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It has been recognized that an integration of neuronal and genetic mechanisms supports brain function, regulates behaviour, and underpins response to environmental or disease stimuli. Several different technologies are available for imaging and studying neuronal activity in living brains, such as functional magnetic resonance imaging (fMRI), and have been translated to humans. However, the tools available to measure gene expression are destructive. Here we present a method, called epigenetic MRI (eMRI), that overcomes this limitation. eMRI achieves for the first time direct and noninvasive imaging of DNA methylation, a major gene expression regulator, in intact brains. eMRI exploits the methionine metabolic pathways that are responsible for DNA methylation to label the methyl-cytosine in brain genomic DNA through carbon-13 enriched diets. It then uses a novel carbon-13 magnetic resonance spectroscopic imaging (13C-MRSI) method to map the spatial distribution of labeled DNA. We demonstrated successful 13C labeling of brain DNA through diet using mass spectrometry, and robust and specific detection of labeled DNA using 13C-MRSI. We used eMRI and a biomedical piglet model to produce the first DNA methylation map of an intact brain hemisphere. With both noninvasive labeling and imaging, we expect eMRI to be readily translated to humans and thus enable many new investigations into the epigenetic basis of brain function, behavior, and disease.

Laboratory experiments are conducted to investigate the mechanism controlling the formation of stable and unstable acoustic fountains at the free surface of a quiescent body of water. Fountains are induced by focused ultrasonic, a new modality that allows for better spatiotemporal control of water flow. Particle image velocimetry was used to characterize the induced flow field in the vicinity of the ultrasonic focal spot. We used two types of ultrasonic transducers with distinct wave frequencies. We examined three fountain formation regimes by varying the pressure level of the transducers, namely weak, intermediate (stable) and highly forced fountains (explosive). Between different regimes, the fountain height underwent a step-change in response to the increase in acoustic pressure. A force estimation obtained from the flow field shows that the magnitude of axial momentum flux is orders of magnitude lower than that of gravity and surface tension, indicating that the dominant driving force for the fountain generation is the acoustic radiation force (Nightingale et al., Ultrasound Med. Biol., vol. 28, 2002, pp. 227–235). We propose a simple model to estimate the shape of a stable fountain; it accounts for the applied acoustic pressure, gravity, surface tension and axial momentum. The model neglects viscous force, which precludes capturing the intermediate fountain surface curvature. However, the model successfully predicts the geometry of the weak and intermediate fountains.

Breast cancer has become the most diagnosed cancer in the world. Microwave detection the breast tumor is attractive due to its high dielectric property contrast between different tissues of tumor. In this paper, we proposed an In-phase-Quadrature (IQ) demodulation-based method to detect the breast tumor with microwave at a frequency of 1.3 GHz. The microwave detection system consists of two signal generators, 12 transmitting/receiving antennas, two talent switches, a phantom and an IQ-Mixer. The amplitude information at the receiving antennas can be obtained by analyzing the difference frequency signals generated with two microwave signal generators. We also use the finite-difference time-domain (FDTD) method for simulation verification, which can simulate the propagation of the electromagnetic wave. Through experiments and simulations of microwave hardware system and FDTD method, it can be proved that the results are consistent. The experimental and simulation results show that when the tumor phantom diameter decreases or its depth from the receiving antenna increases, whether there is a tumor phantom can be clearly distinguished. Moreover, we also explore the effects of different tumor phantom locations on the receiving antennas. The results show that it is feasible to detect the breast tumor with the IQ demodulation method based on microwave.

Heat shock protein expression can be induced by heat shock making it possible to artificially modulate their levels noninvasively in vivo in a spatially and temporally controlled manner. Here, we report the use of the major heat shock protein 70 (HSP70) as an inducible target by using the small molecule deoxyspergualin (DSG) conjugated to the near-infrared fluorophore (Cy5.5). We demonstrate that heat induction in the form of localized hyperthermia of normal tissue in living mice results in sufficient HSP70 overexpression for detection with DSG-Cy5.5 conjugate. This effect is dependent on total energy delivered and reaches maximum fluorescence signal in 6 to 8 hours post heat induction and declines over a period of up to 24 hours. These results suggest that DSG-Cy5.5 agent accumulates in tissue with elevated HSP70 by heat.

Background 1. Studies have found that gut microbiota is a new participant and potential therapeutic target for CVD and even MI. 2. No clinical study to date, however, has investigated whether the changes of gut microbiota associated with coronary lesion degree and prognosis in patients with acute coronary syndrome (ACS). Aim We prospectively investigated associations, of gut microbiota in their feces and coronary lesion degree, and long-term prognosis of patients with ACS. Methods 1. In prospective cohort study, a total 502 subjects including 402 ACS patients and 100 controls. Fecal specimens were used to extract bacterial genomic DNA 2. 16S rDNA sequence of bacteria were generated to analyse specific gut microbial taxa associated with ACS onset for 60 ACS patients and 30 healthy controls. 3. Specific primers were designed according to the 16S rDNA sequence of bacteria for real time PCR reaction to determine the number of different bacteria. 4. All ACS patients calculated SYNTAX score by coronary radiography results and followed up for one year. The correlation of gut microbiota with coronary angiographic severity and prognosis in the ACS patients was analyzed. Results 1. Compared with the control group,the number of bacteria in Escherichia coli, Streptococcus and Enterobacteriaceae increased significantly (P 2. Lactobacillus were independent predictors of coronary angiographic severity in patients with ACS (HR=0.953; 95% CI: 0.935–0.970, P 3. Decreased Lactobacillus levels were independent protection factors with all-cause death (HR=0.954; 95% CI: 0.913–0.997, P=0.038) and risk of major adverse cardiac events (HR=0.952; 95% CI: 0.929–0.976, P Conclusion 1. Number of Lactobacillus are significantly decreased in patients with ACS,and associated with SYNTAX score,suggesting that Lactobacillus is associated with severity of coronary artery disease, all-cause death and MACE. 2. It provides new ideas for the prevention and treatment of ACS. Real time PCR Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Major Science and Technology Projects of Tianjin Science and Technology Commission in 2016

