Publications by authors named "Sarah McGuire"

32 Publications

Optimizing photoswitchable MEK.

Proc Natl Acad Sci U S A 2019 12 3;116(51):25756-25763. Epub 2019 Dec 3.

Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544;

Optogenetic approaches are transforming quantitative studies of cell-signaling systems. A recently developed photoswitchable mitogen-activated protein kinase kinase 1 (MEK1) enzyme (psMEK) short-circuits the highly conserved Extracellular Signal-Regulated Kinase (ERK)-signaling cascade at the most proximal step of effector kinase activation. However, since this optogenetic tool relies on phosphorylation-mimicking substitutions in the activation loop of MEK, its catalytic activity is predicted to be substantially lower than that of wild-type MEK that has been phosphorylated at these residues. Here, we present evidence that psMEK indeed has suboptimal functionality in vivo and propose a strategy to circumvent this limitation by harnessing gain-of-function, destabilizing mutations in MEK. Specifically, we demonstrate that combining phosphomimetic mutations with additional mutations in MEK, chosen for their activating potential, restores maximal kinase activity in vitro. We establish that this modification can be tuned by the choice of the destabilizing mutation and does not interfere with reversible activation of psMEK in vivo in both and zebrafish. To illustrate the types of perturbations enabled by optimized psMEK, we use it to deliver pulses of ERK activation during zebrafish embryogenesis, revealing rheostat-like responses of an ERK-dependent morphogenetic event.
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http://dx.doi.org/10.1073/pnas.1912320116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926043PMC
December 2019

Aircraft Noise Effects on Sleep-Results of a Pilot Study Near Philadelphia International Airport.

Int J Environ Res Public Health 2019 08 31;16(17). Epub 2019 Aug 31.

Unit for Experimental Psychiatry, Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Current objective data on aircraft noise effects on sleep are needed in the US to inform policy. In this pilot field study, heart rate and body movements were continuously measured during sleep of residents living in the vicinity of Philadelphia International Airport (PHL) and in a control region without aircraft noise with sociodemographic characteristics similar to the exposed region ( = 40 subjects each). The primary objective was to establish the feasibility of unattended field measurements. A secondary objective was to compare objective and subjective measures of sleep and health between control and aircraft noise exposed groups. For all measurements, there was less than 10% of data loss, demonstrating the feasibility of unattended home measurements. Based on 2375 recorded aircraft noise events, we found a significant (unadjusted = 0.0136) exposure-response function between the maximum sound pressure level of aircraft noise events and awakening probability inferred from heart rate increases and body movements, which was similar to previous studies. Those living near the airport reported poorer sleep quality and poorer health than the control group in general, but when asked in the morning about their last night's sleep, no significant difference was found between groups. Neither systolic nor diastolic morning blood pressures differed between study regions. While this study demonstrates the feasibility of unattended field study measurements, for a national study around multiple US airports refinements of the study design are necessary to further lower methodological expense and increase participation rates.
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http://dx.doi.org/10.3390/ijerph16173178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747483PMC
August 2019

MRI-only brain radiotherapy: Assessing the dosimetric accuracy of synthetic CT images generated using a deep learning approach.

Radiother Oncol 2019 07 11;136:56-63. Epub 2019 Apr 11.

Medical Artificial Intelligence and Automation Laboratory, Department of Radiation Oncology, University of Texas Southwestern, Dallas, United States. Electronic address:

Purpose: This study assessed the dosimetric accuracy of synthetic CT images generated from magnetic resonance imaging (MRI) data for focal brain radiation therapy, using a deep learning approach.

Material And Methods: We conducted a study in 77 patients with brain tumors who had undergone both MRI and computed tomography (CT) imaging as part of their simulation for external beam treatment planning. We designed a generative adversarial network (GAN) to generate synthetic CT images from MRI images. We used Mutual Information (MI) as the loss function in the generator to overcome the misalignment between MRI and CT images (unregistered data). The model was trained using all MRI slices with corresponding CT slices from each training subject's MRI/CT pair.

Results: The proposed GAN method produced an average mean absolute error (MAE) of 47.2 ± 11.0 HU over 5-fold cross validation. The overall mean Dice similarity coefficient between CT and synthetic CT images was 80% ± 6% in bone for all test data. Though training a GAN model may take several hours, the model only needs to be trained once. Generating a complete synthetic CT volume for each new patient MRI volume using a trained GAN model took only one second.

Conclusions: The GAN model we developed produced highly accurate synthetic CT images from conventional, single-sequence MRI images in seconds. Our proposed method has strong potential to perform well in a clinical workflow for MRI-only brain treatment planning.
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http://dx.doi.org/10.1016/j.radonc.2019.03.026DOI Listing
July 2019

WHO Environmental Noise Guidelines for the European Region: A Systematic Review on Environmental Noise and Effects on Sleep.

Int J Environ Res Public Health 2018 03 14;15(3). Epub 2018 Mar 14.

