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Over the past two decades the feasibility for using transcranial ultrasound as both a therapeutic and diagnostic tool has been established. Various aberration-correction techniques have been proposed to achieve transcranial focusing, including CT-derived model based corrections, ultrasound-derived model based corrections, magnetic resonance acoustic radiation force (MR-ARFI) techniques, and techniques involving the invasive introduction of an acoustic source or receiver into the brain. Here, we investigate the correlation between transcranial infrared light (IR) and transcranial ultrasound, where we examine whether IR could be an indicator of any of the key acoustic properties that affect transcranial transmission (signal attenuation, speed of sound, and bone density). Nine human skull samples were utilized in the study. The interior of each sample was illuminated over its inner surface using a diffuse light source. Light transmitted to the outer surface was detected by a 3-mm diameter 940-nm infrared sensor. Acoustic measurements were likewise obtained in a water tank using a 12.7-mm diameter 1-MHz source and a needle hydrophone receiver. Results reveal a positive correlation between the acoustic time-of-flight and optical intensity (the correlation coefficient is between 0.5 and 0.9). Subsequent investigation shows this correlation to hold independent of the presence or absence of dura mater on the samples. Poor correlation is observed between acoustic amplitude and optical intensity (the correlation coefficient is between 0.1 and 0.7).

Intrinsically disordered proteins or proteins with disordered regions are very common in nature. These proteins have numerous biological functions which are complementary to the biological activities of traditional ordered proteins. A noticeable difference in the amino acid sequences encoding long and short disordered regions was found and this difference was used in the development of length-dependent predictors of intrinsic disorder. In this study, we analyze the scaling of intrinsic disorder in eukaryotic proteins and investigate the presence of length-dependent functions attributed to proteins containing long disordered regions.

Against the received wisdom, Mark Howell-Meri argues here for a continuing tradition between Elizabethan and Restoration (or ‘long eighteenth-century’) playhouses. He bases his argument in part on measurements which suggest the common use of traditional building methods and relationships between measurements and spaces based on ad-quadratum geometry, as shared by theatre builders across the centuries; but also on his own experience as a performance-practitioner specializing in an historiographical approach to making sense of eighteenth-century plays for today's audiences in surviving (or reconstructed) eighteenth-century spaces. He was the first director to restore a three-sided stage front to the Georgian Theatre (now Theatre Royal) in Richmond, Yorkshire, in 1987 with his hit production of Garrick's Miss in her Teens (1747), and other research productions have included Robert Dodsley's The King and the Miller of Mansfield (1737), Colman the Younger's Inkle and Yarico (1787), Inchbald's The Midnight Hour (1787), again at the Georgian Theatre in Richmond, and Lillo's The London Merchant (1731). He is now completing his doctoral thesis, ‘Theatre and Liberty: Eighteenth-Century Play Production on the Three-Sided Stage’.

