uncertainty and cost while promoting sustainability during the ongoing energy transition toward net-zero or low-carbon economies.ISSN:0375-6440ISSN:0305-8719ISSN:2041-492