Investigating the Use of a Liquid Immunogenic Fiducial Eluter Biomaterial in Cervical Cancer Treatment.

Globally, cervical cancer is the fourth leading cancer among women and is dominant in resource-poor settings in its occurrence and mortality. This study focuses on developing liquid immunogenic fiducial eluter (LIFE) Biomaterial with components that include biodegradable polymers, nanoparticles, and an immunoadjuvant. LIFE Biomaterial is designed to provide image guidance during radiotherapy similar to clinically used liquid fiducials while enhancing therapeutic efficacy for advanced cervical cancer. C57BL6 mice were used to grow subcutaneous tumors on bilateral flanks. The tumor on one flank was then treated using LIFE Biomaterial prepared with the immunoadjuvant anti-CD40, with/without radiotherapy at 6 Gy. Computed tomography (CT) and magnetic resonance (MR) imaging visibility were also evaluated in human cadavers. A pharmacodynamics study was also conducted to assess the safety of LIFE Biomaterial in healthy C57BL6 female mice. Results showed that LIFE Biomaterial could provide both CT and MR imaging contrast over time. Inhibition in tumor growth and prolonged significant survival (* p < 0.05) were consistently observed for groups treated with the combination of radiotherapy and LIFE Biomaterial, highlighting the potential for this strategy. Minimal toxicity was observed for healthy mice treated with LIFE Biomaterial with/without anti-CD40 in comparison to non-treated cohorts. The results demonstrate promise for the further development and clinical translation of this approach to enhance the survival and quality of life of patients with advanced cervical cancer.

Pre-Clinical Investigations of the Pharmacodynamics of Immunogenic Smart Radiotherapy Biomaterials (iSRB).

The use of an immunogenic smart radiotherapy biomaterial (iSRB) for the delivery of anti-CD40 is effective in treating different cancers in animal models. This study further characterizes the use of iSRBs to evaluate any associated toxicity in healthy C57BL6 mice. iSRBs were fabricated using a poly-lactic-co-glycolic-acid (PLGA) polymer mixed with titanium dioxide (TiO2) nanoparticles incorporated into its matrix. Animal studies included investigations of freely injected anti-CD40, anti-CD40-loaded iSRBs, unloaded iSRBs and control (healthy) animal cohorts. Mice were euthanized at pre-determined time points post-treatment to evaluate the serum chemistry pertaining to kidney and liver toxicity and cell blood count parameters, as well as pathology reports on organs of interest. Results showed comparable liver and kidney function in all cohorts. The results indicate that using iSRBs with or without anti-CD40 does not result in any significant toxicity compared to healthy untreated animals. The findings provide a useful reference for further studies aimed at optimizing the therapeutic efficacy and safety of iSRBs and further clinical translation work.

Nanoparticles Targeted to Fibroblast Activation Protein Outperform PSMA for MRI Delineation of Primary Prostate Tumors.

Accurate delineation of gross tumor volumes remains a barrier to radiotherapy dose escalation and boost dosing in the treatment of solid tumors, such as prostate cancer. Magnetic resonance imaging (MRI) of tumor targets has the power to enable focal dose boosting, particularly when combined with technological advances such as MRI-linear accelerator. Fibroblast activation protein (FAP) is overexpressed in stromal components of >90% of epithelial carcinomas. Herein, the authors compare targeted MRI of prostate specific membrane antigen (PSMA) with FAP in the delineation of orthotopic prostate tumors. Control, FAP, and PSMA-targeting iron oxide nanoparticles were prepared with modification of a lymphotropic MRI agent (FerroTrace, Ferronova). Mice with orthotopic LNCaP tumors underwent MRI 24 h after intravenous injection of nanoparticles. FAP and PSMA nanoparticles produced contrast enhancement on MRI when compared to control nanoparticles. FAP-targeted MRI increased the proportion of tumor contrast-enhancing black pixels by 13%, compared to PSMA. Analysis of changes in R2 values between healthy prostates and LNCaP tumors indicated an increase in contrast-enhancing pixels in the tumor border of 15% when targeting FAP, compared to PSMA. This study demonstrates the preclinical feasibility of PSMA and FAP-targeted MRI which can enable targeted image-guided focal therapy of localized prostate cancer.

Functionalization of pristine graphene for the synthesis of covalent graphene-polyaniline nanocomposite.

Polyaniline (PANI) is one of the most studied conducting polymers owing to its high electrical conductivity, straightforward synthesis and stability. Graphene-supported PANI nanocomposite materials combine the superior physical properties of graphene, synergistically enhancing the performance of PANI as well as giving rise to new properties. Covalent nanocomposites have shown to give higher stability and better performance than their non-covalent counterparts, however, the covalent graphene-PANI nanocomposite are primarily prepared from graphene oxide. We report a new method to synthesize covalent graphene-PANI nanocomposites from pristine graphene. Using few-layer graphene (FLG) flakes as the model system, we first conjugated aniline to FLG via a perfluorophenyl azide (PFPA)-mediated coupling chemistry. A subsequent in situ polymerization of aniline gave polyaniline covalently grafted on the FLG surface. Characterization by FTIR, TEM, SEM, XPS, XRD and electrochemistry confirmed the successful conjugation of PANI to FLG. The grafting density of PANI was estimated by thermal analysis to be ∼26%. As the PFPA-mediated coupling chemistry is applicable to other carbon materials including carbon nanotubes and fullerene, the method developed in this work can be readily adapted to grow PANI on these materials.

Demonstration of biofilm removal from type 304 stainless steel using pulsed-waveform electropolishing.

This article describes an electrochemical method to remove bacterial biofilm from a stainless steel (SS) surface using a potential pulse/reverse pulse technique. This technique employs a periodic waveform that consists of anodic and cathodic pulses. The pulses can effectively strip a thin layer of metal off the SS surface, along with the adherent biofilm, in a saline solution. Not only can the pulses effectively remove biofilm from the SS surface, but they also regenerate the original mirror-like shiny surface. The importance of this electrochemical biofilm removal method is its wide applicability for any types of biofilms. That is, instead of directly removing the biofilm, it removes a very thin layer of the metal under the biofilm. Thus, the removal process is independent to the nature of the biofilms. Furthermore, this electrochemical biofilm removal method is rapid (less than 30 s of potential pulse time) and does not require hazardous chemicals.

Priming the Abscopal Effect Using Multifunctional Smart Radiotherapy Biomaterials Loaded with Immunoadjuvants.

In this study, we investigate the use of multifunctional smart radiotherapy biomaterials (SRBs) loaded with immunoadjuvants for boosting the abscopal effect of local radiotherapy (RT). SRBs were designed similar to currently used inert RT biomaterials, incorporating a biodegradable polymer with reservoir for loading payloads of the immunoadjuvant anti-CD40 monoclonal antibody. Lung (LLC1) tumors were generated both on the right and left flank of each mouse, with the left tumor representing metastasis. The mice were randomized and divided into eight cohorts with four cohorts receiving image-guided RT (IGRT) at 5 Gy and another similar four cohorts at 0 Gy. IGRT and Computed Tomography (CT) imaging were performed using a small animal radiation research platform (SARRP). Tumor volume measurements for both flank tumors and animal survival was assessed over 25 weeks. Tumor volume measurements showed significantly enhanced inhibition in growth for the right flank tumors of mice in the cohort treated with SRBs loaded with CD40 mAbs and IGRT. Results also suggest that the use of polymeric SRBs with CD40 mAbs without RT could generate an immune response, consistent with previous studies showing such response when using anti-CD40. Overall, 60% of mice treated with SRBs showed complete tumor regression during the observation period, compared to 10% for cohorts administered with anti-CD40 mAbs, but no SRB. Complete tumor regression was not observed in any other cohorts. The findings justify more studies varying RT doses and quantifying the immune-cell populations involved when using SRBs. Such SRBs could be developed to replace currently used RT biomaterials, allowing not only for geometric accuracy during RT, but also for extending RT to the treatment of metastatic lesions.

Wall-Less Flow Phantoms With Tortuous Vascular Geometries: Design Principles and a Patient-Specific Model Fabrication Example.