This study proposes a new cancer drug delivery modality that allows for spatiotemporal control over activation of the therapeutic. Current standard cancer therapies of surgery, chemotherapy, and radiation therapy have their limitations, such as invasiveness and systemic toxicities. Developing a new modality that is localized and triggerable is becoming increasingly advantageous. Currently, photodynamic therapy (PDT) has been shown to be clinically effective but is limited by poor tissue penetration of light. Sonodynamic therapy (SDT) bypasses this pitfall with increased tissue penetration depth of ultrasound. However, PDT has limitations as it relies on the potentially damaging ultrasound cavitation effect and requires sonosensitizers or nanoparticles that have issues with bioavailability, biostability, and biosafety. In this study, we propose a novel ultrasound-based cancer treatment modality called mechanochemical dynamic therapy (MDT). In MDT, high intensity focused ultrasound (HIFU) delivers mechanical forces to force-responsive moieties of azo mechanophores that are embedded into biocompatible polyethylene glycol (PEG) hydrogel polymers. Upon focal sonication with HIFU, these mechanophores generate highly reactive free radicals (FRs) that are converted to reactive oxygen species (ROSs). The sonicated gels are then placed into in vitro cultures, allowing for the diffusion of ROSs into the cells to induce oxidative cytotoxicity and eventually cell death. Cell proliferation is monitored at 24-hour intervals, and by 72 hours, the sonicated gels produced cell killing effects comparable to lethal doses of H2O2 in both in vitro mouse melanoma (B16F10) and breast cancer (E0771) models. Sonication of control hydrogels that did not contain mechanophores showed minimal cytotoxicity. This study shows the potential of MDT as a drug delivery platform that overcomes the limitations of PDT and SDT and has the potential to be applied synergistically with other current cancer treatments. This is the first demonstration of using HIFU-activated mechanophores to non-invasively deliver cancer therapies with spatiotemporal control. Citation Format: Gun Kim, Qiong Wu, James L. Chu, Emily J. Smith, Michael L. Oelze, King C. Li, Jeffrey S. Moore. Mechanochemical dynamic therapy for focal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1318.

High Intensity Focused Ultrasound (HIFU) is an emerging noninvasive, nonionizing physical energy based modality to ablate solid tumors with high power, or increase local permeability in tissues/tumors in pulsed mode with relatively low power. Compared with traditional ablative HIFU, nondestructive pulsed HIFU (pHIFU) is present in the majority of novel applications recently developed for enhancing the delivery of drugs and genes. Previous studies have demonstrated the capability of pHIFU to change tissue local permeability for enhanced drug delivery in both mouse tumors and mouse muscle. Further study based on bulk tissues in large animals and clinical HIFU system revealed correlation between therapeutic effect and thermal parameters, which was absent in the previous mouse studies. In this study, we further investigated the relation between the therapeutic effect of pHIFU and thermal parameters in bulky normal muscle tissues based on a rabbit model and a preclinical HIFU system. Correlation between therapeutic effect and thermal parameters was confirmed in our study on the same bulk tissues although different HIFU systems were used. Following the study in bulky normal muscle tissues, we further created bulky tumor model with VX2 tumors implanted on both hind limbs of rabbits and investigated the feasibility to enhance tumor permeability in bulky VX2 tumors in a rabbit model using pHIFU technique. A radiolabeled peptidomimetic integrin antagonist, 111In-DOTA-IA, was used following pHIFU treatment in our study to target VX2 tumor and serve as the radiotracer for follow-up single-photon emission computed tomography (SPECT) scanning. The results have shown significantly elevated uptake of 111In-DOTA-IA in the area of VX2 tumors pretreated by pHIFU compared with the control VX2 tumors not being pretreated by pHIFU, and statistical analysis revealed averaged 34.5% enhancement 24 h after systematic delivery of 111In-DOTA-IA in VX2 tumors pretreated by pHIFU compared with the control VX2 tumors.

While study in the field of polymer mechanochemistry has yielded mechanophores that perform various chemical reactions in response to mechanical stimuli, there is not yet a triggering method compatible with biological systems. Applications such as using mechanoluminescence to generate localized photon flux in vivo for optogenetics would greatly benefit from such an approach. Here we introduce a method of triggering mechanophores by using high-intensity focused ultrasound (HIFU) as a remote energy source to drive the spatially and temporally resolved mechanical-to-chemical transduction of mechanoresponsive polymers. A HIFU setup capable of controlling the excitation pressure, spatial location, and duration of exposure is employed to activate mechanochemical reactions in a cross-linked elastomeric polymer in a noninvasive fashion. One reaction is the chromogenic isomerization of a naphthopyran mechanophore embedded in a polydimethylsiloxane (PDMS) network. Under HIFU irradiation evidence of the mechanochemical transduction is the observation of a reversible color change as expected for the isomerization. The elastomer exhibits this distinguishable color change at the focal spot, depending on ultrasonic exposure conditions. A second reaction is the demonstration that HIFU irradiation successfully triggers a luminescent dioxetane, resulting in localized generation of visible blue light at the focal spot. In contrast to conventional stimuli such as UV light, heat, and uniaxial compression/tension testing, HIFU irradiation provides spatiotemporal control of the mechanochemical activation through targeted but noninvasive ultrasonic energy deposition. Targeted, remote light generation is potentially useful in biomedical applications such as optogenetics where a light source is used to trigger a cellular response.

Spring-assisted surgery (SAS) can effectively treat scaphocephaly by reshaping crania with the appropriate spring force. However, it is difficult to accurately estimate spring force without considering biomechanical properties of tissues. This study presents and validates a reliable system to accurately predict the spring force for sagittal craniosynostosis surgery. The authors randomly chose 23 patients who underwent SAS and had been followed for at least 2 years. An elastic model was designed to characterize the biomechanical behavior of calvarial bone tissue for each individual. After simulating the contact force on accurate position of the skull strip with the springs, the finite element method was applied to calculating the stress of each tissue node based on the elastic model. A support vector regression approach was then used to model the relationships between biomechanical properties generated from spring force, bone thickness, and the change of cephalic index after surgery. Therefore, for a new patient, the optimal spring force can be predicted based on the learned model with virtual spring simulation and dynamic programming approach prior to SAS. Leave-one-out cross-validation was implemented to assess the accuracy of our prediction. As a result, the mean prediction accuracy of this model was 93.35%, demonstrating the great potential of this model as a useful adjunct for preoperative planning tool.