Division of Sleep and Chronobiology, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

To evaluate the quality of available evidence on the effects of environmental noise exposure on sleep a systematic review was conducted. The databases PSYCINFO, PubMed, Science Direct, Scopus, Web of Science and the TNO Repository were searched for non-laboratory studies on the effects of environmental noise on sleep with measured or predicted noise levels and published in or after the year 2000. The quality of the evidence was assessed using GRADE criteria. Seventy four studies predominately conducted between 2000 and 2015 were included in the review. A meta-analysis of surveys linking road, rail, and aircraft noise exposure to self-reports of sleep disturbance was conducted. The odds ratio for the percent highly sleep disturbed for a 10 dB increase in L was significant for aircraft (1.94; 95% CI 1.61-2.3), road (2.13; 95% CI 1.82-2.48), and rail (3.06; 95% CI 2.38-3.93) noise when the question referred to noise, but non-significant for aircraft (1.17; 95% CI 0.54-2.53), road (1.09; 95% CI 0.94-1.27), and rail (1.27; 95% CI 0.89-1.81) noise when the question did not refer to noise. A pooled analysis of polysomnographic studies on the acute effects of transportation noise on sleep was also conducted and the unadjusted odds ratio for the probability of awakening for a 10 dBA increase in the indoor L was significant for aircraft (1.35; 95% CI 1.22-1.50), road (1.36; 95% CI 1.19-1.55), and rail (1.35; 95% CI 1.21-1.52) noise. Due to a limited number of studies and the use of different outcome measures, a narrative review only was conducted for motility, cardiac and blood pressure outcomes, and for children's sleep. The effect of wind turbine and hospital noise on sleep was also assessed. Based on the available evidence, transportation noise affects objectively measured sleep physiology and subjectively assessed sleep disturbance in adults. For other outcome measures and noise sources the examined evidence was conflicting or only emerging. According to GRADE criteria, the quality of the evidence was moderate for cortical awakenings and self-reported sleep disturbance (for questions that referred to noise) induced by traffic noise, low for motility measures of traffic noise induced sleep disturbance, and very low for all other noise sources and investigated sleep outcomes.
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http://dx.doi.org/10.3390/ijerph15030519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877064PMC
March 2018

Effects of -12° head-down tilt with and without elevated levels of CO on cognitive performance: the SPACECOT study.

J Appl Physiol (1985) 2018 03 14;124(3):750-760. Epub 2017 Dec 14.

Department of Neurology and Center for Space Medicine, Baylor College of Medicine , Houston, Texas.

Microgravity and elevated levels of CO are two common environmental stressors in spaceflight that may affect cognitive performance of astronauts. In this randomized, double-blind, crossover trial (SPACECOT), 6 healthy males (mean ± SD age: 41 ± 5 yr) were exposed to 0.04% (ambient air) and 0.5% CO concentrations during 26.5-h periods of -12° head-down tilt (HDT) bed rest with a 1-wk washout period between exposures. Subjects performed the 10 tests of the Cognition Test Battery before and on average 0.1, 5.2, and 21.0 h after the initiation of HDT bed rest. HDT in ambient air induced a change in response strategy, with increased response speed (+0.19 SD; P = 0.0254) at the expense of accuracy (-0.19 SD; P = 0.2867), resulting in comparable cognitive efficiency. The observed effects were small and statistically significant for cognitive speed only. However, even small declines in accuracy can potentially cause errors during mission-critical tasks in spaceflight. Unexpectedly, exposure to 0.5% CO reversed the response strategy changes observed under HDT in ambient air. This was possibly related to hypercapnia-induced cerebrovascular reactivity that favors cortical regions in general and the frontal cortex in particular, or to the CNS arousing properties of mildly to moderately increased CO levels. There were no statistically significant time-in-CO effects for any cognitive outcome. The small sample size and the small effect sizes are major limitations of this study and its findings. The results should not be generalized beyond the group of investigated subjects until they are confirmed by adequately powered follow-up studies. NEW & NOTEWORTHY Simulating microgravity with exposure to 21 h of -12° head-down tilt bed rest caused a change in response strategy on a range of cognitive tests, with a statistically significant increase in response speed at the expense of accuracy. Cognitive efficiency was not affected. The observed speed-accuracy tradeoff was small but may nevertheless be important for mission-critical tasks in spaceflight. Importantly, the change in response strategy was reversed by increasing CO concentrations to 0.5%.
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http://dx.doi.org/10.1152/japplphysiol.00855.2017DOI Listing
March 2018

Repeated Administration Effects on Psychomotor Vigilance Test Performance.

Sleep 2018 01;41(1)

Department of Psychiatry, Unit of Experimental Psychiatry, Division of Sleep and Chronobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Study Objectives: The Psychomotor Vigilance Test (PVT) is reported to be free of practice effects that can otherwise confound the effects of sleep loss and circadian misalignment on performance. This differentiates the PVT from more complex cognitive tests. To the best of our knowledge, no study has systematically investigated practice effects on the PVT across multiple outcome domains, depending on administration interval, and in ecologically more valid settings.

Methods: We administered a validated 3-minute PVT (PVT-B) 16 times in 45 participants (23 male, mean ± SD age 32.6 ± 7.3 years, range 25-54 years) with administration intervals of ≥10 days, ≤5 days, or 4 times per day. We investigated linear and logarithmic trends across repeated administrations in 10 PVT-B outcome variables.

Results: The fastest 10% of response times (RT; plin = .0002), minimum RT (plog = .0010), and the slowest 10% of reciprocal RT (plog = .0124) increased while false starts (plog = 0.0050) decreased with repeated administration, collectively decreasing RT variability (plog = .0010) across administrations. However, the observed absolute changes were small (e.g., -0.03 false starts per administration, linear fit) and are probably irrelevant in practice. Test administration interval did not modify the effects of repeated administration on PVT-B performance (all p > .13 for interaction). Importantly, mean and median RT, response speed, and lapses, which are among the most frequently used PVT outcomes, did not change systematically with repeated administration.

Conclusions: PVT-B showed stable performance across repeated administrations. Combined with its high sensitivity, this corroborates the status of the PVT as the de facto gold standard measure of the neurobehavioral effects of sleep loss and circadian misalignment.
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http://dx.doi.org/10.1093/sleep/zsx187DOI Listing
January 2018

Validation of the Cognition Test Battery for Spaceflight in a Sample of Highly Educated Adults.

Aerosp Med Hum Perform 2017 Oct;88(10):937-946

Background: Neuropsychological changes that may occur due to the environmental and psychological stressors of prolonged spaceflight motivated the development of the Cognition Test Battery. The battery was designed to assess multiple domains of neurocognitive functions linked to specific brain systems. Tests included in Cognition have been validated, but not in high-performing samples comparable to astronauts, which is an essential step toward ensuring their usefulness in long-duration space missions.

Methods: We administered Cognition (on laptop and iPad) and the WinSCAT, counterbalanced for order and version, in a sample of 96 subjects (50% women; ages 25-56 yr) with at least a Master's degree in science, technology, engineering, or mathematics (STEM). We assessed the associations of age, sex, and administration device with neurocognitive performance, and compared the scores on the Cognition battery with those of WinSCAT. Confirmatory factor analysis compared the structure of the iPad and laptop administration methods using Wald tests.

Results: Age was associated with longer response times (mean β = 0.12) and less accurate (mean β = -0.12) performance, women had longer response times on psychomotor (β = 0.62), emotion recognition (β = 0.30), and visuo-spatial (β = 0.48) tasks, men outperformed women on matrix reasoning (β = -0.34), and performance on an iPad was generally faster (mean β = -0.55). The WinSCAT appeared heavily loaded with tasks requiring executive control, whereas Cognition assessed a larger variety of neurocognitive domains.

Discussion: Overall results supported the interpretation of Cognition scores as measuring their intended constructs in high performing astronaut analog samples.Moore TM, Basner M, Nasrini J, Hermosillo E, Kabadi S, Roalf DR, McGuire S, Ecker AJ, Ruparel K, Port AM, Jackson CT, Dinges DF, Gur RC. Validation of the Cognition Test Battery for spaceflight in a sample of highly educated adults. Aerosp Med Hum Perform. 2017; 88(10):937-946.
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http://dx.doi.org/10.3357/AMHP.4801.2017DOI Listing
October 2017

Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent.

Clin Cancer Res 2017 Nov 18;23(22):6893-6903. Epub 2017 Aug 18.

Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.

The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU). C2Am was labeled with a NIR fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU. Three-dimensional (3D) MSOT images of probe distribution showed development of tumor contrast within 3 hours of probe administration and a signal-to-background ratio in regions containing dead cells of >10 after 24 hours. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated ( = 0.97, value < 0.01) with a marker of apoptotic cell death measured in histologic sections obtained post mortem. The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1029DOI Listing
November 2017

Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I.

J Nucl Med 2017 06 16;58(6):881-887. Epub 2017 Feb 16.

Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.

Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of a phosphatidylserine-binding agent for detecting tumor cell death in vivo based on the C2A domain of synaptotagmin-I. The capability of near-infrared fluorophore-labeled and Tc- and In-labeled derivatives of C2Am for imaging tumor cell death, using planar near-infrared fluorescence imaging and SPECT, respectively, was evaluated in implanted and genetically engineered mouse models of lymphoma and in a human colorectal xenograft. The fluorophore-labeled C2Am derivative showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (2%-5%). There was a significant correlation ( > 0.9, < 0.05) between fluorescently labeled C2Am binding and histologic markers of cell death, including cleaved caspase-3, whereas there was no such correlation with a site-directed mutant of C2Am (iC2Am) that does not bind phosphatidylserine. Tc-C2Am and In-C2Am also showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the liver and spleen at 24 h after probe administration. Tc-C2Am and In-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration. Given the favorable biodistribution profile of Tc- and In-labeled C2Am, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation.
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http://dx.doi.org/10.2967/jnumed.116.183004DOI Listing
June 2017

MRI measurements of reporter-mediated increases in transmembrane water exchange enable detection of a gene reporter.

Nat Biotechnol 2017 Jan 5;35(1):75-80. Epub 2016 Dec 5.

Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.

Non-invasive imaging of gene expression can be used to track implanted cells in vivo but often requires the addition of an exogenous contrast agent that may have limited tissue access. We show that the urea transporter (UT-B) can be used as a gene reporter, where reporter expression is detected using H MRI measurements of UT-B-mediated increases in plasma membrane water exchange. HEK cells transfected with the reporter showed an increased apparent water exchange rate (AXR), which increased in line with UT-B expression. AXR values measured in vivo, in UT-B-expressing HEK cell xenografts, were significantly higher (about twofold, P < 0.0001), compared with non-expressing controls. Fluorescence imaging of a red fluorescent protein (mStrawberry), co-expressed with UT-B showed that UT-B expression correlated in a linear fashion with AXR. Transduction of rat brain cells in situ with a lentiviral vector expressing UT-B resulted in about a twofold increase in AXR at the site of virus injection.
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http://dx.doi.org/10.1038/nbt.3714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5230773PMC
January 2017

Imaging Glycosylation In Vivo by Metabolic Labeling and Magnetic Resonance Imaging.

Angew Chem Weinheim Bergstr Ger 2016 01 3;128(4):1308-1312. Epub 2015 Dec 3.

Cancer Research UK Cambridge Institute Li Ka Shing Centre Cambridge CB2 0RE UK.

Glycosylation is a ubiquitous post-translational modification, present in over 50 % of the proteins in the human genome,1 with important roles in cell-cell communication and migration. Interest in glycome profiling has increased with the realization that glycans can be used as biomarkers of many diseases,2 including cancer.3 We report here the first tomographic imaging of glycosylated tissues in live mice by using metabolic labeling and a gadolinium-based bioorthogonal MRI probe. Significant -azidoacetylgalactosamine dependent  contrast was observed in vivo two hours after probe administration. Tumor, kidney, and liver showed significant contrast, and several other tissues, including the pancreas, spleen, heart, and intestines, showed a very high contrast (>10-fold). This approach has the potential to enable the rapid and non-invasive magnetic resonance imaging of glycosylated tissues in vivo in preclinical models of disease.
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http://dx.doi.org/10.1002/ange.201509858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848764PMC
January 2016

Using [(18)F]Fluorothymidine Imaged With Positron Emission Tomography to Quantify and Reduce Hematologic Toxicity Due to Chemoradiation Therapy for Pelvic Cancer Patients.

Int J Radiat Oncol Biol Phys 2016 09 19;96(1):228-39. Epub 2016 Apr 19.

Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

Purpose: The purpose of the present prospective clinical trial was to determine the efficacy of [(18)F]fluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the FLT uptake change during and after chemoradiation therapy with hematologic toxicity.

Methods And Materials: Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose response of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity.

Results: IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P<.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P<.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received >35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P<.05, paired t test).

Conclusions: IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses >35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts.
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http://dx.doi.org/10.1016/j.ijrobp.2016.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982822PMC
September 2016

Inter-individual Differences in the Effects of Aircraft Noise on Sleep Fragmentation.

Sleep 2016 05 1;39(5):1107-10. Epub 2016 May 1.

Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA.

Study Objectives: Environmental noise exposure disturbs sleep and impairs recuperation, and may contribute to the increased risk for (cardiovascular) disease. Noise policy and regulation are usually based on average responses despite potentially large inter-individual differences in the effects of traffic noise on sleep. In this analysis, we investigated what percentage of the total variance in noise-induced awakening reactions can be explained by stable inter-individual differences.

Methods: We investigated 69 healthy subjects polysomnographically (mean ± standard deviation 40 ± 13 years, range 18-68 years, 32 male) in this randomized, balanced, double-blind, repeated measures laboratory study. This study included one adaptation night, 9 nights with exposure to 40, 80, or 120 road, rail, and/or air traffic noise events (including one noise-free control night), and one recovery night.

Results: Mixed-effects models of variance controlling for reaction probability in noise-free control nights, age, sex, number of noise events, and study night showed that 40.5% of the total variance in awakening probability and 52.0% of the total variance in EEG arousal probability were explained by inter-individual differences. If the data set was restricted to nights (4 exposure nights with 80 noise events per night), 46.7% of the total variance in awakening probability and 57.9% of the total variance in EEG arousal probability were explained by inter-individual differences. The results thus demonstrate that, even in this relatively homogeneous, healthy, adult study population, a considerable amount of the variance observed in noise-induced sleep disturbance can be explained by inter-individual differences that cannot be explained by age, gender, or specific study design aspects.

Conclusions: It will be important to identify those at higher risk for noise induced sleep disturbance. Furthermore, the custom to base noise policy and legislation on average responses should be re-assessed based on these findings.
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http://dx.doi.org/10.5665/sleep.5764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835309PMC
May 2016

Imaging Glycosylation In Vivo by Metabolic Labeling and Magnetic Resonance Imaging.

Angew Chem Int Ed Engl 2016 Jan 3;55(4):1286-90. Epub 2015 Dec 3.

Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.

Glycosylation is a ubiquitous post-translational modification, present in over 50% of the proteins in the human genome, with important roles in cell-cell communication and migration. Interest in glycome profiling has increased with the realization that glycans can be used as biomarkers of many diseases, including cancer. We report here the first tomographic imaging of glycosylated tissues in live mice by using metabolic labeling and a gadolinium-based bioorthogonal MRI probe. Significant N-azidoacetylgalactosamine dependent T1  contrast was observed in vivo two hours after probe administration. Tumor, kidney, and liver showed significant contrast, and several other tissues, including the pancreas, spleen, heart, and intestines, showed a very high contrast (>10-fold). This approach has the potential to enable the rapid and non-invasive magnetic resonance imaging of glycosylated tissues in vivo in preclinical models of disease.
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http://dx.doi.org/10.1002/anie.201509858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737346PMC
January 2016

Development and Validation of the Cognition Test Battery for Spaceflight.

Aerosp Med Hum Perform 2015 Nov;86(11):942-52

Division of Sleep and Chronobiology, Department of Psychiatry, and the Behavior Laboratory, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Background: Sustained high-level cognitive performance is of paramount importance for the success of space missions, which involve environmental, physiological, and psychological stressors that may affect brain functions. Despite subjective symptom reports of cognitive fluctuations in spaceflight, the nature of neurobehavioral functioning in space has not been clarified.

Methods: We developed a computerized cognitive test battery (Cognition) that has sensitivity to multiple cognitive domains and was specifically designed for the high-performing astronaut population. Cognition consists of 15 unique forms of 10 neuropsychological tests that cover a range of cognitive domains, including emotion processing, spatial orientation, and risk decision making. Cognition is based on tests known to engage specific brain regions as evidenced by functional neuroimaging. Here we describe the first normative and acute total sleep deprivation data on the Cognition test battery as well as several efforts underway to establish the validity, sensitivity, feasibility, and acceptability of Cognition.

Results: Practice effects and test-retest variability differed substantially between the 10 Cognition tests, illustrating the importance of normative data that both reflect practice effects and differences in stimulus set difficulty in the population of interest. After one night without sleep, medium to large effect sizes were observed for 3 of the 10 tests addressing vigilant attention (Cohen's d = 1.00), cognitive throughput (d = 0.68), and abstract reasoning (d = 0.65).

Conclusions: In addition to providing neuroimaging-based novel information on the effects of spaceflight on a range of cognitive functions, Cognition will facilitate comparing the effects of ground-based analogues to spaceflight, increase consistency across projects, and thus enable meta-analyses.
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http://dx.doi.org/10.3357/AMHP.4343.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691281PMC
November 2015

Carbonic Anhydrase Activity Monitored In Vivo by Hyperpolarized 13C-Magnetic Resonance Spectroscopy Demonstrates Its Importance for pH Regulation in Tumors.

Cancer Res 2015 Oct 6;75(19):4109-18. Epub 2015 Aug 6.

Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.

Carbonic anhydrase buffers tissue pH by catalyzing the rapid interconversion of carbon dioxide (CO2) and bicarbonate (HCO3 (-)). We assessed the functional activity of CAIX in two colorectal tumor models, expressing different levels of the enzyme, by measuring the rate of exchange of hyperpolarized (13)C label between bicarbonate (H(13)CO3(-)) and carbon dioxide ((13)CO2), following injection of hyperpolarized H(13)CO3(-), using (13)C-magnetic resonance spectroscopy ((13)C-MRS) magnetization transfer measurements. (31)P-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and (13)C-MRS measurements of the H(13)CO3(-)/(13)CO2 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the (13)C measurements overestimated pH due to incomplete equilibration of the hyperpolarized (13)C label between the H(13)CO3(-) and (13)CO2 pools. Paradoxically, tumors overexpressing CAIX showed lower enzyme activity using magnetization transfer measurements, which can be explained by the more acidic extracellular pH in these tumors and the decreased activity of the enzyme at low pH. This explanation was confirmed by administration of bicarbonate in the drinking water, which elevated tumor extracellular pH and restored enzyme activity to control levels. These results suggest that CAIX expression is increased in hypoxia to compensate for the decrease in its activity produced by a low extracellular pH and supports the hypothesis that a major function of CAIX is to lower the extracellular pH.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-0857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594768PMC
October 2015

A new likelihood ratio metric for the psychomotor vigilance test and its sensitivity to sleep loss.

J Sleep Res 2015 Dec 29;24(6):702-13. Epub 2015 Jun 29.

Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

The Psychomotor Vigilance Test (PVT) is a widely used assay of behavioural alertness sensitive to the effects of sleep loss and circadian misalignment. However, there is currently no accepted PVT composite outcome metric that captures response slowing, attentional lapses and compensatory premature reactions observed typically in sleep-deprived subjects. We developed a novel likelihood ratio metric (LRM) based on relative frequency distributions in 50 categories of reaction times (RT) and false starts in alert and sleep-deprived subjects (acute total sleep deprivation: n = 31 subjects). The LRM had the largest effect size both in a 33-h total sleep deprivation protocol [1.96; 95% confidence interval (CI): 1.61-2.44; followed by response speed 1/RT, effect size 1.93, 95% CI: 1.55-2.65] and in a chronic partial sleep restriction protocol (1.22; 95% CI: 0.96-1.59; followed by response speed 1/RT, effect size 1.21, 95% CI: 0.94-1.59; 5 nights at 4 h sleep per night; n = 43 subjects). LRM scores correlated highly with response speed (R(2 ) = 0.986), and less well with five other common PVT outcome metrics (R(2 ) = 0.111-0.886). In conclusion, the new LRM is a sensitive PVT outcome metric with high statistical power that takes subtle sleep loss-related changes in the distribution of reaction times (including false starts) into account, is not prone to outliers, does not require baseline data and can be calculated and interpreted easily. Congruence between LRM and PVT response speed and their similar effect size rankings support the use of response speed as the primary, most sensitive and most parsimonious standard PVT outcome metric for determining neurobehavioural deficits from sleep loss.
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http://dx.doi.org/10.1111/jsr.12322DOI Listing
December 2015

Bone marrow sparing in intensity modulated proton therapy for cervical cancer: Efficacy and robustness under range and setup uncertainties.

Radiother Oncol 2015 Jun 13;115(3):373-8. Epub 2015 May 13.

Department of Radiation Oncology, University of Iowa, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA. Electronic address:

Background And Purpose: This study evaluates the potential efficacy and robustness of functional bone marrow sparing (BMS) using intensity-modulated proton therapy (IMPT) for cervical cancer, with the goal of reducing hematologic toxicity.

Material And Methods: IMPT plans with prescription dose of 45 Gy were generated for ten patients who have received BMS intensity-modulated X-ray therapy (IMRT). Functional bone marrow was identified by (18)F-flourothymidine positron emission tomography. IMPT plans were designed to minimize the volume of functional bone marrow receiving 5-40 Gy while maintaining similar target coverage and healthy organ sparing as IMRT. IMPT robustness was analyzed with ±3% range uncertainty errors and/or ±3 mm translational setup errors in all three principal dimensions.

Results: In the static scenario, the median dose volume reductions for functional bone marrow by IMPT were: 32% for V(5Gy), 47% for V(10Gy), 54% for V(20Gy), and 57% for V(40Gy), all with p<0.01 compared to IMRT. With assumed errors, even the worst-case reductions by IMPT were: 23% for V(5Gy), 37% for V(10Gy), 41% for V(20Gy), and 39% for V(40Gy), all with p<0.01.

Conclusions: The potential sparing of functional bone marrow by IMPT for cervical cancer is significant and robust under realistic systematic range uncertainties and clinically relevant setup errors.
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http://dx.doi.org/10.1016/j.radonc.2015.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508248PMC
June 2015

Spatial mapping of functional pelvic bone marrow using FLT PET.

J Appl Clin Med Phys 2014 07 8;15(4):129–136. Epub 2014 Jul 8.

University of Iowa.

The purpose of this study was to determine the ability of regions identified with bony landmarks on CT imaging to accurately represent active bone marrow when compared to FLT PET imaging. These surrogate regions could then be used to create a bone marrow sparing radiation therapy plan when FLT PET imaging is not available. Whole body (WB) FLT PET images were obtained of 18 subjects prior to chemoradiation therapy. The FLT image of each subject was registered to a CT image acquired for that subject to obtain anatomic information of the pelvis. Seventeen regions were identified based on features of the pelvic bones, sacrum, and femoral heads. The probability of FLT uptake being located in each of 17 different CT-based regions of the bony pelvis was calculated using Tukey's multiple comparison test. Statistical analysis of FLT uptake in the pelvis indicated four distinct groups within the 17 regions that had similar levels of activity. Regions located in the central part of the pelvis, including the superior part of the sacrum, the inner halves of the iliac crests, and the L5 vertebral body, had greater FLT uptake than those in the peripheral regions (p-value < 0.05). We have developed a method to use CT-defined pelvic bone regions to represent FLT PET-identified functional bone marrow. Individual regions that have a statistically significant probability of containing functional bone marrow can be used as avoidance regions to reduce radiation dose to functional bone marrow in radiation therapy planning. However, because likely active bone marrow regions and pelvic targets typically overlap, patient-specific spatial detail may be advantageous in IMRT planning scenarios and may best be provided using FLT PET imaging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161980PMC
http://dx.doi.org/10.1120/jacmp.v15i4.4780DOI Listing
July 2014

3-Dimensional magnetic resonance spectroscopic imaging at 3 Tesla for early response assessment of glioblastoma patients during external beam radiation therapy.

Int J Radiat Oncol Biol Phys 2014 Sep 28;90(1):181-9. Epub 2014 Jun 28.

Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa. Electronic address:

Purpose: To evaluate the utility of 3-dimensional magnetic resonance (3D-MR) proton spectroscopic imaging for treatment planning and its implications for early response assessment in glioblastoma multiforme.

Methods And Materials: Eighteen patients with newly diagnosed, histologically confirmed glioblastoma had 3D-MR proton spectroscopic imaging (MRSI) along with T2 and T1 gadolinium-enhanced MR images at simulation and at boost treatment planning after 17 to 20 fractions of radiation therapy. All patients received standard radiation therapy (RT) with concurrent temozolomide followed by adjuvant temozolomide. Imaging for response assessment consisted of MR scans every 2 months. Progression-free survival was defined by the criteria of MacDonald et al. MRSI images obtained at initial simulation were analyzed for choline/N-acetylaspartate ratios (Cho/NAA) on a voxel-by-voxel basis with abnormal activity defined as Cho/NAA ≥2. These images were compared on anatomically matched MRSI data collected after 3 weeks of RT. Changes in Cho/NAA between pretherapy and third-week RT scans were tested using Wilcoxon matched-pairs signed rank tests and correlated with progression-free survival, radiation dose and location of recurrence using Cox proportional hazards regression.

Results: After a median follow-up time of 8.6 months, 50% of patients had experienced progression based on imaging. Patients with a decreased or stable mean or median Cho/NAA values had less risk of progression (P<.01). Patients with an increase in mean or median Cho/NAA values at the third-week RT scan had a significantly greater chance of early progression (P<.01). An increased Cho/NAA at the third-week MRSI scan carried a hazard ratio of 2.72 (95% confidence interval, 1.10-6.71; P=.03). Most patients received the prescription dose of RT to the Cho/NAA ≥2 volume, where recurrence most often occurred.

Conclusion: Change in mean and median Cho/NAA detected at 3 weeks was a significant predictor of early progression. The potential impact for risk-adaptive therapy based on early spectroscopic findings is suggested.
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http://dx.doi.org/10.1016/j.ijrobp.2014.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183193PMC
September 2014

An evaluation of alertness training for older adults.

Front Aging Neurosci 2014 15;6:67. Epub 2014 Apr 15.

Institute of Neuroscience, Trinity College Dublin Dublin, Ireland.

We present an evaluation of a self-administered, biofeedback-aided, alertness training programme called the Alertness: Training for Focused Living (ATFL) Programme, which was developed as part of the Technology Research for Independent Living (TRIL) collaboration. We conducted two studies in order to evaluate the programme. A randomized controlled trial was, first of all, conducted with 40 older adults aged between 60 and 83. A series of five single case studies was then conducted to examine the suitability of the programme for use with people with more severe memory difficulties. In the randomized controlled trial, participants were assigned to the ATFL Programme or to a placebo programme. Aspects of participants' memory, attention and executive functioning were assessed via telephone prior to and following completion of the training programmes and at 1, 3, and 6-month follow-up sessions. Significant improvements in sustained attention and verbal fluency were noted in the ATFL group. The series of single case studies illustrated the importance of tailoring a programme to the needs and abilities of the clients in question. The potential benefits of the ATFL programme in terms of periodically boosting alertness and aiding executive functioning are discussed.
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http://dx.doi.org/10.3389/fnagi.2014.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990037PMC
April 2014

Detection of transgene expression using hyperpolarized 13C urea and diffusion-weighted magnetic resonance spectroscopy.

Magn Reson Med 2015 Apr 14;73(4):1401-6. Epub 2014 Apr 14.

Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge, UK.

Purpose: To assess the potential of a gene reporter system, based on a urea transporter (UTB) and hyperpolarized [(13) C]urea.

Methods: Mice were implanted subcutaneously with either unmodified control cells or otherwise identical cells expressing UTB. After injection of hyperpolarized [(13) C]urea, a spin echo sequence was used to measure urea concentration, T1 , and diffusion in control and UTB-expressing tissue.

Results: The apparent diffusion coefficient of hyperpolarized urea was 21% lower in tissue expressing UTB, in comparison with control tissue (P < 0.05, 1-tailed t-test, n = 6 in each group). No difference in water apparent diffusion coefficient or cellularity between these tissues was found, indicating that they were otherwise similar in composition.

Conclusion: Expression of UTB, by mediating cell uptake of urea, lowers the apparent diffusion coefficient of hyperpolarized (13) C urea in tissue and thus the transporter has the potential to be used as a magnetic resonance-based gene reporter in vivo. Magn Reson Med 73:1401-1406, 2015. © 2014 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mrm.25254DOI Listing
April 2015

The zebrafish reference genome sequence and its relationship to the human genome.

Nature 2013 Apr 17;496(7446):498-503. Epub 2013 Apr 17.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
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http://dx.doi.org/10.1038/nature12111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703927PMC
April 2013

Improving interstitial transport of macromolecules through reduction in cell volume fraction in tumor tissues.

Nanomedicine 2012 Oct 14;8(7):1088-95. Epub 2012 Jan 14.

Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.

Unlabelled: Interstitial transport of large molecules and nanoparticles is an important concern in nanomedicine-mediated cancer treatment. To that end, the current study was proposed to improve the transport through enlargement of extracellular space by treating tumors with hypertonic solution of mannitol and cytotoxic agents (e.g., ethacrynic acid [ECA]), which could effectively shrink and kill cells, respectively. In the study, the improvement in interstitial penetration of dextran was investigated ex vivo using rat fibrosarcoma tissues sectioned into 600 μm slices. Experimental data showed that the hypertonic solution was more effective than ECA for improving interstitial penetration of dextran with molecular weights ranging from 4000 to 2,000,000. The extent of improvement depended on the size of dextran molecules and the time when the treatment was applied. Results from the study suggested that increases in both size and connectedness of interstitial pathways were important for improvement of interstitial transport of large molecules and nanoparticles.

From The Clinical Editor: This study reports on the optimization of interstitial transport both for large molecules and nanoparticles in nanomedicine-mediated cancer treatment. The study demonstrates that hypertonic solutions could efficiently lead to cancer cell shrinkage and more so than the applied cytotoxic agent thereby improving transport of chemotherapeutic entities.
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http://dx.doi.org/10.1016/j.nano.2011.12.009DOI Listing
October 2012

A methodology for incorporating functional bone marrow sparing in IMRT planning for pelvic radiation therapy.

Radiother Oncol 2011 Apr 22;99(1):49-54. Epub 2011 Mar 22.

Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.

Background And Purpose: The purpose of this study was to design a radiation therapy treatment planning approach that would spare hematopoietically active bone marrow using [(18)F]FLT PET imaging.

Materials And Methods: We have developed an IMRT planning methodology to incorporate functional PET imaging using [(18)F]FLT scans. Plans were generated for two simulated cervical cancer patients, where pelvic active bone marrow regions were incorporated as avoidance regions based on the ranges: SUV4 ≥ 4; 4>SUV3 ≥ 3; and 3 > SUV2 ≥ 2. Dose objectives were set to reduce bone marrow volume that received 10 (V(10)) and 20 (V(20))Gy.

Results: Active bone marrow regions identified by [(18)F]FLT with an SUV ≥ 2, SUV ≥ 3, and SUV ≥ 4 represented an average of 43.0%, 15.3%, and 5.8%, respectively of the total osseous pelvis for the two cases studied. Improved dose-volume histograms for all identified bone marrow SUV volumes and decreases in V(10), and V(20) were achieved without clinically significant changes to PTV or OAR doses.

Conclusions: Incorporation of [(18)F]FLT PET in IMRT planning provides a methodology to reduce radiation dose to active bone marrow without compromising PTV or OAR dose objectives in pelvic malignancies.
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http://dx.doi.org/10.1016/j.radonc.2011.01.025DOI Listing
April 2011

3'-deoxy-3'-[¹⁸F]fluorothymidine PET quantification of bone marrow response to radiation dose.

Int J Radiat Oncol Biol Phys 2011 Nov 6;81(3):888-93. Epub 2011 Feb 6.

Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.

Purpose: The purpose of this study was to quantify the relationship of bone marrow response to radiation dose, using 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT)-labeled uptake quantified in positron-emission tomography (PET) scans.

Methods And Materials: Pre- and post-Week 1 treatment [(18)F]FLT PET images were registered to the CT images used to create the radiation treatment plan. Changes in [(18)F]FLT uptake values were measured using profile data of standardized uptake values (SUVs) and doses along the vertebral bodies located at a field border where a range of radiation doses were present for 10 patients. Data from the profile measurements were grouped into 1 Gy dose bins from 1 to 9 Gy to compare SUV changes for all patients. Additionally, the maximum pretreatment, the post-Week 1 treatment, and the dose values located within the C6-T7 vertebrae that straddled the field edge were measured for all patients.

Results: Both the profile and the individual vertebral data showed a strong correlation between SUV change and radiation dose. Relative differences in SUVs between bins >1 Gy and <7 Gy were statistically significant (p < 0.01, two-sample t test). The reduction in SUV was approximately linear until it reached a reduction threshold of 75%-80% in SUV for doses greater than 6 Gy/week for both the dose-binned data and the vertebral maximum SUVs.

Conclusions: The change in SUV observed in head and neck cancer patients treated with chemoradiation shows the potential for using [(18)F]FLT PET images for identifying active bone marrow and monitoring changes due to radiation dose. Additionally, the change in [(18)F]FLT uptake observed in bone marrow for different weekly doses suggests potential dose thresholds for reducing bone marrow toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2010.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140551PMC
November 2011

Polymorphisms in the mitochondrial DNA control region and frailty in older adults.

PLoS One 2010 Jun 10;5(6):e11069. Epub 2010 Jun 10.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.