Flow phantoms with anatomically realistic geometry and high acoustic compatibility are valuable investigative tools in vascular ultrasound studies. Here, we present a new framework to fabricate ultrasound-compatible flow phantoms to replicate human vasculature that is tortuous, nonplanar, and branching in nature. This framework is based upon the integration of rapid prototyping and investment casting principles. A pedagogical walkthrough of our engineering protocol is presented in this paper using a patient-specific cerebral aneurysm model as an exemplar demonstration. The procedure for constructing the flow circuit component of the phantoms is also presented, including the design of a programmable flow pump system, the fabrication of blood mimicking fluid, and flow rate calibration. Using polyvinyl alcohol cryogel as the tissue mimicking material, phantoms developed with the presented protocol exhibited physiologically relevant acoustic properties [attenuation coefficient: 0.229±0.032 dB/( [Formula: see text]) and acoustic speed: 1535±2.4 m/s], and their pulsatile flow dynamics closely resembled the flow profile input. As a first application of our developed phantoms, the flow pattern of the patient-specific aneurysm model was visualized by performing high-frame-rate color-encoded speckle imaging over multiple time-synchronized scan planes. Persistent recirculation was observed, and the vortex center was found to shift in position over a cardiac cycle, indicating the 3-D nature of flow recirculation inside an aneurysm. These findings suggest that phantoms produced from our reported protocol can serve well as acoustically compatible test beds for vascular ultrasound studies, including 3-D flow imaging.

High Sensitivity, Wearable, Piezoresistive Pressure Sensors Based on Irregular Microhump Structures and Its Applications in Body Motion Sensing.

A pressure sensor based on irregular microhump patterns has been proposed and developed. The devices show high sensitivity and broad operating pressure regime while comparing with regular micropattern devices. Finite element analysis (FEA) is utilized to confirm the sensing mechanism and predict the performance of the pressure sensor based on the microhump structures. Silicon carbide sandpaper is employed as the mold to develop polydimethylsiloxane (PDMS) microhump patterns with various sizes. The active layer of the piezoresistive pressure sensor is developed by spin coating PEDOT: PSS on top of the patterned PDMS. The devices show an averaged sensitivity as high as 851 kPa(-1) , broad operating pressure range (20 kPa), low operating power (100 nW), and fast response speed (6.7 kHz). Owing to their flexible properties, the devices are applied to human body motion sensing and radial artery pulse. These flexible high sensitivity devices show great potential in the next generation of smart sensors for robotics, real-time health monitoring, and biomedical applications.

Naked-Eye Coulometric Sensor Using a Longitudinally Oriented Ag Band Electrode in a Microfluidic Channel.

In this Article, we report a coulometric sensing platform that is capable of sensing analytes on a working electrode and providing a visual readout of the analyte concentration on a silver (Ag) band counter electrode in a microchannel. The display mechanism relies on the electro-oxidation of metallic Ag as a complementary reaction to the sensing reduction reaction. The Ag band counter electrode is arranged longitudinally in a microchannel while the frontal tip of the band electrode directly faces a gold (Au) working electrode, which lies across the microchannel. The Ag oxidation always occurs at the band electrode's tip region that faces the working electrode due to the Ohmic potential drop across the solution in the microchannel. The decrement of the Ag electrode, which is clearly measurable with the naked eye, correlates linearly with an analyte concentration (e.g., 0.1-2.5 mM p-benzoquinone) and with an analyte feeding rate (i.e., a sample solution flow rate of 1.0-75.0 µL min(-1)). The platform design is also effective for a model analyte of horseradish peroxidase (HRP)-avidin in the dynamic range of 0.1-3.0 µg mL(-1).

Computational Fluid Dynamics Study of Bifurcation Aneurysms Treated with Pipeline Embolization Device: Side Branch Diameter Study.

An intracranial aneurysm, abnormal swelling of the cerebral artery, may lead to undesirable rates of mortality and morbidity upon rupture. Endovascular treatment involves the deployment of a flow-diverting stent that covers the aneurysm orifice, thereby reducing the blood flow into the aneurysm and mitigating the risk of rupture. In this study, computational fluid dynamics analysis is performed on a bifurcation model to investigate the change in hemodynamics with various side branch diameters. The condition after the deployment of a pipeline embolization device is also simulated. Hemodynamic factors such as flow velocity, pressure, and wall shear stress are studied. Aneurysms with a larger side branch vessel might have greater risk after treatment in terms of hemodynamics. Although a stent could lead to flow reduction entering the aneurysm, it would drastically alter the flow rate inside the side branch vessel. This may result in side-branch hypoperfusion subsequent to stenting. In addition, two patient-specific bifurcation aneurysms are tested, and the results show good agreement with the idealized models. Furthermore, the peripheral resistance of downstream vessels is investigated by varying the outlet pressure conditions. This quantitative analysis can assist in treatment planning and therapeutic decision-making.

