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At least 1,387 records · Page 77
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Systems and methods for approximating musculoskeletal dynamics

An approximation method and system are provided for more quickly controlling a prosthetic or other device by reducing computational processing time in a muscle model that can be used to control the prosthetic. For a given muscle, the approximation method can quickly compute polynomial structures for a muscle length and for each associated moment arms, which may be used to generate a torque for a joint position of a physics model. The physics model, in turn, produces a next joint position and velocity data for driving a prosthetic. The approximation method expands the polynomial structures as long as expansion is possible and sufficiently beneficial. The computations can be performed quickly by expanding the polynomial structures in a way that constrains the muscle length polynomial to the moment arm polynomial structures, and vice versa.

Sobinov, Anton↗
NASA NTRS2000

The relationship between dietary intake, exercise, energy balance and the space craft environment

Space flight is associated with the loss of skeletal muscle, principally from muscles with anti-gravity functions. Examination of data across different missions can permit a distinction to be made between true microgravity responses and what are mission-specific responses. Protein metabolism has been investigated on six missions, four short-term [Shuttle missions Space Life Sciences 1 (1991, SLSI), Space Life Sciences 2 (1993, SLS2), Deutsche-2 (1993, D2) and the Life and Microgravity Sciences (1996, LMS)] and two long-term missions (Skylab 1993 and NASA/MIR, 1996-1998). Measurements made include dietary intake (six missions), nitrogen balance (four missions), whole-body protein kinetics with [15N]glycine as the tracer (four missions) and cortisol excretion (three missions). Also available for comparison are bed rest studies with and without exercise. The purpose of this paper is to see what can be learnt about the muscle loss problem by comparing metabolic results across the six missions for which data are available and against bed rest. The analysis suggests that there is a linkage between the inability to maintain energy balance and exercise, and the connection is the decreased efficiency of removal of the metabolic by-products of exercise (heat, CO2) during space flight.

long duration↗
DOE OSTI2013

Focal Hydrothermal Ablation: Preliminary Investigation of a New Concept

PurposeTo determine whether focal tissue ablation is possible with interstitial instillation of steam.MethodsFresh swine livers were used. Through a 20 gauge needle, steam was instilled every 5 s, 3 (n = 5), 6 (n = 5), 9 (n = 5), or 12 (n = 5 + 5) times in a liver lobe. The ablated zones were sectioned parallel (n = 20) or perpendicular (n = 5) to the needle track. The longitudinal long and short axis diameters, or transverse long and short axis diameters of areas with discoloration on macroscopic examination, were measured. The experiment was repeated in vivo on a pig. Steam instillation was performed once every 5 s for 5 min in the liver (n = 3) and in muscle (n = 4), and temperature changes at three neighboring sites were monitored. Long and short axis diameters of the discolored areas were measured.ResultsA well-defined area of discoloration was invariably present at the site of steam instillation. The median longitudinal long axis diameter were 2.0, 2.5, 2.5, and 3.5 cm for 3, 6, 9, and 12 steam instillations in vitro, while median short axis diameters were 1.0, 1.5, 1.5, and 1.5 cm, respectively. Six attempts at ablation in vivo could be successfully completed. The long axis diameters of the ablated zones in the liver were 7.0 and 8.0 cm, while in muscle it ranged from 5.5 to 7.0 cm.ConclusionInstillation of steam in the liver in vitro and in vivo, and in muscle in vivo rapidly leads to circumscribed zones of coagulation necrosis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

PGC-1{beta} regulates mouse carnitine-acylcarnitine translocase through estrogen-related receptor {alpha}

Highlights: Black-Right-Pointing-Pointer The Cact gene is induced in mouse skeletal muscle after 24 h of fasting. Black-Right-Pointing-Pointer The Cact gene contains a functional consensus sequence for ERR. Black-Right-Pointing-Pointer This sequence binds ERR{alpha} both in vivo and in vitro. Black-Right-Pointing-Pointer This ERRE is required for the activation of Cact expression by the PGC-1/ERR axis. Black-Right-Pointing-Pointer Our results add Cact as a genuine gene target of these transcriptional regulators. -- Abstract: Carnitine/acylcarnitine translocase (CACT) is a mitochondrial-membrane carrier proteins that mediates the transport of acylcarnitines into the mitochondrial matrix for their oxidation by the mitochondrial fatty acid-oxidation pathway. CACT deficiency causes a variety of pathological conditions, such as hypoketotic hypoglycemia, cardiac arrest, hepatomegaly, hepatic dysfunction and muscle weakness, and it can be fatal in newborns and infants. Here we report that expression of the Cact gene is induced in mouse skeletal muscle after 24 h of fasting. To gain insight into the control of Cact gene expression, we examine the transcriptional regulation of the mouse Cact gene. We show that the 5 Prime -flanking region of this gene is transcriptionally active and contains a consensus sequence for the estrogen-related receptor (ERR), a member of the nuclear receptor family of transcription factors. This sequence binds ERR{alpha}in vivo and in vitro and is required for the activation of Cact expression by the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1/ERR axis. We also demonstrate that XTC790, the inverse agonist of ERR{alpha}, specifically blocks Cact activation by PGC-1{beta} in C2C12 cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

