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ItemOpen Access
A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity.
(eLife, 2019-11) Palmer, Adam C; Chidley, Christopher; Sorger, Peter K
Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here, we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R-CHOP exhibit very low cross-resistance but not synergistic interaction: together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50 year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.
ItemOpen Access
An enhanced isothermal amplification assay for viral detection.
(Nature communications, 2020-11) Qian, Jason; Boswell, Sarah A; Chidley, Christopher; Lu, Zhi-Xiang; Pettit, Mary E; Gaudio, Benjamin L; Fajnzylber, Jesse M; Ingram, Ryan T; Ward, Rebecca H; Li, Jonathan Z; Springer, Michael
Rapid, inexpensive, robust diagnostics are essential to control the spread of infectious diseases. Current state of the art diagnostics are highly sensitive and specific, but slow, and require expensive equipment. Here we report the development of a molecular diagnostic test for SARS-CoV-2 based on an enhanced recombinase polymerase amplification (eRPA) reaction. eRPA has a detection limit on patient samples down to 5 viral copies, requires minimal instrumentation, and is highly scalable and inexpensive. eRPA does not cross-react with other common coronaviruses, does not require RNA purification, and takes ~45 min from sample collection to results. eRPA represents a first step toward at-home SARS-CoV-2 detection and can be adapted to future viruses within days of genomic sequence availability.
ItemOpen Access
A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.
(Nature cell biology, 2024-05) Chidley, Christopher; Darnell, Alicia M; Gaudio, Benjamin L; Lien, Evan C; Barbeau, Anna M; Vander Heiden, Matthew G; Sorger, Peter K
Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism.
ItemOpen Access
Topological optimization of variable area plate capacitors for coupled electromechanical energy harvesters
(Journal of Intelligent Material Systems and Structures, 2019-09-01) Sequeira, D; Coonley, K; Mann, B
This article examines how topological optimization can be applied to identify nonintuitive capacitor plate patterning that maximizes average power dissipated through an electrical circuit during energy harvesting. Coupled electromechanical equations of motion are derived that include both the instantaneous and change in overlapping conductive area as functions of plate rotation. A genetic algorithm is used to optimize these terms and then map them to physical plate configurations. The results obtained apply specifically to the case presented; however, the methods are general and can be used to solve a broad range of electrostatic energy harvesting problems.
ItemOpen Access
Beyond FERC Order 2023: Considerations on Deep Interconnection Reform
(2023-08-23) Norris, Tyler
In late July 2023, the US Federal Energy Regulatory Commission released its much-anticipated rule on interconnection reform, Order 2023. This policy brief explores a deeper reform option known as connect and manage. This less restrictive interconnection approach could speed the deployment of resources in a way that can be managed after their integration with the grid, leading to a larger volume of interconnected generation capacity without sacrificing reliability. The brief summarizes connect and manage in relationship to existing interconnection procedures and reviews foundational issues with current processes not addressed by Order 2023; identifies opportunities to improve energy-only interconnection procedures and potential solutions to manage attendant complications with curtailment risk and hybrid resources; and discusses linkages of interconnection, transmission planning, and competitive procurement in alignment with a connect and manage approach, particularly in jurisdictions not governed by independent system operator/regional transmission organizations (ISO/RTOs).