Because greater Akt substrate of 160 kDa (AS160) phosphorylation has been reported in insulin-stimulated skeletal muscles without improved Akt activation several hours post-exercise, we hypothesized that prior exercise would result in attenuated AS160 dephosphorylation in insulin-stimulated rat skeletal muscle. Epitrochlearis muscles were isolated from rats that were sedentary (SED) or exercised 3 h earlier (3 h post-exercise; 3hPEX). Paired muscles were incubated with [3H]-2-deoxyglucose (2-DG) without insulin or with insulin. Lysates from other insulin-stimulated muscles from SED or 3hPEX rats were evaluated using AS160Thr642 and AS160Ser588 dephosphorylation assays. Prior exercise led to greater 2-DG uptake concomitant with greater AS160Thr642 phosphorylation and a non-significant trend (P=0.087) for greater AS160Ser588. Prior exercise also reduced AS160Thr642 and AS160Ser588 dephosphorylation rates. These results support the idea that attenuated AS160 dephosphorylation may favor greater AS160 phosphorylation post-exercise.
SIFRA was found to have moderate correlations with the previously validated CIRAS score, and demonstrated evidence of being a significant determinant of total and RA-related healthcare costs for RA patients. This study suggests that SIFRA could be an important methodological tool to control for severity in RA-related outcomes research. The algorithm can be applied to any claims dataset.
Purpose: To investigate the dose response of the hepatic extraction fraction derived from HIDA SPECT for assessment of hepatic function in response to radiation therapy (RT). Methods: Eleven patients with intrahepatic cancers were treated by fractionated conformai RT (30–65 Gy), and underwent HIDA SPECT/CT scans before, during and 1 month after the therapy. Voxel‐by‐voxel hepatic extraction fraction (HEF) was estimated from HIDA SPECT by the deconvolution method. The dose distributions were mapped on the HEF images via co‐registration with the treatment planning CT. The liver voxels, excluding gross tumor volumes and vessels, were segregated into subvolumes based upon the accumulated biologically‐ corrected doses at the end of RT for analysis of response of hepatic function to radition. Results: The HEF 1 month after RT decreased compared to pre RT. The averaged regional decreases in the HEF from the 11 patients were correlated linearly with the doses accumulated to the end of RT (R2=0.87). Substantial individual responses of the HEF to doses were observed 1 month after RT. Conclusions: Our study shows dose‐dependent hepatic function changes in local liver regions. There is substantial individual variability in the sensitivity of hepatic function to irradiation. The quantitative HEF images as a measure of spatial hepatic function may be a valuable tool for preserving liver function and avoiding injury after irradiation. The work is supported in part by RO1CA132834.
Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well‐functioning areas without compromising target coverage. Methods: Voxel‐based liver perfusion, a measure of functionality, was computed from dynamic contrast‐enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUD (standard model) and functionality‐weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high‐/low‐functioning voxels receiving a particular dose. Two‐dimensional synthetic and three‐dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high‐/low‐functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high‐/low‐functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD and satisfying dose limits to critical structures. This project is funded by MCubed and grant R01‐CA132834.
Purpose: To develop a local‐and‐global liver function probability model to aid in physiologically adaptive RT in patients with intrahepatic cancer. Methods: Twenty‐two patients enrolled in an IRB‐approved study had liver DCE‐MRI and Indocyanine green (ICG) clearance tests prior to, during and 1 month post RT. The percentage of ICG retention in the blood plasma 15 minutes after administration (ICG‐R15) was used as an overall liver function measure. Portal venous perfusion images were derived from DCE‐MRI. Assuming parallel architecture in the liver and considering both volume and function effects of tissue subunits, a global liver function probability Pl was assumed to be a volume‐weighted summation of local function probabilities p of subunits, excluding the subunits with p<γ, a threshold indicting poor function. The local function probability p was mapped from portal venous perfusion F by a logistic function p(F)=1/(1+(F50/F)^n), where we considered function probabilities saturated at high perfusion and suppressed at low perfusion. Finally, Pl was linearly fitted to a logarithm of ICG‐R15 to determine parameters (F50, n, γ). The leave‐m‐out technique was used to cross‐validate the model. This model was applied to evaluate the doseresponse of the local function probability one month after RT. Results: The best fitted values of (F50, n, γ) were 65.3ml/(100g.min), 2.86 and 0.14, respectively. The leave‐one‐out and 10‐fold tests resulted in 66.34±3.21 and 69.26±}10.35ml/(100g.min) of F50, 2.90±0.76 and 3.25±1.59 of n, and 0.14±0.03 and 0.13±}0.05 of γ, respectively. The derived Pl significantly correlated with ICG‐R15 logarithm (r=0.66, P<;1e‐6). Average percentage reduction in the local function probability post‐RT was related to the local dose by a logistic function (P=1e−6). Conclusion: The local‐and‐global liver function probability model has the potential to guide dose redistribution during a course of treatment to spare liver functional subunits, thereby allowing target d5 ose intensification without increasing the risk for complication. The work was supported by NIH/NCI grant RO1CA132834.
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