MYBPH inhibits NM IIA assembly via direct interaction with NMHC IIA and reduces cell motility

Highlights: Black-Right-Pointing-Pointer MYBPH inhibits NMHC IIA assembly and cell motility. Black-Right-Pointing-Pointer MYBPH interacts to assembly-competent NM IIA. Black-Right-Pointing-Pointer MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA. -- Abstract: Actomyosin filament assembly is a critical step in tumor cell migration. We previously found that myosin binding protein H (MYBPH) is directly transactivated by the TTF-1 lineage-survival oncogene in lung adenocarcinomas and inhibits phosphorylation of the myosin regulatory light chain (RLC) of non-muscle myosin IIA (NM IIA) via direct interaction with Rho kinase 1 (ROCK1). Here, we report that MYBPH also directly interacts with an additional molecule, non-muscle myosin heavy chain IIA (NMHC IIA), which was found to occur between MYBPH and the rod portion of NMHC IIA. MYBPH inhibited NMHC IIA assembly and reduced cell motility. Conversely, siMYBPH-induced increased motility was partially, yet significantly, suppressed by blebbistatin, a non-muscle myosin II inhibitor, while more profound effects were attained by combined treatment with siROCK1 and blebbistatin. Electron microscopy observations showed well-ordered paracrystals of NMHC IIA reflecting an assembled state, which were significantly less frequently observed in the presence of MYBPH. Furthermore, an in vitro sedimentation assay showed that a greater amount of NMHC IIA was in an unassembled state in the presence of MYBPH. Interestingly, treatment with a ROCK inhibitor that impairs transition of NM IIA from an assembly-incompetent to assembly-competent state reduced the interaction between MYBPH and NMHC IIA, suggesting that MYBPH has higher affinity to assembly-competent NM IIA. These results suggest that MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA, and negatively regulates actomyosin organization at 2 distinct steps, resulting in firm inhibition of NM IIA assembly.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

The effect of eicosapentaenoic and docosahexaenoic acid on protein synthesis and breakdown in murine C2C12 myotubes

Highlights: ► EPA can enhance protein synthesis and retard protein breakdown in muscle cells. ► These effects were concurrent with increases in p70s6k and FOXO3a phosphorylation. ► EPA may be a useful tool in the treatment of muscle wasting conditions. -- Abstract: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been found to stimulate protein synthesis with little information regarding their effects on protein breakdown. Furthermore whether there are distinct effects of EPA and DHA remains to be established. The aim of the current study was to determine the distinct effects of EPA and DHA on protein synthesis, protein breakdown and signalling pathways in C2C12 myotubes. Fully differentiated C2C12 cells were incubated for 24 h with 0.1% ethanol (control), 50 μM EPA or 50 μM DHA prior to experimentation. After serum (4 h) and amino acid (1 h) starvation cells were stimulated with 2 mM L-leucine and protein synthesis measured using {sup 3}H-labelled phenylalanine. Protein breakdown was measured using {sup 3}H-labelled phenylalanine and signalling pathways (Akt, mTOR, p70S6k, 4EBP1, rps6 and FOXO3a) via Western blots. Data revealed that after incubation with EPA protein synthesis was 25% greater (P < 0.05) compared to control cells, with no effect of DHA. Protein breakdown was 22% (P < 0.05) lower, compared to control cells, after incubation with EPA, with no effect of DHA. Analysis of signalling pathways revealed that both EPA and DHA incubation increased (P < 0.05) p70s6k phosphorylation, EPA increased (P < 0.05) FOXO3a phosphorylation, with no alteration in other signalling proteins. The current study has demonstrated distinct effects of EPA and DHA on protein metabolism with EPA showing a greater ability to result in skeletal muscle protein accretion.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Mitochondrial impairment observed in fibroblasts from South African Parkinson’s disease patients with parkin mutations