Alterations to NPRA signaling may lead to inhibition of cancer stem cell (CSC) proliferation; we report the development of a 3D tumor/stroma coculture model to study and further define the role that NPRA plays in CSC development and drug resistance. Objectives: Determine changes in cell phenotype caused by culture on a 3D nanofiber scaffold or suspension culture, whether these changes represent an enrichment of CSCs, the mechanism of enrichment/role of NPRA. Examine the roles of stromal cell types in tumor growth, CSC development, and drug resistance in an in vitro coculture. Assess CSC expansion and drug resistance in 3D scaffold tumoroids or suspension with/without cancer associated fibroblasts (CAF) as well as in isolated CSC populations. Methods: CSCs were assayed by flow cytometry (CD44+/CD24-, CD133+) and isolated by FACS or MACS. Stemness was assayed by SOX2 OCT4 NANOG expression and aldehyde dehydrogenase(ALDH) activity with the ALDEFLUOR kit. Sphere forming assays (SFAs) for anchorage independent growth with/without NPRA inhibitors and/or stromal cells were performed and measured by bright field microscopy. Tumor initiation was assayed in the flanks of syngeneic or NSG mice. NPRA KO mice were used to determine the influence of stromal NPRA on tumor growth. Cancer cells were grown on 3D nanofiber scaffold with/without stromal cells as an in vitro model of the tumor microenvironment. CSC enrichment was assayed by CSC marker expression and SFAs. NPRA knockout cell lines were made using CRISPR/Cas9, verified by flow cytometry and qPCR. Knockout cell lines were tested for their tumor initiation, CSC marker expression, and SFA in the presence or absence of stromal cells. Results: Introduction of factors secreted by CAF increased the tumor cells' ability for attachment-independent growth; however, this was not seen with NPRA inhibitor treatment. Putative CSCs collected from tumor spheres initiated tumors in mice at lower cell numbers than their parental cell lines. 3D culture of tumor biopsies increased expression of CD44+ CD24- ALDH+ compared to primary tumor or monolayer. 3D culture increased the drug resistance of cancer cells, compared to 2D. Cells from the CD44+CD24- population initiated tumors at lower numbers than parental. Tumor spheres initiated in vivo tumors at lower cell counts than monolayer cultures. These tumors grew faster in wild type mice vs NPRA KO mice. CRISPR genome editing allowed us to create NPRA knockout cell lines to confirm the results of the inhibitor studies. Coculture of different cell types with/without NPRA KO determined NPRA's influence on CAF supporting tumor growth. Conclusions: The 3D scaffold offers a cell culture environment causing cancer cells to retain more in vivo behavior. This model can increase the CSC phenotype and can be used to study the mechanisms of CSC proliferation, drug resistance, and the role of stromal cells. We hypothesized that NPRA signaling is key for this process and we found that inhibiting NPRA signaling reduces the ability for attachment-independent growth even in the presence of tumor supporting CAF and their in vivo tumor initiation ability. Cancer cell growth was reduced by NPRA inhibition and NPRA signaling is important for the initiation and maintenance of tumors. We plan to use the scaffold model to determine NPRA signaling’s influences on CSC development and its effects on each stromal cell type within tumors. Citation Format: Ryan J. Green, Mark Howell, Rajesh Nair, Shruti Padhee, Scott Antonia, Eva Samal, Jit Banerjee, Shyam Mohapatra, Subhra Mohapatra. NPRA signaling in the tumor/stroma microenvironment influences the growth of stem-like cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A066.

Objectives: Lung cancer is the number one cause of cancer-related deaths. About 20% of all non-small cell lung cancer (NSCLC) patients are expected to harbor an Epidermal Growth Factor Receptor (EGFR) activating mutation. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) are clinically approved to treat advanced NSCLC patients. However, despite the initial clinical responses to these EGFR-targeted therapies, long-term efficacy is not possible because acquired drug resistance hampers the effectiveness of these therapies. Even with gradually increasing knowledge, many routes to resistance have yet to be discovered. We found that a polymeric nanofibrous scaffold platform established in our laboratory allows growth of three-dimensional (3D) tumor-like aggregates (tumoroids), which resemble in vivo tumors. We hypothesize that 3D scaffold will allow us to elucidate EGFR TKI resistance mechanisms and help design more efficient treatment strategies to block resistance. Methods: To investigate drug resistance to EGFR TKIs, we have developed lapatinib-resistant human lung cancer cell lines as models for de novo drug resistance. To derive drug-resistant (DR) cells, three human lung cancer cell lines with different EGFR-activating mutations were grown in static concentrations of lapatinib for up to 30 days. The drug sensitivity of the parental and DR cells on both the monolayer and 3D scaffold was determined by testing a panel of standard-of-care chemotherapeutics along with EGFR TKIs. Mass spectroscopy was used to determine the relative levels of certain key proteins being expressed in the H1975 and lapatinib DR-H1975 cell lines. Expression of intriguing proteins found in the mass spec data was confirmed and validated in our EGFR TKI resistant models using other methods, including Western blotting and mRNA transcript analysis. Inhibitors, as well as siRNA, of selected proteins were then used to determine if these proteins played a role in EGFR TKI resistance. Results: A comparison of the drug sensitivity showed that parental cells were at least 3-fold more sensitive to the EGFR TKIs compared to the DR cells. The sensitivity to EGFR TKIs was further decreased when DR cells were cultured on our fibrous 3D scaffold. EGFR TKI resistant cells were also resistant to other anticancer agents, such as taxol and gemcitabine. Data mining the significantly differentially expressed proteins list generated by the mass spectroscopic analysis revealed that the protein expression is skewed in lapatinib DR-H1975 cell line as compared to the H1975 cell line. Proteins involved in all aspects of homeostasis including metabolism, biosynthesis, and oxidative regulation were significantly upregulated in the lapatinib-resistant cell line. We are currently working to determine if all the EGFR TKI resistant cell lines are producing similar mechanisms of resistance. Conclusions: Studying the cellular effects of acquired EGFR TKI resistance, as well as the mechanism through which this resistance is maintained, can help to better understand how lung cancer cells become drug resistant to EGFR TKIs and help strategize potential ways of overcoming this resistance. Research supported by: R01CA152005, HHSN261201400022C, HHSN261201400028C. Citation Format: Mark C. Howell, Ryan Green, Rajesh Nair, Stanley Stevens, Jit Banerjee, Shyam Mohapatra, Subhra Moahpatra. Mechanism of treatment-induced drug resistance in lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A139.