The influence of orientation and temperature on fatigue short crack propagation behavior of Inconel 718 alloy was studied at both 25 °C and 650 °C by in-situ fatigue testing under scanning electron microscope. The fatigue crack growth rates (FCGR) showed evident dependence on orientation at both temperatures, following: XZ

The blood-brain barrier (BBB), comprised of brain endothelial cells with tight junctions (TJ) between them, regulates the extravasation of molecules and cells into and out of the central nervous system (CNS). Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of a broad range of brain disorders. Current strategies for BBB opening are invasive, not specific, and lack precise control over the site and timing of BBB opening, which may limit their clinical translation. In the present report, we describe a novel approach based on a combination of stem cell delivery, heat-inducible gene expression and mild heating with high-intensity focused ultrasound (HIFU) under MRI guidance to remotely permeabilize BBB. The permeabilization of the BBB will be controlled with, and limited to where selected pro-inflammatory factors will be secreted secondary to HIFU activation, which is in the vicinity of the engineered stem cells and consequently both the primary and secondary disease foci. This therapeutic platform thus represents a non-invasive way for BBB opening with unprecedented spatiotemporal precision, and if properly and specifically modified, can be clinically translated to facilitate delivery of different diagnostic and therapeutic agents which can have great impact in treatment of various disease processes in the central nervous system.

Purpose: Spring-assisted surgery is an effective and minimally invasive treatment for sagittal craniosynostosis (CSO). The principal barrier to the advancement of spring-assisted surgery is the patient-specific spring selection. The selection of spring force depends on the suture involved, subtypes of sagittal CSO, and age of the infant, among other factors. Clinically, physicians manually judge the subtype of sagittal CSO patients based on their CT image data, which may cause bias from different clinicians. An objective system would be helpful to stratify the sagittal CSO patients and make spring choice less subjective. Methods: The authors developed a novel informatics system to automatically segment and characterize sutures and classify sagittal CSO. The proposed system is composed of three phases: preprocessing, sutures segmentation, and classification. First, the three-dimensional (3D) skull was extracted from the CT images and aligned with the symmetry of the cranial vault. Second, a “hemispherical projection” algorithm was developed to transform 3D surface of the skull to a polar two-dimensional plane. Through the transformation, an “effective” projected region can be obtained to enable easy segmentation of sutures. Then, the different types of sutures, such as coronal sutures, lambdoid sutures, sagittal suture, and metopic suture, obtained from the segmented sutures were further identified by a dual-projection technique of the midline of the sutures. Finally, 108 quantified features of sutures were extracted and selected by a proposed multiclass feature scoring system. The sagittal CSO patients were classified into four subtypes: anterior, central, posterior, and complex with the support vector machine approach. Fivefold cross validation (CV) was employed to evaluate the capability of selected features in discriminating the four subtypes in 33 sagittal CSO patients. Receiver operating characteristics (ROC) curves were used to assess the robustness of the developed system. Results: The segmentation results of the proposed method were clinically acceptable for the qualitative evaluation. For the quantitative evaluation, the fivefold CV accuracy of the classification for the four subtypes was 72.7%. This classification system was reliable with the area under curve (in ROC analysis) being greater than 0.8 for four two-class problems. Conclusions: The proposed hemispherical projection algorithm based on backtracking search can successfully segment sutures of the cranial vault. The classification system can also offer a desirable performance. As a result, the proposed segmentation and classification system is expected to bring insights into clinic research and the selection of the spring force to facilitate widespread application of this minimally invasive treatment.

Disease in the central nervous system (CNS) is a challenge to treat with systemic therapies due to the presence of the blood–brain barrier (BBB), which excludes common and novel therapeutics. For example, glioblastoma (GBM) is the most common and aggressive primary brain tumor, with an extremely poor prognosis due to infiltrating tumor cells in areas of normal brain. A primary challenge of treating this devastating disease is the exclusion of systemic therapies from the CNS. While efforts are being made to develop strategies for designing drugs that can pass through the BBB, there are also efforts to use novel engineering techniques to safely allow any systemic therapy into the CNS and areas of disease. In this chapter, we focus on using high intensity focused ultrasound (HIFU) to circumvent the BBB.

Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood-brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors.

Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 (LOX-1) plays a key role in atherosclerotic plaque initiation, formation and rupture, as well as in hyperlipidemia-induced glomerular disease. Here we report a sensitive, specific and biocompatible LOX-1-targeted-USPIO for the noninvasive MR imaging of LOX-1 within carotid atherosclerotic lesions and glomerular disease in apoE-deficient mice. In vitro analysis showed the highest uptake of targeted USPIOs in only activated RAW264.7 macrophages, and in vivo MRI studies showed signal loss in carotid atherosclerotic lesions after administration of targeted USPIOs at 8 h and 24 h. These areas of signal loss were correlated with the presence of nanoparticles in the atherosclerotic lesions, and immunohistochemistry and Perl’s staining confirmed the co-localization of the LOX-1/macrophages/MMP-9 and targeted nanoparticles. Finally, additional studies suggest that this targeted probe may have potential to noninvasively image early glomerular disease. This finding may provide important methods for characterizing vulnerable atherosclerotic plaques and hyperlipidemia-induced glomerular diseases. From the Clinical Editor A functionalized USPIO-based negative contrast material was used in this study, demonstrating feasibility of sensitive MRI-based detection of atherosclerotic plaque formation in the carotid arteries and in the renal cortex, paving the way to potential future clinical applications.

In the era of medical cost containment, radiologists must continually maintain their actual and perceived value to patients, payers, and referring providers. Exploitation of current and future digital technologies may be the key to defining and promoting radiology's "brand" and assure our continued relevance in providing predictive, preventive, personalized, and participatory medicine. The Association of University of Radiologists Radiology Research Alliance Digitization of Medicine Task Force was formed to explore the opportunities and challenges of the digitization of medicine that are relevant to radiologists, which include the reporting paradigm, computational biology, and imaging informatics. In addition to discussing these opportunities and challenges, we consider how change occurs in medicine, and how change may be effected in medical imaging community. This review article is a summary of the research of the task force and hopefully can be used as a stimulus for further discussions and development of action plans by radiology leaders.

The aim of this study was to explore the feasibility of detecting plaques using an NIR797 fluorochrome-labeled, anti-oxLDL antibody (anti-oxLDL-NIR797) and near-infrared fluorescence (NIRF) imaging in a murine model of atherosclerosis. Anti-mouse oxLDL polyclonal antibodies were conjugated to NIR797 dyes to synthesis oxLDL-targeted NIRF probe. In situ and ex vivo NIRF imaging of the high-cholesterol diet-induced atherosclerotic lesions of apoE-/- mice (baseline) as well as ex vivo NIRF imaging in the progression and regression group (without or with atorvastatin treatment for another 8 weeks) were performed 24 h after an intravenous injection of 1 mg/kg of anti-oxLDL-NIR797, while phosphate-buffered saline (PBS) was used for the controls. The plaque areas were investigated using Oil Red O (ORO) staining. Aortas isolated from the apoE-/- mice 24 h post-injection exhibited a selective, strong, heterogeneous NIRF signal enhancement in the aortic root, arch, and bifurcation, whereas the PBS and competitive inhibition groups had limited NIRF signal changes (p < 0.05). There was a significant correlation between ORO staining and NIRF in the atherosclerotic aortas that received anti-oxLDL-NIR797. Immunofluorescence studies confirmed the colocalization of the oxLDL/macrophages and NIR797 fluorochromes. Furthermore, the atherosclerotic lesions of atorvastatin-treated mice showed reduced anti-oxLDL-NIR797 uptake and oxLDL expression. These results indicate that NIRF plaque imaging is feasible with an oxLDL-targeted NIRF probe. Thus, oxLDL-based molecular imaging of atherosclerotic plaques is feasible and may provide important methods for characterizing vulnerable plaques and monitoring the response to therapeutic interventions for atherosclerosis.

A series of polycrystalline Sr1−1.5xHoxBi2Nb2O9 (SHoBNx) (x = 0.0, 0.01, 0.03, 0.05, 0.1, 0.15, 0.2 and 0.3) samples were synthesized through solid-state reaction method, and their micro-structural, ferroelectric, dielectric and photoluminescence properties were carefully investigated. Significant enhancement of polarization and dielectric permittivity has been confirmed in SHoBNx system through ferroelectric and dielectric measurement. More importantly, the photoluminescence properties of SHoBNx system have also been explored for the first time. Sharp green emission band was observed and photoluminescence mechanism was simply discussed. It is believed that SHoBNx ferroelectric ceramics can also act as a potential blue exciting green light emission phosphor.

Purpose To design an algorithm for optimizing pulsed high intensity focused ultrasound (p-HIFU) treatment parameters to maximize tissue transport while minimizing thermal necrosis based on MR image guidance.

Objective: Although the use of temozolomide in chemoradiotherapy is effective, the challenging clinical problem of pseudo progression has been raised in brain tumor treatment. This study aims to distinguish pseudo progression from true progression.Materials and Methods: Between 2000 and 2012, a total of 161 patients with glioblastoma multiforme (GBM) were treated with chemoradiotherapy at our hospital. Among the patients, 79 had their diffusion tensor imaging (DTI) data acquired at the earliest diagnosed date of pseudo progression or true progression, and 23 had both DTI data and genomic data. Clinical records of all patients were kept in good condition. Volumetric fractional anisotropy (FA) images obtained from the DTI data were decomposed into a sequence of sparse representations. Then, a feature selection algorithm was applied to extract the critical features from the feature matrix to reduce the size of the feature matrix and to improve the classification accuracy.Results: The proposed approach was validated using the 79 samples with clinical DTI data. Satisfactory results were obtained under different experimental conditions. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.87 for a given dictionary with 1024 atoms. For the subgroup of 23 samples, genomics data analysis was also performed. Results implied further perspective on pseudo progression classification.Conclusions: The proposed method can determine pseudo progression and true progression with improved accuracy. Laboring segmentation is no longer necessary because this skillfully designed method is not sensitive to tumor location. HighlightsDiscriminating between the pseudo progression and the true progression of Glioblastoma with AUC of 0.87.Dictionary learning developed to process the DTI/FA volumetric images.A feature selection approach for the large number of sparse representation calculated by dictionary learning.ROI segmentation is not needed.Location restriction regarding the tumor position has been solved.

Prostate immune system plays a critical role in the regulation of prostate cancer development regarding androgen-deprivation therapy (ADT) and/or immunotherapy (vaccination). In this study, we developed a mathematical model to explore the interactions between prostate tumor and immune microenvironment. This model was used to predict treatment outcomes for prostate cancer with ADT, vaccination, Treg depletion and/or IL-2 neutralization. Animal data were used to guide construction, parameter selection, and validation of our model. Our analysis shows that Treg depletion and/or IL-2 neutralization can effectively improve the treatment efficacy of combined therapy with ADT and vaccination. Treg depletion has a higher synergetic effect than that from IL-2 neutralization. This study highlights a potential therapeutic strategy in effectively managing prostate tumor growth and provides a framework of systems biology approach in studying tumor-related immune mechanism and consequent selection of therapeutic regimens.

Summary Objective Unicompartmental knee arthroplasty (UKA) revision is usually due to the degenerative degree of knee articular osteochondral tissue in the untreated compartment. However, it is difficult to simulate the biomechanical behavior on this tissue accurately. This study presents and validates a reliable system to predict which osteoarthritis (OA) patients may suffer revision as a result of biomechanical reasons after having UKA. Design We collected all revision cases available ( n = 11) and randomly selected 67 UKA cases to keep the revision prevalence of almost 14%. All these 78 cases have been followed at least 2 years. An elastic model is designed to characterize the biomechanical behavior of the articular osteochondral tissue for each patient. After calculated the force on the tissue, finite element method (FEM) is applied to calculating the strain of each tissue node. Kernel Ridge Regression (KRR) method is used to model the relationship between the strain information and the risk of revision. Therefore, the risk of UKA revision can be predicted by this integrated model. Results Leave-one-out (LOO) cross-validation (CV) is implemented to assess the prediction accuracy. As a result, the mean prediction accuracy is 93.58% for all these cases, demonstrating the high value of this model as a decision-making assistant for surgical plaining of knee OA. Conclusions The results of this study demonstrated that this integrated model can predict the risk of UKA revision with theoretically high accuracy. It combines bio-mechanical and statistical learning approach to create a surgical planning tool which may support clinical decision in the future.