Highlights: • Mitochondrial dysfunction observed in patients with parkin-null mutations. • Mitochondrial ATP levels were decreased. • Electron-dense vacuoles were observed in the patients. • Mitochondria from muscle biopsies appeared within normal limits. • One patient did not show these defects possibly due to compensatory mechanisms. - Abstract: Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD pathogenesis will have important implications for the design of new and more effective therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Plasma acylcarnitines during insulin stimulation in humans are reflective of age-related metabolic dysfunction

The purpose of this study was to determine if plasma acylcarnitine (AC) profiling is altered under hyperinsulinemic conditions as part of the aging process. Fifteen young, lean (19–29 years) and fifteen middle-to older-aged (57–82 years) individuals underwent a 2-hr euglycemic-hyperinsulinemic clamp. Plasma samples were obtained at baseline, 20 min, 50 min, and 120 min for analysis of AC species and amino acids. Skeletal muscle biopsies were performed after 60 min of insulin-stimulation for analysis of acetyl-CoA carboxylase (ACC) phosphorylation. Insulin infusion decreased the majority of plasma short-, medium-, and long-chain (SC, MC, and LC, respectively) AC. However, during the initial 50 min, a number of MC and LC AC species (C10, C10:1, C12:1, C14, C16, C16:1, C18) remained elevated in aged individuals compared to their younger counterparts indicating a lag in responsiveness. Additionally, the insulin-induced decline in skeletal muscle ACC phosphorylation was blunted in the aged compared to young individuals (−24% vs. −56%, P < 0.05). These data suggest that a desensitization to insulin during aging, possibly at the level of skeletal muscle ACC phosphorylation, results in a diminished ability to transition to glucose oxidation indicative of metabolic inflexibility. - Highlights: • Plasma acylcarnitine profiling reveals metabolic inflexibility in aged individuals. • Time course acylcarnitine profiling is critical to identify metabolic dysfunction. • Acetyl-CoA carboxylase phosphorylation status is related to metabolic dysfunction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Regulator of G protein signaling 4 is a novel target of GATA-6 transcription factor

GATA transcription factors regulate an array of genes important in cell proliferation and differentiation. Here we report the identification of regulator of G protein signaling 4 (RGS4) as a novel target for GATA-6 transcription factor. Although three sites (a, b, c) within the proximal region of rabbit RGS4 promoter for GATA transcription factors were predicted by bioinformatics analysis, only GATA-a site (16 bp from the core TATA box) is essential for RGS4 transcriptional regulation. RT-PCR analysis demonstrated that only GATA-6 was highly expressed in rabbit colonic smooth muscle cells but GATA-4/6 were expressed in cardiac myocytes and GATA-1/2/3 expressed in blood cells. Adenovirus-mediated expression of GATA-6 but not GATA-1 significantly increased the constitutive and IL-1β-induced mRNA expression of the endogenous RGS4 in colonic smooth muscle cells. IL-1β stimulation induced GATA-6 nuclear translocation and increased GATA-6 binding to RGS4 promoter. These data suggest that GATA factor could affect G protein signaling through regulating RGS4 expression, and GATA signaling may develop as a future therapeutic target for RGS4-related diseases. - Highlights: • GATA-6 is highly expressed in colonic smooth muscle cells. • RGS4 is a novel target for GATA-6 transcription factor. • GATA-a response element is essential to regulate the core promoter of RGS4. • GATA-6 regulates IL-1β-induced RGS4 upregulation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Protective effects of estrogen against vascular calcification via estrogen receptor α-dependent growth arrest-specific gene 6 transactivation