Skull-induced distortion and attenuation present a challenge to both transcranial imaging and therapy. Whereas therapeutic procedures have been successful in offsetting aberration using images from prior CTs, this approach is impractical for imaging. In an effort to provide a simplified means for aberration correction, we have been investigating the use of diffuse infrared light as an indicator of acoustic properties. Infrared wavelengths were specifically selected for tissue penetration; however this preliminary study was performed through bone alone via a transmission mode to facilitate comparison with acoustic measurements. The inner surface of a half human skull, cut along the sagittal midline, was illuminated using an infrared heat lamp, and images of the outer surface were acquired with an IR-sensitive camera. A range of source angles was acquired and averaged to eliminate source bias. Acoustic measurements were likewise obtained over the surface with a source (1 MHz, 12.7 mm-diam) oriented parallel to the skull surface and hydrophone receiver (1 mm PVDF). Preliminary results reveal a positive correlation between sound speed and optical intensity, whereas poor correlation is observed between acoustic amplitude and optical intensity.

As part of a larger investigation into the archaeological origins of the blues, I seek to re-create the sound environments that surrounded and informed the initial emanations of this important American music genre. This study is warranted because the music has had such a pronounced influence on global musics, as well as on broader sociological concerns like race, regionalism, nationalism, capitalism, and gender. It is also of value for archaeo-acoustic studies in that it concerns a study of an archaeo-historic site that is not in the deep past. For the ASA meeting-forum I will report on two related acoustic processes: one is the digital reconstruction of the physical structures where the blues was first heard, such as wood-framed shotgun-shaped performance spaces (juke joints, general stores), some of which still exist in the Mississippi Delta (Po Monkeys near Merigold and Mary’s in Indianola), or can be archaeologically recovered (the general store at Dockery Farms); and the second process is a recreatio...

Patient motion is known to be a major cause of image artifact during magnetic resonance imaging (MRI). Especially in functional MRI (fMRI), head motion can corrupt signals from brain activity, and deviations of under a millimeter can accumulate nonlinearly, rendering the fMRI technique altogether incapable of brain imaging. It is apparent that the addition of a real time MR-compatible motion tracking system could provide critical information that, if combined with MR-motion correction techniques, could result in more reliable imaging. Here an MR-compatible air ultrasound transducer array was developed, with the goal of quantifying fMRI-relevant motions of under 0.5 mm. The array was designed to track nose position so that, by approximating head movement as a rigid body rotation about the second cervical vertebra (C2), the position of the entire head could be estimated. The array consisted of 5 planar air transducers (400 kHz, 1-cm-diameter) whose axes were oriented to coincide at the tip of the nose, approximately 6 cm in front of the array. One transducer, working as a transmitter, was situated in the array center and aligned approximately parallel with the tip of the nose. The remaining 4 elements were situated left, right, above and below the transmitter, all relative to the head position. After verifying MR-compatibility and optimizing element spacing, preliminary bench top measurements were made using a plastic head phantom affixed to a rotational motor. By analyzing the phase shift in back-scattered acoustic signals, the angle of head shaking or nodding, were estimated; motions that correspond to the most commonly observed movements during fMRI. In five measurements over a range of one degree rotation, predicted angles were found to agree within 85% of the actual head position. Finally, we verified the device on a human volunteer. Overall results demonstrated the ability of the array to identify sub-millimeter (0.2 mm) head motion, thereby allowing estimation of head rotation angles as small as 0.10. This method, applied as feedback into existing MR-motion correction algorithms, may lead to a practical approach to more robust fMRI imaging.

Chiari Type I Malformation is a condition in which the cerebellar tonsils, small lobes on the undersurface of each half of the cerebellum, protrude through the base of the skull and press against the spinal cord. Assessing the motion of these herniated structures and their effects on cerebrospinal fluid dynamics is of significant clinical interest, particularly since the condition has been implicated in the formation of serious secondary disorders affecting the brain and spinal cord, such as hydrocephalus and syringomyelia. While MRI studies have shown no statistically significant differences in tonsillar motion of Chiari Type I patients compared to healthy individuals, surgeons have reported rapid tonsil motion as observed by intraoperative sonography during decompression surgery. However, it remains unclear whether this discrepancy is due to limitations of the MRI technique or decompression facilitating increased movement. Therefore, we aim to test the hypothesis that localized movement of cerebellar tonsils can be assessed non-invasively in the intact skull using ultrasound. Here, an investigation into the use of a novel methodology for transkull imaging in assessing cerebellar tonsil motion is presented. Two transducers (1MHz, 0.5 inches in diameter) were placed rostrocaudally on the frontal and suboccipital surfaces of a water-filled ex vivo human skull. A sinusoidal pulse was transmitted into the specimen from one transducer, and recorded by the receiving transducer at the opposite surface. Starting at the edge of the foramen magnum, the transducers were rotated at 8mm intervals in a counterclockwise direction. A tissue phantom was also used to mimic the cerebellar tonsils. Attenuation through the skull and motion detection in the tissue phantom was analyzed. It is shown that at a transducer frequency of 1MHz, our through transmission ultrasonic technique allows for a substantial energy transmission of up 8.6%. No signal was observed at the same points in reflection mode. To our knowledge, this level of energy transmission has been achievable only through a very limited temporal acoustic window, which fails in up to 29% of patients in a general population. Results demonstrate the feasibility of using this type of transducer system for a non-invasive pre-surgical assessment of cerebellar tonsil motion without the need for an acoustic window.

Combing chemotherapy with gene therapy has been one of the most promising strategies for the treatment of cancer. The noninvasive MRI with superparamagnetic iron oxide (SPIO) as contrast agent is one of the most effecitve techniques for evaluating the antitumor therapy. However, to construct a single system that can deliver efficiently gene, drug and SPIO to the cancer site remains a challenge. Herein, we report a chitosan functionalized magnetic graphene nanoparticle (CMG) platform for simultaneous gene/drug and SPIO delivery to tumor. The phantom and ex vivo MRI images suggest CMG as a strong T2 contrast-enhancing agent. The CMGs are biocompatible as evaluated by the WST assay and predominantly accumulate in tumors as shown by biodistribution studies and MRI. The anticancer drug doxorubicin (DOX) loaded CMGs (DOX-CMGs) release DOX faster at pH 5.1 than at pH 7.4, and more effective (IC50 = 2 μM) in killing A549 lung cancer cells than free DOX (IC50 = 4 μM). CMGs efficiently deliver DNA into A549 lung cancer cells and C42b prostate cancer cells. In addition, i.v. administration of GFP-plasmid encapsulated within DOX-CMGs into tumor-bearing mice has showed both GFP expression and DOX accumulation at the tumor site at 24 and 48 hrs after administration. These results indicate CMGs provide a robust and safe theranostic platform, which integrates targeted delivery of both gene medicine and chemotherapeutic drug(s), and enhanced MR imaging of tumors. The integrated chemo- and gene- therapeutic and diagnostic design of CMG nanoparticles shows promise for simultaneous targeted imaging, drug delivery and real -time monitoring of therapeutic effect for cancer.