Methodology/principal Findings: To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989-1990, 1992-1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07-3.60, p = 0.020) and lower grip strength (adjusted coefficient = -2.04, 95% CI = -3.33- -0.74, p = 0.002).

Conclusions: This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883558PMC
June 2010

Investigation of the pharmacokinetics of 3'-deoxy-3'-[18F]fluorothymidine uptake in the bone marrow before and early after initiation of chemoradiation therapy in head and neck cancer.

Nucl Med Biol 2010 May;37(4):433-8

Division of Nuclear Medicine, Department of Radiology, University of Iowa Hospitals and Clinics Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.

Introduction: The kinetics of the bone marrow uptake of 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) before and early after initiation of chemoradiation therapy was investigated in patients with head and neck cancer.

Methods: Fourteen subjects with head and neck cancer underwent FLT positron emission tomography (PET) at baseline and after 10 Gy of radiation therapy. Thirteen subjects also received one cycle of platinum-based chemotherapy before the second FLT PET. Kinetic parameters, including the flux constant based on compartmental analysis (K(FLT)) and the Patlak constant (K(Patlak)) for cervical marrow, were calculated. Standardized uptake values (SUVs) for the cervical marrow (inside the radiation field) and lumbar spine marrow (outside the radiation field) were also determined.

Results: There was a significant drop in FLT uptake in the bone marrow inside the radiation field. Mean pretreatment uptake values for the cervical spine were SUV=3.08+/-0.66, K(FLT)=0.045+/-0.016 min(-1) and K(Patlak)=0.039+/-0.013 min(-1). After treatment, these values were SUV=0.74+/-0.19, K(FLT)=0.011+/-0.005 min(-1) and K(Patlak)=0.005+/-0.002 min(-1). Compartmental analysis revealed a significant drop in k(3) in irradiated cervical marrow. FLT uptake in the bone marrow outside the radiation field exhibited a significantly smaller decrease.

Conclusions: There is a marked decrease in FLT uptake in irradiated bone marrow after 10 Gy of radiation therapy to the head and neck. The drop in FLT uptake in irradiated marrow is due to a significant decrease in the net phosphorylation rate of FLT.
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http://dx.doi.org/10.1016/j.nucmedbio.2010.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920567PMC
May 2010

Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity.

J Clin Endocrinol Metab 2007 Mar 12;92(3):1073-9. Epub 2006 Dec 12.

Division of Pediatric Endocrinology, Department of Pediatrics, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.

Context: Obesity is a prominent feature of Albright hereditary osteodystrophy (AHO), a disorder caused by heterozygous GNAS mutations that disrupt the stimulatory G protein alpha-subunit Galpha(s). Because Galpha(s) is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [pseudohypoparathyroidism type 1a (PHP1a)], whereas paternal inheritance leads to AHO alone [pseudopseudohypoparathyroidism (pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions.

Setting: This observational study was conducted at the General Clinical Research Center, Johns Hopkins University School of Medicine; National Institutes of Health.

Patients: Fifty-three patients with AHO (40 with PHP1a and 13 with pseudoPHP) and two with progressive osseous heteroplasia were studied.

Main Outcome Measures: Main outcome measures were weight and height sd score (SDS), body mass index (BMI) percentiles, and BMI z-scores.

Results: Patients with PHP1a had significantly greater mean weight SDS, BMI percentages, and BMI z-scores compared with patients with pseudoPHP. These differences in BMI were secondary to adipose content based on dual energy x-ray absorptiometry analysis. The mean BMI z-score +/- sem for PHP1a was 2.31 +/- 0.18 compared with 0.65 +/- 0.31 in pseudoPHP (P = 0.000032). Twenty-five of 40 (62.5%) patients with PHP1a had mean BMI z-scores greater than two SDS above the mean, whereas no patients with pseudoPHP had BMI z-scores in this range.

Conclusions: Although the AHO phenotype for PHP1a and pseudoPHP has been thought to be similar, we have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings may implicate paternal imprinting of Galpha(s) in the development of human obesity.
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http://dx.doi.org/10.1210/jc.2006-1497DOI Listing
March 2007

A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung.

Int J Radiat Oncol Biol Phys 2006 Dec;66(5):1543-52

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: Single photon emission computed tomography (SPECT) provides a map of the spatial distribution of lung perfusion. Thus, SPECT guidance can be used to divert dose away from higher-functioning lung, potentially reducing lung toxicity. We present a methodology for achieving this aim and test it in intensity-modulated radiotherapy (IMRT) treatment-planning.

Methods And Materials: IMRT treatment plans were generated with and without SPECT guidance and compared for 5 patients. Healthy lung was segmented into four regions on the basis of SPECT intensity in the SPECT plan. Dose was sequentially allowed to the target via regions of increasing SPECT intensity. This process results in reduction of dose to functional lung, reflected in the dose-function histogram (DFH). The plans were compared using DFHs and F(20)/F(30) values (F(x) is the functional lung receiving dose above x Gy).

Results: In all cases, the SPECT-guided plan produced a more favorable DFH compared with the non-SPECT-guided plan. Additionally, the F(20) and F(30) values were reduced for all patients by an average of 13.6% +/- 5.2% and 10.5% +/- 5.8%, respectively. In all patients, DFHs of the two highest-functioning SPECT regions were reduced, whereas DFHs of the two lower-functioning regions were increased, illustrating the dose "give-take" between SPECT regions during redistribution.

Conclusions: SPECT-guided IMRT shows potential for reducing the dose delivered to highly functional lung regions. This dose reduction could reduce the number of high-grade pneumonitis cases that develop after radiation treatment and improve patient quality of life.
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http://dx.doi.org/10.1016/j.ijrobp.2006.07.1377DOI Listing
December 2006