Vascular calcification is one of the major complications of cardiovascular disease and is an independent risk factor for myocardial infarction and cardiac death. Postmenopausal women have a higher prevalence of vascular calcification compared with premenopausal women, suggesting protective effects of estrogen (E2). However, the underlying mechanisms of its beneficial effects remain unclear. In the present study, we examined the inhibitory effects of E2 on vascular smooth muscle cell (VSMC) calcification, and found that growth arrest-specific gene 6 (Gas6), a crucial molecule in vascular calcification, is transactivated by estrogen receptor α (ERα) in response to E2. In human aortic smooth muscle cells, physiological levels of E2 inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner. This inhibitory effect was significantly abolished by MPP, an ERα-selective antagonist, and ERα siRNA, but not by PHTPP, an ERβ-selective antagonist, and ERβ siRNA, implicating an ERα-dependent action. Apoptosis, an essential process for Pi-induced VSMC calcification, was inhibited by E2 in a concentration-dependent manner and further, MPP abolished this inhibition. Mechanistically, E2 restored the inhibited expression of Gas6 and phospho-Akt in Pi-induced apoptosis through ERα. Furthermore, E2 significantly activated Gas6 transcription, and MPP abrogated this E2-dependent Gas6 transactivation. E2-BSA failed to activate Gas6 transcription and to inhibit Ca deposition in VSMC, suggesting beneficial actions of genomic signaling by E2/nuclear ERα. Taken together, these results indicate that E2 exerts inhibitory effects on VSMC apoptosis and calcification through ERα-mediated Gas6 transactivation. These findings indicate a potential therapeutic strategy for the prevention of vascular calcification, especially in postmenopausal women. - Highlights: • E2 inhibits Pi-induced calcification in vascular smooth muscles cells. • E2 inhibits Pi-induced apoptosis by restoration of Gas6-mediated survival pathway. • Gas6 transactivation by E2 is mediated by ERα.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Saturation of SERCA's lipid annulus may protect against its thermal inactivation

The sarco(endo)plasmic reticulum Ca{sup 2+}-ATPase (SERCA) pumps are integral membrane proteins that catalyze the active transport of Ca{sup 2+} into the sarcoplasmic reticulum, thereby eliciting muscle relaxation. SERCA pumps are highly susceptible to oxidative damage, and cytoprotection of SERCA dampens thermal inactivation and is a viable therapeutic strategy in combating diseases where SERCA activity is impaired, such as muscular dystrophy. Here, we sought to determine whether increasing the percent of saturated fatty acids (SFA) within SERCA's lipid annulus through diet could protect SERCA pumps from thermal inactivation. Female Wistar rats were fed either a semi-purified control diet (AIN93G, 7% soybean oil by weight) or a modified AIN93G diet containing high SFA (20% lard by weight) for 17 weeks. Soleus muscles were extracted and SERCA lipid annulus and activity under thermal stress were analyzed. Our results show that SERCA's lipid annulus is abundant with short-chain (12–14 carbon) fatty acids, which corresponds well with SERCA's predicted bilayer thickness of 21 Å. Under control-fed conditions, SERCA's lipid annulus was already highly saturated (79%), and high-fat feeding did not increase this any further. High-fat feeding did not mitigate the reductions in SERCA activity seen with thermal stress; however, correlational analyses revealed significant and strong associations between % SFA and thermal stability of SERCA activity with greater %SFA being associated with lower thermal inactivation and greater % polyunsaturation and unsaturation index being associated with increased thermal inactivation. Altogether, these findings show that SERCA's lipid annulus may influence its susceptibility to oxidative damage, which could have implications in muscular dystrophy and age-related muscle wasting. - Highlights: • SERCA's lipid annulus in rat soleus was measured after immunoconcentration. • Short fatty acid chains surround SERCA and may ensure optimal hydrophobic matching. • SERCA's annulus is highly saturated in control-fed and high-fat fed rats. • Greater saturation associates with small levels of thermal inactivation. • Greater unsaturation associates with large levels of thermal inactivation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

(-)-Epigallocatechin-3-gallate stimulates myogenic differentiation through TAZ activation

Muscle loss is a typical process of aging. Green tea consumption is known to slow down the progress of aging. Their underlying mechanisms, however, remain largely unknown. In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG), a polyphenolic compound of green tea, on myogenic differentiation and found that EGCG significantly increases myogenic differentiation. After EGCG treatment, the expression of myogenic marker genes, such as myosin heavy chain, are increased through activation of TAZ, a transcriptional coactivator with a PDZ-binding motif. TAZ-knockdown does not stimulate EGCG-induced myogenic differentiation. EGCG facilitates the interaction between TAZ and MyoD, which stimulates MyoD-mediated gene transcription. EGCG induces nuclear localization of TAZ through the dephosphorylation of TAZ at its Ser89 residue, which relieves 14-3-3 binding in the cytosol. Interestingly, inactivation of Lats kinase is observed after EGCG treatment, which is responsible for the production of dephosphorylated TAZ. Together, these results suggest that EGCG induces myogenic differentiation through TAZ, suggesting that TAZ plays an important role in EGCG induced muscle regeneration. - Highlights: • EGCG stimulates myogenesis in C2C12 and muscle stem cells. • EGCG stimulates MyoD-mediated gene transcription through TAZ activation. • EGCG induces nuclear localization of TAZ through Lats kinase inhibition.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