Blood flow in intracranial aneurysms treated with Pipeline embolization devices: computational simulation and verification with Doppler ultrasonography on phantom models.

PURPOSE: The aim of this study was to validate a computational fluid dynamics (CFD) simulation of flow-diverter treatment through Doppler ultrasonography measurements in patient-specific models of intracranial bifurcation and side-wall aneurysms. METHODS: Computational and physical models of patient-specific bifurcation and sidewall aneurysms were constructed from computed tomography angiography with use of stereolithography, a three-dimensional printing technology. Flow dynamics parameters before and after flow-diverter treatment were measured with pulse-wave and color Doppler ultrasonography, and then compared with CFD simulations. RESULTS: CFD simulations showed drastic flow reduction after flow-diverter treatment in both aneurysms. The mean volume flow rate decreased by 90% and 85% for the bifurcation aneurysm and the side-wall aneurysm, respectively. Velocity contour plots from computer simulations before and after flow diversion closely resembled the patterns obtained by color Doppler ultrasonography. CONCLUSION: The CFD estimation of flow reduction in aneurysms treated with a flow-diverting stent was verified by Doppler ultrasonography in patient-specific phantom models of bifurcation and side-wall aneurysms. The combination of CFD and ultrasonography may constitute a feasible and reliable technique in studying the treatment of intracranial aneurysms with flow-diverting stents.

Rogue wave modes for a derivative nonlinear Schrödinger model.

Rogue waves in fluid dynamics and optical waveguides are unexpectedly large displacements from a background state, and occur in the nonlinear Schrödinger equation with positive linear dispersion in the regime of positive cubic nonlinearity. Rogue waves of a derivative nonlinear Schrödinger equation are calculated in this work as a long-wave limit of a breather (a pulsating mode), and can occur in the regime of negative cubic nonlinearity if a sufficiently strong self-steepening nonlinearity is also present. This critical magnitude is shown to be precisely the threshold for the onset of modulation instabilities of the background plane wave, providing a strong piece of evidence regarding the connection between a rogue wave and modulation instability. The maximum amplitude of the rogue wave is three times that of the background plane wave, a result identical to that of the Peregrine breather in the classical nonlinear Schrödinger equation model. This amplification ratio and the resulting spectral broadening arising from modulation instability correlate with recent experimental results of water waves. Numerical simulations in the regime of marginal stability are described.

Electronic conductivity of films of electroflocculated 2 nm iridium oxide nanoparticles.

The electronic conductivity of films of iridium oxide (IrO(x)) composed of ca. 2 nm nanoparticles (NPs) is strongly dependent on the film oxidation state. The Ir(IV)O(x) NPs can be electrochemically converted to several oxidation states, ranging from Ir(III) to Ir(V) oxides. The NP films exhibit a very high apparent conductivity, e.g., 10(-2) S cm(-1), when the NPs are in the oxidized +4/+5 state. When the film is fully reduced to its Ir(III) state, the apparent conductivity falls to 10(-6) S cm(-1).

A rapid low-cost high-density DNA-based multi-detection test for routine inspection of meat species.

The increasing occurrence of food frauds suggests that species identification should be part of food authentication. Current molecular-based species identification methods have their own limitations or drawbacks, such as relatively time-consuming experimental steps, expensive equipment and, in particular, these methods cannot identify mixed species in a single experiment. This project proposes an improved method involving PCR amplification of the COI gene and detection of species-specific sequences by hybridisation. Major innovative breakthrough lies in the detection of multiple species, including pork, beef, lamb, horse, cat, dog and mouse, from a mixed sample within a single experiment. The probes used are species-specific either in sole or mixed species samples. As little as 5 pg of DNA template in the PCR is detectable in the proposed method. By designing species-specific probes and adopting reverse dot blot hybridisation and flow-through hybridisation, a low-cost high-density DNA-based multi-detection test suitable for routine inspection of meat species was developed.

Head and neck squamous cell carcinoma: diagnostic performance of diffusion-weighted MR imaging for the prediction of treatment response.

