Abstract DIII-D experiments demonstrate that high pressure, broad current profile equilibria can be accessed in the high poloidal beta regime by optimizing the MHD mode control poloidal spectrum. A ...novel, variable spectrum (VS) magnetic feedback scheme implemented using the DIII-D internal non-axisymmetric coils (I-coils) facilitated access to reduced internal inductance ℓ i operation above the no-wall beta limit compared with both no feedback and fixed spectrum feedback. In addition, the VS feedback helped avoid beta collapses caused by marginally unstable resistive wall mode activity. The lower and upper I-coil rows were configured in two independent feedback loops, allowing the feedback field’s poloidal spectrum to vary and track changes in the plasma mode structure as the edge safety factor q 95 varied from 11 to 6 during the discharges. The q 95 dependence of the measured phase difference between the lower and upper I-coil rows during VS feedback is qualitatively compatible with ideal MHD simulations of the least-stable plasma kink mode and with plasma response simulations that included kinetic modifications to ideal MHD. The VS feedback approach is a straightforward way to improve resilience to variations in mode structure that occur as plasma parameters change. The demonstrated expansion of the operating space to lower ℓ i is expected to improve the coupling of the plasma kink mode to external fields and beneficial wall eddy currents, and is compatible with high bootstrap fraction operation.
The objective of the Fusion Development Facility (FDF) under consideration is to fill the gaps between ITER and current experiments and a fusion demonstration power plant (DEMO). FDF should carry ...forward advanced tokamak (AT) physics and enable development of fusion's energy applications. Near-term AT physics and nonsuperconducting magnet technology will be used to achieve steady state with burn, producing 100-250 MW fusion power with modest energy gain (Q<5) in a modest sized device (between DIII-D and Joint European Torus). FDF will further develop all elements of AT physics for an advanced performance DEMO. With neutron flux at the outboard midplane of 1-2 MW/m 2 , continuous operation for periods of up to two weeks, and a goal of a duty factor of 0.3 per year, FDF can produce fluences of 3-6 MW·year/m 2 in ten years of operation, for fusion nuclear component research and development. The development of blankets suitable for tritium, electricity, and hydrogen production will be done first in port modules. Then, the most promising candidates will be deployed as full blankets in FDF. Two to three full blankets and about a dozen port-blanket types could be tested. The goal of FDF is to demonstrate closure of the fusion fuel cycle, producing its own tritium. FDF, ITER, International Fusion Materials Irradiation Facility, and other AT devices will provide the basis for a fusion DEMO power plant of the ARIES-AT type.
Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. ...Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.
Molecular Monitoring of Lymphomas Schroers-Martin, Joseph G; Alig, Stefan; Garofalo, Andrea ...
Annual review of pathology,
01/2023, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the ...clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the existence of stereotyped variants enabling focused interrogation of recurrently altered regions. Here, we review the clinical scenarios and key technologies applicable for the molecular monitoring of lymphomas, summarizing current evidence in the literature regarding molecular subtyping and classification, evaluation of treatment response, the surveillance of active cellular therapies, and emerging clinical trial strategies.
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over ...700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.
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•Tumors and CAR T cell effectors can be simultaneously profiled using cell-free DNA•Alterations in multiple classes of genes influence outcomes after CAR19 therapy•Tumor genotype and phenotype influence CAR19 T cell expansion, and vice versa•A multivariable model incorporating tumor and effector features predicts outcomes
Sworder et al. develop and apply a tool to simultaneously profile tumor and effector-mediated determinants of resistance to anti-CD19 CAR T cells using cell-free DNA. The authors profile two independent cohorts of patients with relapsed/refractory large B cell lymphoma and identify genomic alterations, molecular thresholds, and microenvironmental changes associated with resistance.
A path to a new high performance regime has been discovered in tokamaks that could improve the attractiveness of a fusion reactor. Experiments on DIII-D using a quiescent H-mode edge have navigated a ...valley of improved edge peeling-ballooning stability that opens up with strong plasma shaping at high density, leading to a doubling of the edge pressure over the standard H mode with edge localized modes at these parameters. The thermal energy confinement time increases as a result of both the increased pedestal height and improvements in the core transport and reduced low-k turbulence. Calculations of the pedestal height and width as a function of density using constraints imposed by peeling-ballooning and kinetic-ballooning theory are in quantitative agreement with the measurements.
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