Joint entropy of continuously differentiable ultrasonic waveforms

This study is based on an extension of the concept of joint entropy of two random variables to continuous functions, such as backscattered ultrasound. For two continuous random variables, X and Y, the joint probability density p(x,y) is ordinarily a continuous function of x and y that takes on values in a two dimensional region of the real plane. However, in the case where X=f(t) and Y=g(t) are both continuously differentiable functions, X and Y are concentrated exclusively on a curve, γ(t)=(f(t),g(t)), in the x,y plane. This concentration can only be represented using a mathematically singular object such as a (Schwartz) distribution. Its use for imaging requires a coarse-graining operation, which is described in this study. Subsequently, removal of the coarse-graining parameter is accomplished using the ergodic theorem. The resulting expression for joint entropy is applied to several data sets, showing the utility of the concept for both materials characterization and detection of targeted liquid nanoparticle ultrasonic contrast agents. In all cases, the sensitivity of these techniques matches or exceeds, sometimes by a factor of two, that demonstrated in previous studies that employed signal energy or alternate entropic quantities

Additional results for Joint entropy of continuously differentiable ultrasonic waveforms [J. Acoust. Soc. Am. 133(1), 283-300 (2013)]

Previous results on the use of joint entropy for detection of targeted nanoparticles accumulating in the neovasculature of MDA435 tumors [Fig. 7 of M. S. Hughes et al., J. Acoust. Soc. Am. 133, 283–300 (2013)] are extended, with sensitivity improving by nearly another factor of 2. This result is obtained using a “quasi-optimal” reference waveform in the computation of the joint entropy imaging technique used to image the accumulating nanoparticles

Detection and quantification of angiogenesis in experimental valve disease with integrin-targeted nanoparticles and 19-fluorine MRI/MRS

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is a critical early feature of atherosclerotic plaque development and may also feature prominently in the pathogenesis of aortic valve stenosis. It has been shown that MRI can detect and quantify specific molecules of interest expressed in cardiovascular disease and cancer by measuring the unique fluorine signature of appropriately targeted perfluorocarbon (PFC) nanoparticles. In this study, we demonstrated specific binding of α_νβ₃integrin targeted nanoparticles to neovasculature in a rabbit model of aortic valve disease. We also showed that fluorine MRI could be used to detect and quantify the development of neovasculature in the excised aortic valve leaflets.</p> <p>Methods</p> <p>New Zealand White rabbits consumed a cholesterol diet for ~180 days and developed aortic valve thickening, inflammation, and angiogenesis mimicking early human aortic valve disease. Rabbits (n = 7) were treated with α_νβ₃integrin targeted PFC nanoparticles or control untargeted PFC nanoparticles (n = 6). Competitive inhibition <it>in vivo </it>of nanoparticle binding (n = 4) was tested by pretreatment with targeted nonfluorinated nanoparticles followed 2 hours later by targeted PFC nanoparticles. 2 hours after treatment, aortic valves were excised and ¹⁹F MRS was performed at 11.7T. Integrated ¹⁹F spectral peaks were compared using a one-way ANOVA and Hsu's MCB (multiple comparisons with the best) post hoc t test. In 3 additional rabbits treated with α_νβ₃integrin targeted PFC nanoparticles, ¹⁹F spectroscopy was performed on a 3.0T clinical scanner. The presence of angiogenesis was confirmed by immunohistochemistry.</p> <p>Results</p> <p>Valves of rabbits treated with targeted PFC nanoparticles had 220% more fluorine signal than valves of rabbits treated with untargeted PFC nanoparticles (p < 0.001). Pretreatment of rabbits with targeted oil-based nonsignaling nanoparticles reduced the fluorine signal by 42% due to competitive inhibition, to a level not significantly different from control animals. Nanoparticles were successfully detected in all samples scanned at 3.0T. PECAM endothelial staining and α_νβ₃integrin staining revealed the presence of neovasculature within the valve leaflets.</p> <p>Conclusion</p> <p>Integrin-targeted PFC nanoparticles specifically detect early angiogenesis in sclerotic aortic valves of cholesterol fed rabbits. These techniques may be useful for assessing atherosclerotic components of preclinical aortic valve disease in patients and could assist in defining efficacy of medical therapies.</p

High contrast ultrasonic imaging of resin-rich regions in graphite/epoxy composites using entropy

This study compares different approaches for imaging a near-surface resin-rich defect in a thin graphite/epoxy plate using backscattered ultrasound. The specimen was created by cutting a circular hole in the second ply; this region filled with excess resin from the graphite/epoxy sheets during the curing process. Backscat-tered waveforms were acquired using a 4 in. focal length, 5MHz center frequency broadband transducer, scanned on a 100 × 100 grid of points that were 0.03 × 0.03 in. apart. The specimen was scanned with the defect side closest to the transducer. Consequently, the reflection from the resin-rich region cannot be gated from the large front-wall echo. At each point in the grid 256 waveforms were averaged together and subsequently used to produce peak-to-peak, Signal Energy (sum of squared digitized waveform values), as well as entropy images of two different types (a Renyi entropy, and a joint entropy). As the figure shows, all of the entropy images exhibit better border delineation and defect contrast than the either the peak-to-peak or Signal Energy. The best results are obtained using the joint entropy of the backscattered waveforms with a reference function. Two different references are examined. The first is a reflection of the insonifying pulse from a stainless steel reflector. The second is an approximate optimum obtained from an iterative parametric search. The joint entropy images produced using this reference exhibit three times the contrast obtained in previous studies

Entropy vs. Energy Waveform Processing: A Comparison Based on the Heat Equation

Virtually all modern imaging devices collect electromagnetic or acoustic waves and use the energy carried by these waves to determine pixel values to create what is basically an “energy” picture. However, waves also carry “information,” as quantified by some form of entropy, and this may also be used to produce an “information” image. Numerous published studies have demonstrated the advantages of entropy, or “information imaging”, over conventional methods. The most sensitive information measure appears to be the joint entropy of the collected wave and a reference signal. The sensitivity of repeated experimental observations of a slowly-changing quantity may be defined as the mean variation (i.e., observed change) divided by mean variance (i.e., noise). Wiener integration permits computation of the required mean values and variances as solutions to the heat equation, permitting estimation of their relative magnitudes. There always exists a reference, such that joint entropy has larger variation and smaller variance than the corresponding quantities for signal energy, matching observations of several studies. Moreover, a general prescription for finding an “optimal” reference for the joint entropy emerges, which also has been validated in several studies

Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient therapeutic effect. We assessed the ability of a peptide based, oligonucleotide condensing, endosomolytic nanoparticle (NP) system to deliver siRNA to KRAS-driven cancers. We show that this peptide-based NP is avidly taken up by cancer cell

Attenuated Superoxide Dismutase 2 Activity Induces Atherosclerotic Plaque Instability During Aging in Hyperlipidemic Mice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142527/1/jah32679-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142527/2/jah32679_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142527/3/jah32679.pd

Anti-angiogenesis therapy in the Vx2 rabbit cancer model with a lipase-cleavable Sn 2 taxane phospholipid prodrug using αvβ3-targeted theranostic nanoparticles

In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of α(v)β(3)-integrin targeted perfluorocarbon (PFC) nanoparticles (α(v)β(3)-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of α(v)β(3)-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of α(v)β(3)-Dxtl-PD NP in endothelial cell culture was as effective as Taxol(®) or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of α(v)β(3)-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same α(v)β(3)-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane(®) given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that α(v)β(3)-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit