Compressed Sensing for Few-View Multi-Pinhole Spect with Applications to Preclinical Imaging

Single Photon Emission Computed Tomography (SPECT) can be used to identify and quantify changes in molecular and cellular targets involved in disease. A radiopharmaceutical that targets a specific metabolic function is administered to a subject and planar projections are formed by imaging emissions at different view angles around the subject. The reconstruction task is to determine the distribution of radioactivity within the subject from the projections. We present a reconstruction approach that utilizes only a few view angles, resulting in a highly underdetermined system, which could be used for dynamic imaging applications designed to quantify physiologic processes altered with disease. We developed an approach to solving the underdetermined problem that incorporates a fast matrix- based multi-pinhole projection model into a primal-dual algorithm (Chambolle-Pock), tailored to perform penalized data fidelity minimization using the reconstruction’s total variation as a sparse regularizer. The resulting algorithm was implemented on a Graphics Processing Unit (GPU), and validated by solving an idealized quadratic problem. Simulated noisy data from a digital rat thorax phantom was reconstructed using a range of regularizing parameters and primal-dual scale factors to control the smoothness of the reconstruction and the step-size in the iterative algorithm, respectively. The approach was characterized by evaluating data fidelity, convergence, and noise properties. The proposed approach was then applied to few-view experimental data obtained in a preclinical SPECT study. 99mTc-labeled macroaggregated albumin (MAA) that accumulates in the lung was administered to a rat and multi-pinhole image data was acquired and reconstructed. The results demonstrate MAA uptake in the lungs is accurately quantified over a wide range of activity levels using as few as three view angles. In a pilot experiment, we also showed using 15 and 60 view angles that uptake of 99mTc-hexamethylpropyleneamineoxime in hyperoxia-exposed rats is higher than that in control rats, consistent with previous studies in our laboratory. Overall these experiments demonstrate the potential utility of the proposed method for few-view three-dimensional reconstruction of SPECT data for dynamic preclinical studies

Overexpression of SPARC obliterates the in vivo tumorigenicity of human hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide. Current treatments are extremely disappointing. SPARC (Secreted protein, acidic and rich in cysteine) is a matricellular glycoprotein with differential expression in several tumors, including HCC, which significance remains unclear. We infected HCC cells (HepG2, Hep3B and Huh7) with an adenovirus expressing SPARC (AdsSPARC) to examine the role of SPARC expression on HCC cells and its effect on tumor aggressiveness. The in vitro HCC cells substrate-dependent proliferation and cell cycle profile were unaffected; however, SPARC overexpression reduced HCC proliferation when cells were grown in spheroids. A mild induction of cellular apoptosis was observed upon SPARC overexpression. SPARC overexpression resulted in spheroid growth inhibition in vitro while no effects were found when recombinant SPARC was exogenously applied. Moreover, the clonogenic and migratory capabilities were largely decreased in SPARC-overexpressing HCC cells, altogether suggesting a less aggressive HCC cell phenotype. Consistently, AdsSPARC-transduced cells showed increased E-cadherin expression and a concomitant decrease in N-cadherin expression. Furthermore, SPARC overexpression was found to reduce HCC cell viability in response to 5-FU-based chemotherapy in vitro, partially through induction of apoptosis. In vivo experiments revealed that SPARC overexpression in HCC cells inhibited their tumorigenic capacity and increased animal survival through a mechanism that partially involves host macrophages. Our data suggest that SPARC overexpression in HCC cells results in a reduced tumorigenicity partially through the induction of mesenchymal-to-epithelial transition (MET). These evidences point to SPARC as a novel target for HCC treatment.Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bolontrade, Marcela Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rizzo, Manglio Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Protection by Inhaled Hydrogen Therapy in a Rat Model of Acute Lung Injury can be Tracked \u3cem\u3ein vivo\u3c/em\u3e Using Molecular Imaging

Inhaled hydrogen gas (H2) provides protection in rat models of human acute lung injury (ALI). We previously reported that biomarker imaging can detect oxidative stress and endothelial cell death in vivo in a rat model of ALI. Our objective was to evaluate the ability of 99mTc-hexamethylpropyleneamineoxime (HMPAO) and 99mTc-duramycin to track the effectiveness of H2 therapy in vivo in the hyperoxia rat model of ALI. Rats were exposed to room air (normoxia), 98% O2 + 2% N2 (hyperoxia) or 98% O2 + 2% H2 (hyperoxia+H2) for up to 60 h. In vivo scintigraphy images were acquired following injection of 99mTc-HMPAO or 99mTc-duramycin. For hyperoxiarats, 99mTc-HMPAO and 99mTc-duramycin lung uptake increased in a time-dependent manner, reaching a maximum increase of 270% and 150% at 60 h, respectively. These increases were reduced to 120% and 70%, respectively, in hyperoxia+H2 rats. Hyperoxia exposure increased glutathione content in lung homogenate (36%) more than hyperoxia+H2 (21%), consistent with increases measured in 99mTc-HMPAO lung uptake. In 60-h hyperoxia rats, pleural effusion, which was undetectable in normoxia rats, averaged 9.3 gram/rat, and lung tissue 3-nitrotyrosine expression increased by 790%. Increases were reduced by 69% and 59%, respectively, in 60-h hyperoxia+H2 rats. This study detects and tracks the anti-oxidant and anti-apoptotic properties of H2 therapy in vivo after as early as 24 h of hyperoxia exposure. The results suggest the potential utility of these SPECT biomarkers for in vivo assessment of key cellular pathways in the pathogenesis of ALI and for monitoring responses to therapies

Serialization of Behavior During Car Following in Older Drivers

Age-related declines in cognitive functioning can push older adults to adopt strategies that may or may not improve their driving safety. Previous research suggests one strategy involves performing complex driving tasks (e.g., right turn negotiation) in discrete steps (“serialization”) rather than fluidly. The current study used simulator scenarios developed to test possible age-related serialization of behavior during complex car following. In all scenarios, participants closely monitored a lead vehicle using sustained attention. During multi-tasking scenarios, drivers performed an additional localization task designed to increase the demands on attention. The results demonstrate that older adults showed general impairments in multi-tasking and vehicle control during car following. Importantly, ageassociated changes in task execution were observed, demonstrating older adults also serialize car following behavior under certain conditions. As a result, older drivers withdrew attention from the lead vehicle for several seconds. This pattern of behavior identifies a remediable situation where age-associated impairments may increase crash risk

Pharmacokinetics of \u3csup\u3e99m\u3c/sup\u3eTc-HMPAO in Isolated Perfused Rat Lungs

Lung uptake of technetium-labeled hexamethylpropyleneamine oxime (HMPAO) increases in rat models of human acute lung injury, consistent with increases in lung tissue glutathione (GSH). Since 99mTc-HMPAO uptake is the net result of multiple cellular and vascular processes, the objective was to develop an approach to investigate the pharmacokinetics of 99mTc-HMPAO uptake in isolated perfused rat lungs. Lungs of anesthetized rats were excised and connected to a ventilation-perfusion system. 99mTc-HMPAO (56 MBq) was injected into the pulmonary arterial cannula, a time sequence of images was acquired, and lung time-activity curves were constructed. Imaging was repeated with a range of pump flows and perfusate albumin concentrations and before and after depletion of GSH with diethyl maleate (DEM). A pharmacokinetic model of 99mTc-HMPAO pulmonary disposition was developed and used for quantitative interpretation of the time-activity curves. Experimental results reveal that 99mTc-HMPAO lung uptake, defined as the steady-state value of the 99mTc-HMPAO lung time-activity curve, was inversely related to pump flow. Also, 99mTc-HMPAO lung uptake decreased by ~65% after addition of DEM to the perfusate. Increased perfusate albumin concentration also resulted in decreased 99mTc-HMPAO lung uptake. Model simulations under in vivo flow conditions indicate that lung tissue GSH is the dominant factor in 99mTc-HMPAO retention in lung tissue. The approach allows for evaluation of the dominant factors that determine imaging biomarker uptake, separation of the contributions of pulmonary versus systemic processes, and application of this knowledge to in vivo studies

Single low-dose cyclophosphamide combined with interleukin-12 gene therapy is superior to a metronomic schedule in inducing immunity against colorectal carcinoma in mice

The use of conventional cytotoxic agents at metronomic schedules, alone or in combination with targeted agents or immunotherapy, is being explored as a promising anticancer strategy. We previously reported a potent antitumor effect of a single low-dose cyclophosphamide and interleukin-12 (IL-12) gene therapy against advanced gastrointestinal carcinoma, in mice. Here, we assessed whether the delivery of IL-12 by gene therapy together with metronomic cyclophosphamide exerts antitumor effects in a murine model of colorectal carcinoma. This combination therapy was able, at least in part, to reverse immunosuppression, by decreasing the number of regulatory T cells (Tregs) as well as of splenic myeloid-derived suppressor cells (MDSC s). However, metronomic cyclophosphamide plus IL-12 gene therapy failed to increase the number of tumor-infiltrating T lymphocytes and, more importantly, to induce a specific antitumor immune response. With respect to this, cyclophosphamide at a single low dose displayed a superior anticancer profile than the same drug given at a metronomic schedule. Our results may have important implications in the design of new therapeutic strategies against colorectal carcinoma using cyclophosphamide in combination with immunotherapy.Fil: Malvicini, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Bayo Fina, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: García, Mariana Gabriela. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Fiore, Esteban Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Atorrasagasti, María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Aquino, Jorge Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Matar, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentin

Effectiveness of a Heads-Up Adaptive Lane Deviation Warning System for Middle-Aged and Older Adults

46 participants (24 younger and 22 older) completed at least one out of four simulated drives designed to test the effectiveness of an Adaptive Lane Deviation Warning (LDW) system, and they drove through both a warnings-on and warnings-off version of each drive. Findings showed that LDW was effective in reducing reaction time for lane deviation corrections for both older (by 1.2 seconds) and younger drivers (by 1.6 seconds). The older and younger drivers did not differ in correction RTs when the warnings were turned off. But older drivers showed slower correction RTs than younger drivers in the warning-on drives. The data indicate that these benefits were specific to LDW rather than general improvement in driving performance. Cognitive processing speed emerged as a particularly robust predictor of benefits from the LDW compared to other domains of cognitive function

Pilot Results on Forward Collision Warning System Effectiveness in Older Drivers

Advanced Driver Assistance Systems (ADAS) have largely been developed with a “one-size-fits-all” approach. This approach neglects the large inter-individual variability in perceptual and cognitive abilities that affect aging ADAS users. We investigated the effectiveness of a forward collision warning (FCW) with fixed response parameters in young and older drivers with differing levels of cognitive functioning. Drivers responded to a pedestrian stepping into the driver’s path on a simulated urban road. Behavioral metrics included response times (RT) for pedal controls and two indices of risk penetration (e.g., maximum deceleration and minimum time-to-collision (TTC)). Older drivers showed significantly slower responses at several time points compared to younger drivers. The FCW facilitated response times (RTs) for older and younger drivers. However, older drivers still showed smaller safety gains compared to younger drivers at accelerator pedal release and initial brake application when the FCW was active. No significant differences in risk metrics were observed within the condition studied. The results demonstrate older drivers likely differ from younger drivers using a FCW with a fixed parameter set. Finally, we briefly discuss how future research should examine predictive relationships between domains of cognitive functioning and ADAS responses to develop parameter sets to fit the individual

Renormalization Group and Black Hole Production in Large Extra Dimensions

It has been suggested that the existence of a non-Gaussian fixed point in general relativity might cure the ultraviolet problems of this theory. Such a fixed point is connected to an effective running of the gravitational coupling. We calculate the effect of the running gravitational coupling on the black hole production cross section in models with large extra dimensions.Comment: 4 pages, 3 figures, corrected typos, shorten titl

Exclusion of black hole disaster scenarios at the LHC

The upcoming high energy experiments at the LHC are one of the most outstanding efforts for a better understanding of nature. It is associated with great hopes in the physics community. But there is also some fear in the public, that the conjectured production of mini black holes might lead to a dangerous chain reaction. In this paper we summarize the most straight forward arguments that are necessary to rule out such doomsday scenarios.Comment: 17 pages, 2 figure