A 2 bp deletion in the mitochondrial ATP 6 gene responsible for the NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome

Highlights: • A 2 bp deletion of the ATP6 gene causes a truncated a subunit. • The truncated a subunit is responsible for a decrease of complex V activity. • A 2 bp deletion of the ATP6 gene causes a NARP syndrome. Mitochondrial (mt) DNA-associated NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) syndrome is due to mutation in the MT-ATP6 gene. We report the case of a 18-year-old man who presented with deafness, a myoclonic epilepsy, muscle weakness since the age of 10 and further developed a retinitis pigmentosa and ataxia. The whole mtDNA analysis by next-generation sequencing revealed the presence of the 2 bp microdeletion m.9127–9128 del AT in the ATP6 gene at 82% heteroplasmy in muscle and to a lower load in blood (10–20%) and fibroblasts (50%). Using the patient's fibroblasts, we demonstrated a 60% reduction of the oligomycin-sensitive ATPase hydrolytic activity, a 40% decrease in the ATP synthesis and determination of the mitochondrial membrane potential using the fluorescent probe tetramethylrhodamine, ethyl ester indicated a significant reduction in oligomycin sensitivity. In conclusion, we demonstrated that this novel AT deletion in the ATP6 gene is pathogenic and responsible for the NARP syndrome.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Measurement of enzymatic and motile activities of Arabidopsis myosins by using Arabidopsis actins

Highlights: • Enzymatic activities of Arabidopsis myosins are measured by using Arabidopsis actin isoforms. • Motile activities of Arabidopsis myosins are measured by using Arabidopsis actin isoforms. • These values are different from those measured by using animal muscle actin isoforms. • Arabidopsis myosins show different activities when using different Arabidopsis actin isoforms. There are two classes of myosin, XI and VIII, in higher plants. Myosin XI moves actin filaments at high speed and its enzyme activity is also very high. In contrast, myosin VIII moves actin filaments very slowly with very low enzyme activity. Because most of these enzymatic and motile activities were measured using animal skeletal muscle α-actin, but not plant actin, they would not accurately reflect the actual activities in plant cells. We thus measured enzymatic and motile activities of the motor domains of two Arabidopsis myosin XI isoforms (MYA2, XI-B), and one Arabidopsis myosin VIII isoform (ATM1), by using three Arabidopsis actin isoforms (ACT1, ACT2, and ACT7). The measured activities were different from those measured by using muscle actin. Moreover, Arabidopsis myosins showed different enzymatic and motile activities when using different Arabidopsis actin isoforms. Our results suggest that plant actin should be used for measuring enzymatic and motile activities of plant myosins and that different actin isoforms in plant cells might function as different tracks along which affinities and velocities of each myosin isoform are modulated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

A novel approach to determine post mortem interval using neutron radiography

In this study, neutron radiography (NR) is used non-destructively to measure changes in hydrogen (H) content in decaying tissues as a mean to estimate post-mortem invertal (PMI). After death, tissue undergoes sequential changes consisting of organic and inorganic phase variations, as well as a gradual reduction of tissue water content. H is the primary contributor to NR contrast in biological specimens because (1) it is the most abundant element in biological tissues and (2) its nucleus scatter thermal and cold neutrons more strongly than any other atomic nucleus. These contrast differences can be advantageous in a forensic context to determine small changes in hydrogen concentrations. Dog cadavers were used as a model for human cadavers. Canine tissues and cadavers were exposed to controlled (laboratory settings) and uncontrolled (University of Tennessee Anthropology Research Facility) environmental conditions during putefraction, respectively. Neutron radiographs were supplemented with photographs and histology data to assess the decomposition stage of cadavers. Results demonstrated that the increase in neutron transmission likely corresponded to a decrease in hydrogen content in the tissue, which was correlated with the time of decay of the tissue. Tissues depleted in hydrogen are brighter in the neutron transmission radiographs of skeletal muscles, lung, and bone, under controlled conditions. Over a period of 10 days, changes in neutron transmission through lung and muscle were found to be higher than bone by 8.3%, 7.0 %, and 2.0 %, respectively. Estimation of the PMI was calculated from a natural logarithmic fitting of the NR data. Under controlled conditions, estimation of the PMI was 70% and 63.9 % accurate for bone and lung tissues, while being 1.4% accurate for muscle tissue. All results underestimated the true PMI. In conclusion, neutron radiography can be used for detection of hydrogen changes in decaying tissues to estimate PMI.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2014