Adoptive transfer of primary T cells genetically modified to have desired specificity can exert an anti-tumor response in some patients. To improve our understanding of their therapeutic potential we have developed a clinically-appealing approach to reveal their in vivo biodistribution using nanoparticles that serve as a radiotracer for imaging by positron emission tomography (PET). T cells electroporated with DNA plasmids from the Sleeping Beauty transposon/transposase system to co-express chimeric antigen receptor (CAR) specific for CD19 and Firefly luciferase (ffLuc) were propagated on CD19+ K562-derived artificial antigen presenting cells. The approach to generating our clinical-grade CAR+ T cells was adapted to electro-transfer of gold nanoparticles (GNP) functionalized with 64Cu2+ using the macrocyclic chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA) and polyethyleneglycol (GNP-64Cu/PEG2000). MicroPET/CT was used to visualize CAR+EGFPffLucHyTK+GNP-64Cu/PEG2000+ T cells and correlated with bioluminescence imaging and assessment of radioactivity. These data demonstrate that GNPs conjugated with 64Cu2+ can be prepared as radiotracer for PET and used to image T cells using an approach that has translational implications.

Gadolinium chelates, which are currently approved for clinical MRI use, provide relaxivities well below their theoretical limit, and they also lack tissue specificity. Recently, the geometrical confinement of Gd3+-based contrast agents (CAs) within porous structures has been proposed as a novel, alternative strategy to improve relaxivity without chemical modification of the CA. Here, we have characterized and optimized the performance of MRI nanoconstructs obtained by loading [Gd(DTPA)(H2O)]2− (Magnevist®) into the pores of injectable mesoporous silicon particles. Nanoconstructs with three different pore sizes were studied, and at 60 MHz, they exhibited longitudinal relaxivities of ~24 m m−1 s−1 for 5–10 nm pores and ~10 m m−1 s−1 for 30 – 40 nm pores. No enhancement in relaxivity was observed for larger pores sizes. Using an outer-sphere compound, [GdTTHA]3−, and mathematical modeling, it was demonstrated that the relaxivity enhancement is due to the increase in rotational correlation times (CA adsorbed on the pore walls) and diffusion correlation times (reduced mobility of the water molecules), as the pore sizes decreases. It was also observed that extensive CA adsorption on the outer surface of the silicon particles negates the advantages offered by nanoscale confinement. Upon incubation with HeLa cells, the nanoconstructs did not demonstrate significant cytotoxicity for up to 3 days post incubation, at different particle/cell ratios. In addition, the nanoconstructs showed complete degradation after 24 h of continuous agitation in phosphate-buffered saline. These data support and confirm the hypothesis that the geometrical confinement of Gd3+-chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H2O)]2−, and 4 times for [GdTTHA]3−) and, potentially, improved stability, reduced toxicity and tissue specificity. Copyright © 2012 John Wiley & Sons, Ltd.

Purpose—To evaluate whether MR thermometry is sufficiently fast, accurate, and spatially resolved for monitoring the thermal safety of non-ablative pulsed HIFU (pHIFU) treatments. Materials and Methods—A combination of real MR thermometry data and modeling was used to analyze the effects of temporal and spatial averaging as well as noise on the peak temperatures and thermal doses that would be measured by MR thermometry. Results—MR thermometry systematically underestimates the temperature and thermal doses during pHIFU treatment. Small underestimates of peak temperature can lead to large underestimates of thermal dose. Spatial averaging errors are small for ratios of pixel dimension to heating zone radius less than 0.25, which may be achieved by reducing the voxel size or steering the acoustic beam. Thermal dose might also be underestimated for very short, high power pulses due to temporal averaging. A simple correction factor based on the applied power and duty cycle may be applied to determine the upper bound of this effect. Conclusion—The temperature and thermal dose measured using MR thermometry during pulsed HIFU treatment is probably sufficinet in most instances. Simple corrections may be used to calculate an upper bound where this is a critical factor.

OBJECTIVE. A theranostic system integrates some form of diagnostic testing to determine the presence of a molecular target for which a specific drug is intended. Molecular imaging serves this diagnostic function and provides powerful means for noninvasively detecting disease. We briefly review the paradigms rooted in nuclear medicine and highlight recent advances in this field. We also explore how nanometer-sized complexes, called nanomedicines, present an excellent theranostic platform applicable to both drug discovery and clinical use. CONCLUSION. For imagers, molecular theranostics represents a powerful emerging platform that intimately couples targeted therapeatic entities with noninvasive imaging that yields information on the presence of defined molecular targets before, during, and after cognate therapy.

Computer modeling approaches to identify new inhibitors are essentially a very sophisticated and efficient way to design drugs. In this study, a bivalent nonpeptide intergrin alpha(v)beta(3) antagonist (bivalent IA) has been synthesized on the basis of an in silico rational design approach. A near-infrared (NIR) fluorescent imaging probe has been developed from this bivalent compound. In vitro binding assays have shown that the bivalent IA (IC(50) = 0.40 +/- 0.11 nM) exhibited improved integrin alpha(v)beta(3) affinity in comparison with the monovalent IA (IC(50) = 22.33 +/- 4.51 nM), resulting in an over 50-fold improvement in receptor affinity. NIR imaging probe, bivalent-IA-Cy5.5 conjugate, also demonstrated significantly increased binding affinity (IC(50) = 0.13 +/- 0.02 nM). Fluorescence microscopy studies showed integrin-mediated endocytosis of bivalent-IA-Cy5.5 in U87 cells which was effectively blocked by nonfluorescent bivalent IA. We also demonstrated tumor accumulation of this NIR imaging probe in U87 mouse xenografts.

