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ABSTRACT: Purpose: Despite of superior target dose uniformity, previous studies of helical tomotherapy (HT) show inferior longitudinal conformity and longer deliver time compared to volumetric-modulated arc therapy (VMAT) plans, due to fixed jaw size with conventional HT. Dynamic delivery techniques were introduced to overcome these problems. This study is to compare the dosimetric performance of dynamic tomotherapy delivery (5.0cm jaw running-start-stop (RSS)) with fixed jaw HT and VMAT deliveries. Methods: Sixteen patient cases, including brain, head&neck (HN), lung and prostate, were selected and de-identified prior to treatment planning. VMAT plans were generated using Varian RapidArc™ (RA) (one or two arcs) and HT plans using TomoTherapy® (fixed 2.5cm jaw). The tomotherapy RSS plans were generated using tomotherapy's research engine and optimized based on 5.0cm dynamic jaw, which allows larger jaw opening for lower dose gradient and smaller jaw opening at the target border when sharp penumbra is required. All 16 cases were planned based on identical contours, prescriptions, and planning objectives. Dose indices for targets and critical organs were compared based on dose-volume histograms, delivery time, and monitor units. Results: The average delivery time was reduced from 4.8min (HT) to 2.92min (RSS). RSS showed comparable target dose homogeneity to HT. Three delivery techniques showed comparable normal tissue sparing for lung cases, with improved sparing of cord with RSS. For prostate cases, RSS showed improved bladder and rectum doses compared to HT due to better longitudinal sparing. Superior normal tissue sparing was observed in RSS plans for optical nerves in brain cases and larynx or parotids for HN cases. Conclusions: Tomotherapy RSS with 5.0cm dynamic jaw is overall comparable, if not better, to 2.5cm fixed jaw HT, with faster treatment delivery. It also showed improved longitudinal dose conformity to critical structures adjacent to the target, which is comparable to RA technique. Yu Chen is employee of Accuray-Tomotherapy, Inc.
Medical Physics 06/2012; 39(6):3781. · 2.83 Impact Factor
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ABSTRACT: Cocaine causes cardiac arrhythmias, sudden death, and occasionally long QT syndrome in humans. We investigated the effect of cocaine on the human K(+) channels HERG and KvLQT1+minK that encode native rapidly (I(Kr)) and slowly (I(Ks)) activating delayed rectifier K(+) channels in the heart. HERG and KvLQT1+minK channels were heterologously expressed in human embryonic kidney 293 cells, and whole-cell currents were recorded. Cocaine had no effect on KvLQT1+minK current in concentrations up to 200 microM. In contrast, cocaine reversibly blocked HERG current with half-maximal block of peak tail current of 7.2 microM. By using a protocol to quickly activate HERG channels, we found that cocaine block developed rapidly after channel activation. At 0 mV, the time constants for the development of block were 38.2 +/- 2.1, 15.2 +/- 0.8, and 6.9 +/- 1.1 ms in 10, 50 and 200 microM cocaine, respectively. Cocaine-blocked channels also recovered rapidly from block after repolarization. At -100 mV, recovery from block followed a biphasic time course with fast and slow time constants of 3.5 +/- 0.7 and 100.3 +/- 15.4 ms, respectively. Using N-methyl-cocaine, a permanently charged, membrane-impermeable cocaine analog, block of HERG channels rapidly developed when the drug was applied intracellularly through the patch pipette, suggesting that the cocaine binding site on the HERG protein is located on a cytoplasmic accessible domain. These results indicate that cocaine suppresses HERG, but not KvLQT1+minK, channels by preferentially blocking activated channels, that it unblocks upon repolarization, and does so with unique ultrarapid kinetics. Because the cocaine concentration range we studied is achieved in humans, HERG block may provide an additional mechanism for cocaine-induced arrhythmias and sudden death.
Molecular Pharmacology 06/2001; 59(5):1069-76. · 4.88 Impact Factor
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Methods in molecular biology (Clifton, N.J.) 02/2000; 126:315-27.
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ABSTRACT: Salmeterol is a long-acting beta2-adrenergic receptor (beta 2AR) agonist used clinically to treat asthma. In addition to binding at the active agonist site, it has been proposed that salmeterol also binds with very high affinity at a second site, termed the "exosite", and that this exosite contributes to the long duration of action of salmeterol. To determine the position of the phenyl ring of the aralkyloxyalkyl side chain of salmeterol in the beta 2AR binding site, we designed and synthesized the agonist photoaffinity label [(125)I]iodoazidosalmeterol ([125I]IAS). In direct adenylyl cyclase activation, in effects on adenylyl cyclase after pretreatment of intact cells, and in guinea pig tracheal relaxation assays, IAS and the parent drug salmeterol behave essentially the same. Significantly, the photoreactive azide of IAS is positioned on the phenyl ring at the end of the molecule which is thought to be involved in exosite binding. Carrier-free radioiodinated [125I]IAS was used to photolabel epitope-tagged human beta 2AR in membranes prepared from stably transfected HEK 293 cells. Labeling with [(125)I]IAS was blocked by 10 microM (-)-alprenolol and inhibited by addition of GTP gamma S, and [125I]IAS migrated at the same position on an SDS-PAGE gel as the beta 2AR labeled by the antagonist photoaffinity label [125I]iodoazidobenzylpindolol ([125I]IABP). The labeled receptor was purified on a nickel affinity column and cleaved with factor Xa protease at a specific sequence in the large loop between transmembrane segments 5 and 6, yielding two peptides. While the control antagonist photoaffinity label [125I]IABP labeled both the large N-terminal fragment [containing transmembranes (TMs) 1-5] and the smaller C-terminal fragment (containing TMs 6 and 7), essentially all of the [125I]IAS labeling was on the smaller C-terminal peptide containing TMs 6 and 7. This direct biochemical evidence demonstrates that when salmeterol binds to the receptor, its hydrophobic aryloxyalkyl tail is positioned near TM 6 and/or TM 7. A model of IAS binding to the beta 2AR is proposed.
Biochemistry 09/1999; 38(35):11278-86. · 3.42 Impact Factor
