• Comparison between 4D Robust Optimization Methods for Carbon-Ion Treatment Planning

    分类: 核科学技术 >> 核科学与技术 提交时间: 2023-08-27

    摘要: Intensity-modulated particle therapy (IMPT) with carbon ions is comparatively susceptible to various uncertainties caused by breathing motion, including range, setup, and target positioning uncertainties. To determine relative biological effectiveness-weighted dose (RWD) distributions that are resilient to these uncertainties, the reference phase-based four-dimensional (4D) robust optimization (RP-4DRO) and each phase-based 4D robust optimization (EP-4DRO) method in carbon-ion IMPT treatment planning were evaluated and compared. Based on RWD distributions, 4DRO methods were compared with 4D conventional optimization using planning target volume (PTV) margins (PTV-based optimization) to assess the effectiveness of the robust optimization methods. Carbon-ion IMPT treatment planning was conducted in a cohort of five lung cancer patients. The results indicated that the EP-4DRO method provided better robustness (P=0.080) and improved plan quality (P=0.225) for the clinical target volume (CTV) in the individual respiratory phase when compared with the PTV-based optimization. Compared with the PTV-based optimization, the RP-4DRO method ensured the robustness (P = 0.022) of the dose distributions in the reference breathing phase, albeit with a slight sacrifice of the target coverage (P=0.450). Both 4DRO methods successfully maintained the doses delivered to the organs at risk (OARs) below tolerable levels, which were lower than the doses in the PTV-based optimization (P<0.05). Furthermore, the RP-4DRO method exhibited significantly superior performance when compared with the EP-4DRO method in enhancing overall OAR sparing in either the individual respiratory phase or reference respiratory phase (P<0.05). In general, both 4DRO methods outperformed the PTV-based optimization in terms of OAR sparing and robustness.

  • Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex

    分类: 生物学 >> 生物物理学 提交时间: 2016-05-12

    摘要: Nonstructural protein 14 (nsp14) of coronaviruses (CoV) is important for viral replication and transcription. The N-terminal exoribonuclease (ExoN) domain plays a proofreading role for prevention of lethal mutagenesis, and the C-terminal domain functions as a (guanine-N7) methyl transferase (N7-MTase) for mRNA capping. The molecular basis of both these functions is unknown. Here, we describe crystal structures of severe acute respiratory syndrome (SARS)-CoV nsp14 in complex with its activator nonstructural protein10 (nsp10) and functional ligands. One molecule of nsp10 interacts with ExoN of nsp14 to stabilize it and stimulate its activity. Although the catalytic core of nsp14 ExoN is reminiscent of proofreading exonucleases, the presence of two zinc fingers sets it apart from homologs. Mutagenesis studies indicate that both these zinc fingers are essential for the function of nsp14. We show that a DEEDh (the five catalytic amino acids) motif drives nucleotide excision. The N7-MTase domain exhibits a noncanonical MTase fold with a rare beta-sheet insertion and a peripheral zinc finger. The cap-precursor guanosine-P3-adenosine-5', 5'-triphosphate and S-adenosyl methionine bind in proximity in a highly constricted pocket between two beta-sheets to accomplish methyl transfer. Our studies provide the first glimpses, to our knowledge, into the architecture of the nsp14-nsp10 complex involved in RNA viral proofreading.