Background Declining cognitive function is relatively common and increasingly prevalent. Studies have shown that different nutrients (e.g., Ginkgo biloba and vitamin E) appear to be effective at improving memory and concentration, while less is known about their effect on immunity. Methods This study investigated the effect of Ginkgo Synergy® plus Choline (n = 33) and OPC Synergy® plus Catalyn® (n = 31) versus placebo (n = 33) in a 6-month, randomized, double-blind trial on cognitive and immune functioning among English-speaking, non-smoking, healthy older adults. The Stroop Color and Word Test, Trail Making Test A and B, Controlled Oral Word Association, Hopkins Verbal Learning, Mini-Mental State Exam, and Digit Symbol were administered at baseline and 3 and 6 months follow-up to assess cognitive functioning. Cytokines and growth factors were measured at baseline and 6 months to assess inflammation and immune functioning. Data were analyzed with linear mixed modeling. Results No serious adverse events were noted in this study. According to time on the Trail Making Test-B, the Ginkgo Synergy® plus Choline arm showed improvement from baseline to 3 months follow-up (mean difference = 24.2; SE = 6.4; 95% CI: 8.6, 39.7; p = 0.01). On the Controlled Oral Word Association Trial-S, the scores significantly increased for the Ginkgo Synergy® plus Choline arm from baseline to 6 months follow-up (mean difference = 2.1; SE = 0.8; 95% CI: 0.2, 3.9; p

Theranostic nanoparticles with both therapeutic and imaging abilities have the promise to revolutionize diagnosis, therapy, and prognosis. Early and accurate detection along with swift treatment are the most important steps in the successful treatment of any disease. Over the last decade, a variety of nanotechnology-based platforms have been created in the hope of improving the treatment and diagnosis of a wide variety of diseases. However, significant hurdles still remain before theranostic nanoparticles can bring clinical solutions to the fight against chronic respiratory diseases. Some fundamental issues such as long-term toxicity, a precise understanding of the accumulation, degradation and clearance of these particles, and the correlation between basic physicochemical properties of these nanoparticles and their in vivo behavior have to be fully understood before they can be used clinically. To date, very little theranostic nanoparticle research has focused on the treatment and diagnosis of chronic respiratory illnesses. Nanomedicine approaches incorporating these theranostic nanoparticles could potentially be translated into clinical advances to improve diagnosis and treatment of these chronic respiratory diseases and enhance quality of life for the patients.

Gadolinium (Gd) contrast agents are predominantly used for T(1) MR imaging. However, the high toxicity of Gd(3+) and potential side effects including nephrogenic systemic fibrosis have led to the search for alternative T(1) contrast agents. Since manganese (Mn) has paramagnetic properties with five unpaired electrons that permit high spin number, long electronic relaxation times, and labile water exchange, we evaluated Mn as a T(1) magnetic resonance imaging (MRI) contrast agent for lung imaging. Here we report on the design and synthesis of multifunctional lipid-micellar nanoparticles (LMNs) containing Mn oxide (M-LMNs) for MRI that can also be used for DNA and drug delivery. Oleic acid-coated MnO nanoparticles were encapsulated in micelles composed of polyethylene glycol (PEG-2000), phosphatidylethanolamine (PE), DC-cholesterol, and dioleoyl-phosphatidylethanolamine (DOPE). The particles are taken up in vitro by human embryonic kidney (HEK293), Lewis lung carcinoma (LLC1), and A549 cells and are devoid of cytotoxicity. When administered to mice intranasally, they preferentially accumulate in the lungs. In vitro phantom and ex vivo lung MRI results confirmed that M-LMNs are able to enhance T(1) MRI contrast. M-LMNs loaded with plasmid DNA and/or doxorubicin are efficiently taken up by HEK293 cells in vitro and by target cells in vivo. Taken together, these results demonstrate that M-LMNs are capable of simultaneously providing MRI contrast and DNA and/or drug delivery to target cells in the lung and therefore may prove useful as a lung theranostic, especially for lung cancers.