Hypofractionated Intensity Modulated Radiation Therapy in Combined Modality Treatment for Bladder Preservation in Elderly Patients With Invasive Bladder Cancer

Purpose/Objective(s): To review our experience with bladder-preserving trimodality treatment (TMT) using hypofractionated intensity modulated radiation therapy (IMRT) for the treatment of elderly patients with muscle-invasive bladder cancer. Methods and Materials: Retrospective study of elderly patients treated with TMT using hypofractionated IMRT (50 Gy in 20 fractions) with concomitant weekly radiosensitizing chemotherapy. Eligibility criteria were as follows: age ≥70 years, a proven diagnosis of muscle-invasive transitional cell bladder carcinoma, stage T2-T3N0M0 disease, and receipt of TMT with curative intent. Response rate was assessed by cystoscopic evaluation and bladder biopsy. Results: 24 patients with a median age of 79 years were eligible. A complete response was confirmed in 83% of the patients. Of the remaining patients, 1 of them underwent salvage cystectomy, and no disease was found in the bladder on histopathologic assessment. After a median follow-up time of 28 months, of the patients with a complete response, 2 patients had muscle-invasive recurrence, 1 experienced locoregional failure, and 3 experienced distant metastasis. The overall and cancer-specific survival rates at 3 years were 61% and 71%, respectively. Of the surviving patients, 75% have a disease-free and functioning bladder. All patients completed hypofractionated IMRT, and 19 patients tolerated all 4 cycles of chemotherapy. Acute grade 3 gastrointestinal or genitourinary toxicities occurred in only 4% of the patients, and acute grade 3 or 4 hematologic toxicities, liver toxicities, or both were experienced by 17% of the cohort. No patient experienced grade 4 gastrointestinal or genitourinary toxicity. Conclusions: Hypofractionated IMRT with concurrent radiosensitizing chemotherapy appears to be an effective and well-tolerated curative treatment strategy in the elderly population and should be considered for patients who are not candidates for cystectomy or who wish to avoid cystectomy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Evaluation of a Knowledge-Based Planning Solution for Head and Neck Cancer

Purpose: Automated and knowledge-based planning techniques aim to reduce variations in plan quality. RapidPlan uses a library consisting of different patient plans to make a model that can predict achievable dose-volume histograms (DVHs) for new patients and uses those models for setting optimization objectives. We benchmarked RapidPlan versus clinical plans for 2 patient groups, using 3 different libraries. Methods and Materials: Volumetric modulated arc therapy plans of 60 recent head and neck cancer patients that included sparing of the salivary glands, swallowing muscles, and oral cavity were evenly divided between 2 models, Model{sub 30A} and Model{sub 30B}, and were combined in a third model, Model{sub 60}. Knowledge-based plans were created for 2 evaluation groups: evaluation group 1 (EG1), consisting of 15 recent patients, and evaluation group 2 (EG2), consisting of 15 older patients in whom only the salivary glands were spared. RapidPlan results were compared with clinical plans (CP) for boost and/or elective planning target volume homogeneity index, using HI{sub B}/HI{sub E} = 100 × (D2% − D98%)/D50%, and mean dose to composite salivary glands, swallowing muscles, and oral cavity (D{sub sal}, D{sub swal}, and D{sub oc}, respectively). Results: For EG1, RapidPlan improved HI{sub B} and HI{sub E} values compared with CP by 1.0% to 1.3% and 1.0% to 0.6%, respectively. Comparable D{sub sal} and D{sub swal} values were seen in Model{sub 30A}, Model{sub 30B}, and Model{sub 60}, decreasing by an average of 0.1, 1.0, and 0.8 Gy and 4.8, 3.7, and 4.4 Gy, respectively. However, differences were noted between individual organs at risk (OARs), with Model{sub 30B} increasing D{sub oc} by 0.1, 3.2, and 2.8 Gy compared with CP, Model{sub 30A}, and Model{sub 60}. Plan quality was less consistent when the patient was flagged as an outlier. For EG2, RapidPlan decreased D{sub sal} by 4.1 to 4.9 Gy on average, whereas HI{sub B} and HI{sub E} decreased by 1.1% to 1.5% and 2.3% to 1.9%, respectively. Conclusions: RapidPlan knowledge-based treatment plans were comparable to CP if the patient's OAR-planning target volume geometry was within the range of those included in the models. EG2 results showed that a model including swallowing-muscle and oral-cavity sparing can be applied to patients with only salivary gland sparing. This may allow model library sharing between institutes. Optimal detection of inadequate plans and population of model libraries requires further investigation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