ABSTRACT
In this study, we evaluated the performance of an Elekta linac in the delivery of gated radiotherapy. Delivery accuracy was examined with an emphasis on the impact of using short gating windows (low monitor unit beam-on segments) or long beam hold times. The performance was assessed using a 20cm by 20cm open field with the radiation delivered using a range of beam-on and beam-off time periods. Gated delivery measurements were also performed for two SBRT plans delivered using volumetric modulated arc therapy (VMAT). Tests included both free-breathing based gating (covering a variety of gating windows) and simulated breath-hold based gating. An IBA MatriXX 2D ion chamber array was used for data collection, and the gating accuracy at low MU was evaluated using gamma passing rates. For the 20 cm by 20 cm open field, the measurements generally showed close agreement between the gated and non-gated beam deliveries. Discrepancies, however, began to appear with a 5-to-1 ratio of the beam-off to beam-on times. The discrepancies observed for these tight gating windows can be attributed to the small number of monitor units delivered during each beam-on segment. Dose distribution analysis from the delivery of the two SBRT plans showed gamma passing rates (± 1%, 2%/1 mm) in the range of 95% to 100% for gating windows of 25%, 38%, 50%, 63%, 75%, and 83%. Using a simulated sinusoidal breathing signal with a 4 second period, the gamma passing rate of free-breathing gating and breath-hold gating deliveries were measured in the range of 95.7% to 100%. In conclusion, the results demonstrate that Elekta linacs can accurately deliver respiratory gated treatments for both free-breathing and breath-hold patients. Some caution should be exercised with the use of very tight gating windows.
Subject(s)
Lung Neoplasms/surgery , Particle Accelerators/instrumentation , Phantoms, Imaging , Radiosurgery/methods , Radiotherapy Planning, Computer-Assisted/methods , Respiratory-Gated Imaging Techniques/methods , Breath Holding , Humans , Radiotherapy Dosage , Radiotherapy, Intensity-Modulated/methodsABSTRACT
SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.
Subject(s)
Oxazoles/chemical synthesis , Oxazoles/metabolism , Pyridines/chemical synthesis , Pyridines/metabolism , Sirtuins/metabolism , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Enzyme Activation/drug effects , Enzyme Activation/physiology , Humans , Mice , Mice, Transgenic , Oxazoles/pharmacology , Pyridines/pharmacology , Rats , Rats, Zucker , Sirtuin 1 , Sirtuins/agonists , Structure-Activity RelationshipABSTRACT
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
Subject(s)
Caloric Restriction , Diabetes Mellitus, Type 2/drug therapy , Sirtuins/agonists , Acetylation , Allosteric Site , Animals , Blood Glucose/metabolism , Catalytic Domain , Cell Line , Dietary Fats/administration & dosage , Dietary Fats/pharmacology , Disease Models, Animal , Drosophila melanogaster , Heterocyclic Compounds, 4 or More Rings/pharmacology , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Insulin/metabolism , Insulin/pharmacology , Male , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Rats , Rats, Sprague-Dawley , Rats, Zucker , Resveratrol , Sirtuin 1 , Sirtuins/metabolism , Stilbenes/chemistry , Stilbenes/pharmacologyABSTRACT
Novel antibacterials agents, 2-(1H-indol-3-yl)tetrahydroquinolines, were prepared using hetero Diels-Alder chemistry and found to be effective in vitro against methicillin-resistant Staphylococcus aureus (MRSA). A structure-activity relationship (SAR) study was conducted to determine the important features of this series and to increase the potency of these compounds. Compounds were prepared that had minimum inhibitory concentrations (MIC's) < 1.0 microg/mL against MRSA, but had no activity versus vancomycin-resistant Enterococcus (VRE).