OBJECTIVES: The aim of this research was to synthesize radiolabeled peptidomimetic integrin alpha(v)beta(3) antagonist with (99m)Tc for rapid targeting of integrin alpha(v)beta(3) receptors in tumor to produce a high tumor to background ratio. METHODS: The amino terminus of 4-[2-(3,4,5,6-tetra-hydropyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonyl-amino-beta-alanine hydrochloride (IAC) was conjugated with N-hydroxysuccinimide ester of HYNIC and labeled with (99m)Tc using tricine with either 1,5-pyridinedicarboxylic acid (PDA) or ethylenediamine-N,N'-diacetic acid (EDDA) as the co-ligand. The products, (99m)Tc EDDA(2)/HYNIC-IAC (P1) and (99m)Tc PDA (tricin)/HYNIC-IAC (P2) were subjected to in vitro serum stability, receptor-binding, biodistribution and imaging studies. RESULTS: P1 and P2 were synthesized with an overall yield of >80%. P1 was slightly more stable than P2 when incubated in serum at 37 degrees C for 18 hrs (84 vs 77% intact). The In vitro receptor-binding of P1 was higher than that of P2 (78.02 +/- 13.48 vs 51.05 +/- 14.05%) when incubated with alpha(v)beta(3) at a molar excess (0.8 muM). This receptor binding was completely blocked by a molar excess of an unlabeled peptidomimetic antagonist. Their differences shown in serum stability and the receptor-binding appeared to be related to their biological behaviors in tumor uptake and retention; the 1 h tumor uptakes of P1 and P2 were 3.17+/-0.52 and 2.13+/-0.17 % ID/g, respectively. P1 was retained in the tumor longer than P2. P1 was excreted primarily through the renal system whereas P2 complex was excreted equally via both renal and hepatobiliary systems. Thus, P1 was retained in the whole-body with 27.25 +/- 3.67% ID at 4 h whereas 54.04 +/- 3.57% ID of P2 remained in the whole-body at 4 h. This higher whole-body retention of P2 appeared to be resulted from a higher amount of radioactivity retained in liver and intestine. These findings were supported by imaging studies showing higher tumor-to-abdominal contrast for P1 than for P2 at 3 h postinjection. CONCLUSIONS: P1 showed good tumor targeting properties with a rapid tumor uptake, prolonged tumor retention and fast whole-body clearance kinetics. These findings warrant further investigation of the HYNIC method of (99m)Tc labeling of other peptidomimetic antagonists using EDDA as a coligand.

We have modeled, by finite element analysis, the process of heating of a spherical gold nanoparticle by nanosecond laser pulses and of heat transfer between the particle and the surrounding medium, with no mass transfer. In our analysis, we have included thermal conductivity changes, vapor formation, and changes of the dielectric properties as a function of temperature. We have shown that such changes significantly affect the temperature reached by the particle and surrounding microenvironment and therefore the thermal and dielectric properties of the medium need to be known for a correct determination of the temperature elevation. We have shown that for sufficiently low intensity and long pulses, it is possible to establish a quasi-steady temperature profile in the medium with no vapor formation. As the intensity is increased, a phase-change with vapor formation takes place around the gold nanoparticle. As phase-transition starts, an additional increase in the intensity does not significantly increase the temperature of the gold nanoparticle and surrounding environment. The temperature starts to rise again above a given intensity threshold which is particle and environment dependent. The aim of this study is to provide useful insights for the development of molecular targeting of gold nanoparticles for applications such as remote drug release of therapeutics and photothermal cancer therapy.

The term "Molecular Imaging" has hit the consciousness of radiologists only in the past decade although many of the concepts that molecular imaging encompasses has been practiced in biomedical imaging, especially in nuclear medicine, for many decades. Many new imaging techniques have allowed us to interrogate biologic events at the cellular and molecular level in vivo in four dimensions but the challenge now is to translate these techniques into clinical practice in a way that will enable us to revolutionize healthcare delivery. The purpose of this article is to introduce the term "Systems Diagnostics" and examine how radiologists can become translators of disparate sources of information into medical decisions and therapeutic actions.

Conventional biomarker discovery focuses mostly on the identification of single markers and thus often has limited success in disease diagnosis and prognosis. This study proposes a method to identify an optimized protein biomarker panel based on MS studies for predicting the risk of major adverse cardiac events (MACE) in patients. Since the simplicity and concision requirement for the development of immunoassays can only tolerate the complexity of the prediction model with a very few selected discriminative biomarkers, established optimization methods, such as conventional genetic algorithm (GA), thus fails in the high-dimensional space. In this paper, we present a novel variant of GA that embeds the recursive local floating enhancement technique to discover a panel of protein biomarkers with far better prognostic value for prediction of MACE than existing methods, including the one approved recently by FDA (Food and Drug Administration). The new pragmatic method applies the constraints of MACE relevance and biomarker redundancy to shrink the local searching space in order to avoid heavy computation penalty resulted from the local floating optimization. The proposed method is compared with standard GA and other variable selection approaches based on the MACE prediction experiments. Two powerful classification techniques, partial least squares logistic regression (PLS-LR) and support vector machine classifier (SVMC), are deployed as the MACE predictors owing to their ability in dealing with small scale and binary response data. New preprocessing algorithms, such as low-level signal processing, duplicated spectra elimination, and outliner patient's samples removal, are also included in the proposed method. The experimental results show that an optimized panel of seven selected biomarkers can provide more than 77.1% MACE prediction accuracy using SVMC. The experimental results empirically demonstrate that the new GA algorithm with local floating enhancement (GA-LFE) can achieve the better MACE prediction performance comparing with the existing techniques. The method has been applied to SELDI/MALDI MS datasets to discover an optimized panel of protein biomarkers to distinguish disease from control.

To investigate whether combining pulsed high-intensity focused ultrasound (HIFU) with the chemotherapeutic drug bortezomib could improve antitumor activity against murine squamous cell carcinoma (SCC) tumors.All experiments were conducted with animal care and use committee approval. Murine SCC cells were implanted subcutaneously in C3H mice. When tumors reached 100 mm(3), mice were randomized to one of three groups for twice weekly intraperitoneal injections of 1.5 mg of bortezomib per kilogram of body weight, a proteasome inhibitor (n = 10); 1.0 mg/kg bortezomib (n = 11); or a control vehicle (n = 12). Within each group, half of the mice received pulsed HIFU exposure to their tumors immediately prior to each injection. The time for tumors to reach 650 mm(3) was compared among groups. Additional tumors were stained with terminal deoxynucledotidyl transferase-mediated dUTP nick end labeling and CD31 to assess apoptotic index and blood vessel density, respectively.Tumors in the control group, pulsed HIFU and control group, and 1.0 mg/kg of bortezomib alone group reached the size end point in 5.2 days +/- 0.8 (standard deviation), 5.3 days +/- 0.8, and 5.6 days +/- 1.1, respectively. However, pulsed HIFU and 1.0 mg/kg bortezomib increased the time to end point to 9.8 days +/- 2.9 (P.02), not significantly different from the 8.8 days +/- 2.1 in tumors treated with 1.5 mg/kg bortezomib alone (P.05). Combination therapy was also associated with a significantly higher apoptotic index (P.05).Treatment of tumors with pulsed HIFU lowered the threshold level for efficacy of bortezomib, resulting in significant tumor cytotoxicity and growth inhibition at lower dose levels.