The development of a suitable three dimensional (3D) culture system for anticancer drug development remains an unmet need. Despite progress, a simple, rapid, scalable and inexpensive 3D-tumor model that recapitulates in vivo tumorigenesis is lacking. Herein, we report on the development and characterization of a 3D nanofibrous scaffold produced by electrospinning a mixture of poly(lactic-co-glycolic acid) (PLGA) and a block copolymer of polylactic acid (PLA) and mono-methoxypolyethylene glycol (mPEG) designated as 3P. Cancer cells cultured on the 3P scaffold formed tight irregular aggregates similar to in vivo tumors, referred to as tumoroids that depended on the topography and net charge of the scaffold. 3P scaffolds induced tumor cells to undergo the epithelial-to-mesenchymal transition (EMT) as demonstrated by up-regulation of vimentin and loss of E-cadherin expression. 3P tumoroids showed higher resistance to anticancer drugs than the same tumor cells grown as monolayers. Inhibition of ERK and PI3K signal pathways prevented EMT and reduced tumoroid formation, diameter and number. Fine needle aspirates, collected from tumor cells implanted in mice when cultured on 3P scaffolds formed tumoroids, but showed decreased sensitivity to anticancer drugs, compared to tumoroids formed by direct seeding. These results show that 3P scaffolds provide an excellent platform for producing tumoroids from tumor cell lines and from biopsies and that the platform can be used to culture patient biopsies, test for anticancer compounds and tailor a personalized cancer treatment.

Transcranial ultrasound (tUS) is a plausible means of measuring motion of the brain due to traumatic force or structural abnormalities. However, limited data in the literature on the mechanical properties of human brain tissue make it practically impossible to develop a mechanically realistic ultrasound phantom that can mimic the brain under these conditions. The present study aimed to determine, by indirect qualitative assessment, the stiffness of in-vivo brain tissue. Six surgeon examiners under blinded conditions physically examined 16 gelatin-based tissue phantoms (0.020-0.095 g/mL) to determine which sample best matched the stiffness of brain tissue in-vivo. Ten cylindrical phantom samples, acoustically matched to human brain tissue, were prepared based on the examiners’ responses (0.030±0.008 g/mL), and stress-strain behavior was characterized under compression up to 50% strain. The average compressive stress at 50% strain was 10.3±1.4 kPa. These results correlate well with those previously reported...

While the antimicrobial effects of ultrasound have been well established, application as a bactericide in medicine has been hindered in part by significant variation in reported efficacy. Non-thermal mechanisms of cell death are generally attributed to cavitation, prompting us to investigate the potential for locally applied microbubbles to serve as a catalyst for reliably increasing bacterial death, while sparing surrounding cells. This preliminary study was limited to gram-negative bacteria (E-coli) suspended in buffered saline. Preliminary work at 40 kHz continuous-wave sonication established a threshold time for our setup of 15 minutes, below which negligible cell death was observed relative to control samples. Experiments were then performed with and without the introduction of octofluropropane-filled lipid shells microbubbles, sonicated over the 15 minute period. Thermometry and passive cavitation monitoring (PCD) were both conducted. Analysis by dilution and plating indicate a 65-80% reduction in b...

In our ongoing work toward transskull ultrasound brain imaging, we investigate an optically-registered “belt-type” conformal transducer designed to maximize energy transfer while maintaining precise phase control. Previous simulations determined that approximately 500 channels is sufficient for two-dimensional brain imaging by utilizing a tomographic approach valid on irregular boundaries [Clement, Inverse Problems 30 125010 (2014)]. The present design is based around an assembly of rigid planar sub-arrays with flexible interconnects. Each piezo-composite sub-array (500 kHz, 1-3 random-fiber, 20 mm X 20 mm) is formed by electroding both faces of the composite before partially dicing the rear surface to produce 19 signal electrode terminals (width~0.85 mm, height~20 mm, and kerf~0.18 mm) with a shared ground face. Sub-arrays are bonded to a custom printed circuit boards and wired to shielded ribbon cable. The full transducer is then created by UV bonding the electrodes to a flexible band, forming the front...

n an article that first appeared in US magazine, Medical ConstructionDesign, Mark Howell, senior vice-president of Skanska USA Building, based in Seattle, describes the design and construction of a new nine-storey, 350,000 ft2 extension to the Good Samaritan Hospital in Puyallup, Washington state. He explains how the use of an Integrated Project Delivery (IPD) approach by the key players, and extensive use of building information modelling (BIM), combined to deliver a healthcare facility that he believes should meet the needs of patients, families, and the clinical care team, 'well into the future'.