The mass spectrometry (MS) technology in clinical proteomics is very promising for discovery of new biomarkers for diseases management. To overcome the obstacles of data noises in MS analysis, we proposed a new approach of knowledge-integrated biomarker discovery using data from Major Adverse Cardiac Events (MACE) patients. We first built up a cardiovascular-related network based on protein information coming from protein annotations in Uniprot, protein–protein interaction (PPI), and signal transduction database. Distinct from the previous machine learning methods in MS data processing, we then used statistical methods to discover biomarkers in cardiovascular-related network. Through the tradeoff between known protein information and data noises in mass spectrometry data, we finally could firmly identify those high-confident biomarkers. Most importantly, aided by protein–protein interaction network, that is, cardiovascular-related network, we proposed a new type of biomarkers, that is, network biomarkers, composed of a set of proteins and the interactions among them. The candidate network biomarkers can classify the two groups of patients more accurately than current single ones without consideration of biological molecular interaction.

Mass spectrometry (MS) has shown great potential in detecting disease-related biomarkers for early diagnosis of stroke. To discover potential biomarkers from large volume of noisy MS data, peak detection must be performed first. This article proposes a novel automatic peak detection method for the stroke MS data. In this method, a mixture model is proposed to model the spectrum. Bayesian approach is used to estimate parameters of the mixture model, and Markov chain Monte Carlo method is employed to perform Bayesian inference. By introducing a reversible jump method, we can automatically estimate the number of peaks in the model. Instead of separating peak detection into substeps, the proposed peak detection method can do baseline correction, denoising and peak identification simultaneously. Therefore, it minimizes the risk of introducing irrecoverable bias and errors from each substep. In addition, this peak detection method does not require a manually selected denoising threshold. Experimental results on both simulated dataset and stroke MS dataset show that the proposed peak detection method not only has the ability to detect small signal-to-noise ratio peaks, but also greatly reduces false detection rate while maintaining the same sensitivity. Contact: XZhou@tmhs.org

Purpose: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between non–thermosensitive liposomes (NTSL) and low temperature–sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42°C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.

Objectives The aim of this research was to synthesize radiolabeled peptidomimetic integrin α v β 3 antagonists that selectively target integrin α v β 3 receptor and clear rapidly from the whole body. Methods Integrin α v β 3 antagonists, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-( S )-aminoethylsulfonyl-amino-β-alanine (IA) and 4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethyloxy]benzoyl-2-( S )-[ N -(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-β-alanine hydrochloride (IAC), a hydrophobic carbamate derivative of IA, were conjugated with 2- p -isothiocyanatobenzyl-DOTA at the amino terminus and labeled with 111 In. The 111 In labeled IA and IAC were subjected to in vitro receptor binding, biodistribution and imaging studies using nude mice bearing the receptor-positive M21 human melanoma xenografts. Results The 111 In-labeled IA (40%) and -IAC (72%) specifically bound in vitro to α v β 3 (0.8 μM) at a molar excess. This receptor binding was completely blocked by a molar excess of cold IA to α v β 3 . The higher receptor-binding affinity of the 111 In-labeled IAC was reflected in higher tumor uptake and retention: 5.6±1.4 and 4.5±0.7 %ID/g vs. 3.8±0.9 and 2.0±0.3 %ID/g for the 111 In-labeled IA at 0.33 and 2 h. The tumor uptakes were inhibited by the co-injection of 200 μg of IA, indicating that the uptake was receptor mediated. These antagonists were excreted primarily via the renal system. The 111 In activity retained in the whole body was quite comparable between the 111 In-labeled IA (24% ID) and the 111 In-labeled IAC (33% ID) at 2 h. The higher peak tumor uptake and longer retention resulted in higher tumor-to-background ratios for the 111 In-labeled IAC at 2 h with 9.7, 2.3, 0.8, 1.9, 7.1, 2.2, 0.9, 3.7 and 9.9 for blood, liver, kidney, lung, heart, stomach, intestine, bone and muscle, respectively. The imaging studies with the 111 In-labeled IAC also clearly visualized the receptor-positive tumor at 4 h. Conclusions The 111 In-labeled IAC showed an improve tumor targeting kinetics with rapid accumulation and prolonged retention in the α v β 3 receptor-positive tumor. This together with the rapid whole-body clearance pharmacokinetics warrants further studies on this IAC analog for molecular imaging of tumor-induced angiogenic vessels and various malignant human tumors expressing the receptor.

This paper presents a new way of designing bulk metallic glasses in Cu–Ti–Zr–Ni system based upon binary deep eutectic. By conventional copper mold casting method, these alloys can be quenched into single amorphous structure with the diameter ranging from 3 to 5 mm. Experimental results show that among the alloy series designed Cu 52.55 Ti 30.05 Zr 11.4 Ni 6 and Cu 53.1 Ti 31.4 Zr 9.5 Ni 6 possess the relatively higher T rg of 0.603 and 0.598, respectively, which contribute to their good glass forming ability, and Cu 52.55 Ti 30.05 Zr 11.4 Ni 6 exhibits a relatively higher T g (694 K) and Δ T x (52 K), which indicate its good thermal stability.

Mathematical modeling of influenza epidemic is important for analyzing the main cause of the epidemic and finding effective interventions towards it. The epidemic is a dynamic process. In this process, daily infections are caused by people's contacts and the frequency of contacts can be mainly influenced by their cognition to the disease. The cognition is in turn influenced by daily illness attack rate, climate and other environment factors. Few existing methods considered the dynamic process in their models. Therefore, their prediction results can hardly be explained by the mechanisms of epidemic spreading. In this paper, we developed a heterogeneous graph modeling approach (HGM) to describe the dynamic process of influenza virus transmission by taking advantage of our unique clinical data. We built social network of studied region and embedded an Agent-Based Model (ABM) in the HGM to describe the dynamic change of an epidemic. Our simulations have a good agreement with clinical data. Parameter sensitivity analysis showed that temperature influences the dynamic of epidemic significantly and system behavior analysis showed social network degree is a critical factor determining the size of an epidemic. Finally, multiple scenarios for vaccination and school closure strategies were simulated and their performance was analyzed.