Gene therapy is a promising therapeutic approach for treating disease, but the efficient delivery of genes to desired locations with minimal side effects remains a challenge. In addition to gene therapy, it is also highly desirable to provide sensitive imaging information in patients for disease diagnosis, screening and post-therapy monitoring. Here, we report on the development of dual-purpose chitosan and polyethyleneimine (PEI) coated magnetic micelles (CP-mag-micelles) that can deliver nucleic acid-based therapeutic agents and also provide magnetic resonance imaging (MRI). These 'theranostic' CP-mag-micelles are composed of monodisperse hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) loaded into the cores of micelles that are self-assembled from a block copolymer of poly (D, L-lactide) (PLA) and monomethoxy polyethylene glycol (mPEG). For efficient loading and protection of the nucleic acids the micelles were coated with cationic polymers, such as chitosan and PEI. The morphology and size distribution of the CP-mag-micelles were characterized and their potential for use as an MRI-probe was tested using an MRI scanner. The T(2) relaxivity of mag-micelles was similar to CP-mag-micelles confirming that coating with cationic polymers did not alter magnetism. Nanoparticles coated with chitosan:PEI at a weight ratio of 5:5 showed higher transfection efficiency in HEK293, 3T3 and PC3 cells than with weight ratios of 3:7 or 7:3. CP-mag-micelles are biocompatible, can be delivered to various organs and are safe. A single injection of CP-mag-micelles carrying reporter plasmids in vivo expressed genes for at least one week. Collectively, our results demonstrate that a structural reinforcement of SPIONs loaded in the core of an mPEG-PLA micelle coated with cationic polymers provides efficient DNA delivery and enhanced MRI potential, and affords a promising candidate for theranostics in the future.

Natriuretic peptide receptor A (NPRA), the receptor for the cardiac hormone atrial natriuretic peptide (ANP), is expressed abundantly on cancer cells and disruption of ANP-NPRA signaling inhibits tumor burden and metastasis. Since antagonists of NPRA signaling have not provided reproducible results, we reasoned that a synthetic neutralizing antibody to ANP, which has high selectivity and affinity for ANP, could be used to regulate ANP levels and attenuate NPRA signaling. In this study, we prepared molecularly imprinted polymer nanoparticles (MIPNPs) for ANP using a short peptide of ANP as the template and determined their binding affinity and selectivity. The MIPNPs were prepared by precipitation polymerization using NH2-SLRRSS-CONH2, which is a short peptide from ANP as template, methacrylic acid (MAA) and N-isopropylacrylamide (NIPAm) as functional monomers, bis-acrylamide (BIS) as crosslinker. The average diameter of MIPNPs and non-imprinted nanoparticles (NIPNPs) in water is 215.8 ±4.6 nm and 197.7±3.1 nm respectively. The binding isotherm analysis showed that MIPNPs have a much higher binding affinity for template peptide and ANP than NIPNPs. Scatchard analysis gave an equilibrium dissociation constant, Kd of 7.3 μM with a binding capacity 106.7 μmol/g for template peptide and Kd of 7.9 μM with a binding capacity of 36.0 μmol/g for ANP. Measurements of binding kinetics revealed that MIPNPs reach protein adsorption equilibrium in 30 min. MIPNPs found to have high specificity for ANP with little affinity for BSA or scrambled ANP peptide. MIPNPs also recognized and adsorbed ANP in cell culture media spiked with ANP and human plasma. Taken together, these results indicate that MIPNPs have high affinity and selectivity for ANP and can be used as a synthetic antibody for modulating ANP-NPRA signaling in cancers.

Currently, there are few simple-to-construct in vitro, wall-less phantoms that have accurate acoustic properties while mimicking the complex normal and neoplastic geometries of the vascular network. The purpose of this study was to develop agar-based tissue-mimicking phantoms (TMP) to model such networks. Three types of vascular networks were considered: (1) single vessel, (2) multi-vessel with artery bifurcations, and (3) multi-vessel with artery bifurcations and structural abnormalities typical of diseased (tumor) vascular networks. Blood-flow related parameters were derived from the time-intensity curves obtained from the bolus injection of a lipid-based microbubble ultrasound contrast agent (UCA) under varying flow conditions relevant to our ongoing work in developing techniques to simultaneously quantify both the total volume and flow measurements within a tumor phantom. A Fukuda Denshi Ultrasound system was used with a linear probe (LG308-16A) positioned transversely and longitudinally to the direction of the flow. B-mode image acquisition was performed with 0.5 mL of UCA bolus injected into a 500 mL degassed water reservoir and then pumped through the vessels at rates ranging from 20 mL/min to 100 mL/min. Offline analysis of time-intensity curves in response to varied flow conditions indicated the TMP ability to yield easily reproducible simulations of vascular microcirculation.

We demonstrate the capacity of detecting magnetically weak manganese oxide (MnO) nanoparticles and the Lewis lung carcinoma (LLC) cancer cells that have taken up these nanoparticles using a novel biosensor based on the magneto-reactance (MX) effect of a soft ferromagnetic amorphous ribbon with a microhole-patterned surface. While the magnetic moment of the MnO nanoparticles is relatively small, and a magneto-impedance based sensor fails to detect them in solution (0.05 mg/ml manganese oxide lipid micellar nanoparticles) and inside cells at low concentrations (8.25 × 104 cells/ml), the detection of these nanoparticles and the LLC cells containing them is achieved with the MX-based sensor, which, respectively, reaches the detection sensitivity of ∼3.6% and 2.8% as compared to the blank cells. Since the MnO nanoparticles are a promising contrast agent for magnetic resonance imaging (MRI) of lung cells, the MX-based biosensing technique can be developed as a pre-detection method for MRI of lung cancer cells.

Recently, we reported on our observation that diffuse infrared (IR) light transmitted through human skull bone exhibits an intensity that correlates positively with acoustic (1 MHz) time-of-flight data acquired at equivalent locations [POMA 22, 020002 (2015)]. Presently, we investigate the potential to exploit this correlation as a means of correcting for skull-induced aberration. For measurement, a dual ultrasonic/infrared array capable of illuminating a localized region of the skull bone and recording the backscattered light was constructed. The array design utilized 940 nm IR emitters (TSAL4400, 3-mm-diameter) and a single detector (TEFD4300-3 mm) configured to transmit and record under the face of an ultrasonic PZT ring transducer. Initial tests consisted of a three-emitter configuration, with fiberglass-reinforced foil used to isolate the direct infrared signal between the emitters and the receiver. Effects of skin were considered by attaching a skin-mimicking layer to the skull and comparing results...

This study compared the usability of 3 different metaphor-based versions of a speech activated mobile city guide service. The effects of individual differences on attitude towards and performance with the mobile service were also explored. A Wizard of Oz methodology was used to provide the service functionality. All participants completed tasks with a standard control service, and then with one of the 3 metaphor-based services (shopping, office filing system, and transport system). Subjective and objective measures were recorded and analysed to compare services. The office filing system service was rated as being the most usable, and the transport system service least usable. Correlation data suggested that verbal ability and previous telephone experience may be important factors to consider when developing metaphor-based services.

We encapsulated gadolinium oxide (Gd2O3) nanoparticles within phospholipid micelles as a novel low cytotoxic T1-weighted MRI imaging contrast agent (MGdNPs) that can also deliver small molecules such as DNA plasmids. MGdNPs show relatively good MRI relaxivity values, negligible cytotoxicity, excellent cellular uptake and expression of DNA plasmids in vivo. Biodistribution studies in mice show that intranasal and intraperitoneal administration of MGdNPs can effectively target specific organs.