The theranostic potential of (225)Ac-based radiopharmaceuticals continues to increase as researchers seek innovative ways to harness the nuclear decay of this radioisotope for therapeutic and imaging applications. This communication describes the evaluation of (225)Ac-DOTA-c(RGDyK) in both biodistribution and Cerenkov luminescence imaging (CLI) studies. Initially, La-DOTA-c(RGDyK) was prepared as a non-radioactive surrogate to evaluate methodologies that would contribute to an optimized radiochemical synthetic strategy and estimate the radioactive conjugate's affinity for αvβ3, using surface plasmon resonance spectroscopy. Surface plasmon resonance spectroscopy studies revealed the IC50 and Ki of La-DOTA-c(RGDyK) to be 33 ± 13 nM and 26 ± 11 nM, respectively, and suggest that the complexation of the La(3+) ion to the conjugate did not significantly alter integrin binding. Furthermore, use of this surrogate allowed optimization of radiochemical synthesis strategies to prepare (225)Ac-DOTA-c(RGDyK) with high radiochemical purity and specific activity similar to other (225)Ac-based radiopharmaceuticals. This radiopharmaceutical was highly stable in vitro. In vivo biodistribution studies confirmed the radiotracer's ability to target αvβ3 integrin with specificity; specificity was detected in tumor-bearing animals using Cerenkov luminescence imaging. Furthermore, tumor growth control was achieved using non-toxic doses of the radiopharmaceutical in U87mg tumor-bearing nude mice. To our knowledge, this is the first report to describe the CLI of αvβ3 (+) tumors in live animals using the daughter products derived from (225)Ac decay in situ. This concept holds promise to further enhance development of targeted alpha particle therapy.

Optical properties of star-shaped ZnO nanostructures were studied. The temperature-dependent photoluminescence (PL) was examined up to fourth-order longitudinal optical (LO) phonon assisted emissions of free excitons and confirmed that the nature of the room temperature PL in ZnO is 1-LO phonon assisted emission of free excitons. Low threshold ultraviolet stimulated emissions (SE) were obtained for our powder samples at room temperature. Picosecond time-resolved PL measurements detected a bi-exponential decay behavior which is strongly dependent on the excitation intensity: the slow decay term decreased faster than the fast decay term as the excitation intensity increased and the emission decays were dominated by the fast one. We also found that the emission decays decreased super-linearly before the appearance of the SE. This behavior may be used to deduce the threshold of SE or lasing.

Rationale and Objectives To investigate the potential of using pulsed high-intensity focused ultrasound (HIFU) exposures to enhance the delivery, and hence therapeutic effect of liposomal doxorubicin (Doxil) in a murine breast cancer tumor model. Materials and Methods Tumors were grown in the bilateral flanks of mice using a mammary adenocarcinoma cell line. Experiments consisted of exposing one of two tumors to pulsed-HIFU, followed by tail vein injections of Doxil. Tumor growth rates were monitored, and assays carried out for doxorubicin concentration in these tumors as well as in a second (squamous cell carcinoma) tumor model and in muscle. Laser scanning confocal microscopy was used with fluorescent probes to observe both the uptake of polystyrene nanoparticles and dilation of exposed blood vessels. Additional experiments involving histologic analysis and real-time temperature measurements were performed to determine the safety of the exposures. Results Pulsed-HIFU exposures were shown to be safe, producing no apparent deleterious effects in the tumors. The exposures, however, were not found to enhance the delivery of Doxil, and consequently did not allow for lower doses for obtaining tumor regression. Imaging with a fluorescent dextran showed blood vessels to be dilated as a result of the exposures. Experiments with polystyrene nanoparticles of similar size to the liposomes showed a greater abundance to be present in the treated tumors. Conclusion Although past studies have shown the advantages of pulsed-HIFU exposures for enhancing delivery, this was not observed with the liposomes, apparently because of their inherent ability to preferentially accumulate into tumors on their own. Potential mechanisms for enhanced uptake of non-liposomal nanoparticles are discussed.

To evaluate the use of pulsed high-intensity focused ultrasound exposures to improve tissue plasminogen activator (tPA)-mediated thrombolysis in an in vitro model.All experimental work was compliant with institutional guidelines and HIPAA. Clots were formed by placing 1 mL of human blood in closed-off sections of pediatric Penrose tubes. Four experimental groups were evaluated: control (nontreated) clots, clots treated with pulsed high-intensity focused ultrasound only, clots treated with tPA only, and clots treated with pulsed high-intensity focused ultrasound plus tPA. The focused ultrasound exposures (real or sham) were followed by incubations of the clots in tPA with saline or in saline only. Thrombolysis was measured as the relative reduction in the mass of the clot. D-Dimer assays also were performed. Two additional experiments were performed and yielded dose-response curves for two exposure parameters: number of pulses per raster point and total acoustic power. Radiation force-induced displacements caused by focused ultrasound exposures were simulated in the clots. A Tukey-Kramer honestly significant difference test was performed for comparisons between all pairs of experimental groups.The clots treated with focused ultrasound alone did not show significant increases in thrombolysis compared with the control clots. The clots treated with focused ultrasound plus tPA showed a 50% ([30.2/20.1]/20.1) increase in the degree of thrombolysis compared with the clots treated with tPA only (P.001), further corroborating the d-dimer assay results (P.001). Additional experiments revealed how increasing both the number of pulses per raster point and the total acoustic power yielded corresponding increases in the thrombolysis rate. In the latter experiment, simulations performed at a range of power settings revealed a direct correlation between increased displacement and observed thrombolysis rate.The rate of tPA-mediated thrombolysis can be enhanced by using pulsed high-intensity focused ultrasound exposure in vitro.

As the understanding of human cancer biology increases, new potential strategies for gene therapy are being proposed and evaluated. However, safe and efficient gene transfer continues to be the major hurdle for its implementation in the clinic. Preclinical studies have shown how pulsed-high intensity focused ultrasound (HIFU) exposures can be combined with different modes of administration (local, intravascular and systemic) to improve local delivery of genes and other therapeutic agents. Using image guidance, exposures are given, where short pulses of energy create predominantly mechanical/structural effects in the tissues as opposed to thermal ones. The result is an increase in both extravasation and interstitial diffusion of macromolecules, which occur nondestructively and reversibly. Ultrasound contrast agents can also be added, which enhance acoustic cavitation activity and consequently sonoporation. By being able to locally increase the uptake and expression of DNA, pulsed-HIFU holds much promise to further the use and applications of gene therapy for treating cancer and other pathological conditions.