PURPOSE: To determine the diagnostic performance of diffusion-weighted (DW) imaging for the prediction of treatment failure in primary head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The study was approved by the local institutional ethics committee and conducted with informed written consent in patients with primary HNSCC treated with radiation therapy and chemotherapy. DW imaging of the primary tumor was performed before treatment in 37 patients and was repeated within 2 weeks of treatment in 30 patients. Histograms of apparent diffusion coefficients (ADCs) were analyzed, and mean ADC, kurtosis, skewness, and their respective percentage change were correlated for local failure and local control at 2 years by using the Student t test. Univariate and multivariate analyses of the ADC parameters, T stage, and tumor volume were performed by using logistic regression for prediction of local failure. RESULTS: Local failure occurred in 16 of 37 (43%) patients and local control occurred in 21 of 37 (57%) patients. Pretreatment ADC parameters showed no correlation with local failure. There was significant intratreatment increase in mean ADC and a decrease in skewness and kurtosis (P < .001, P < .001, P = .024, respectively) for the whole group of patients when compared with those before treatment. During treatment, primary tumors showed a significantly lower increase in percentage change of mean ADC, higher skewness, and higher kurtosis for local failure than for local control (P = .016, .015, and .040, respectively). These ADC parameters also were significant for predicting local failure with use of univariate but not multivariate analysis. CONCLUSION: Early intratreatment DW imaging has the potential to allow prediction of treatment response at the primary site in patients with HNSCC.

Two-channel microelectrochemical bipolar electrode sensor array.

We report a two-channel microelectrochemical sensor that communicates between separate sensing and reporting microchannels via one or more bipolar electrodes (BPEs). Depending on the contents of each microchannel and the voltage applied across the BPE, faradaic reactions may be activated simultaneously in both channels. As presently configured, one end of the BPE is designated as the sensing pole and the other as the reporting pole. When the sensing pole is activated by a target, electrogenerated chemiluminescence (ECL) is emitted at the reporting pole. Compared to previously reported single-channel BPE sensors, the key advantage of the multichannel architecture reported here is physical separation of the ECL reporting cocktail and the solution containing the target. This prevents chemical interference between the two channels.

Novel fungicidal benzylsulfanyl-phenylguanidines.

A series of substituted benzylsulfanyl-phenylamines was synthesized, of which four substituted benzylsulfanyl-phenylguanidines (665, 666, 667 and 684) showed potent fungicidal activity (minimal fungicidal concentration, MFC ≤ 10 µM for Candida albicans and Candida glabrata). A benzylsulfanyl-phenyl scaffold with an unsubstituted guanidine resulted in less active compounds (MFC=50-100 µM), whereas substitution with an unsubstituted amine group resulted in compounds without fungicidal activity. Compounds 665, 666, 667 and 684 also showed activity against single C. albicans biofilms and biofilms consisting of C. albicans and Staphylococcus epidermidis (minimal concentration resulting in 50% eradication of the biofilm, BEC50 ≤ 121 µM for both biofilm setups). Compounds 665 and 666 combined potent fungicidal (MFC=5 µM) and bactericidal activity (minimal bactericidal concentration, MBC for S. epidermidis ≤ 4 µM). In an in vivo Caenorhabditis elegans model, compounds 665 and 667 exhibited less toxicity than 666 and 684. Moreover, addition of those compounds to Candida-infected C. elegans cultures resulted in increased survival of Candida-infected worms, demonstrating their in vivo efficacy in a mini-host model.

Multistable dissipative structures pinned to dual hot spots.

We analyze the formation of one-dimensional localized patterns in a nonlinear dissipative medium including a set of two narrow "hot spots" (HSs), which carry the linear gain, local potential, cubic self-interaction, and cubic loss, while the linear loss acts in the host medium. This system can be realized as a spatial-domain one in optics and also in Bose-Einstein condensates of quasiparticles in solid-state settings. Recently, exact solutions were found for localized modes pinned to the single HS represented by the δ function. The present paper reports analytical and numerical solutions for coexisting two- and multipeak modes, which may be symmetric or antisymmetric with respect to the underlying HS pair. Stability of the modes is explored through simulations of their perturbed evolution. The sign of the cubic nonlinearity plays a crucial role: in the case of the self-focusing, only the fundamental symmetric and antisymmetric modes, with two local peaks tacked to the HSs, and no additional peaks between them, may be stable. In this case, all the higher-order multipeak modes, being unstable, evolve into the fundamental ones. Stability regions for the fundamental modes are reported. A more interesting situation is found in the case of the self-defocusing cubic nonlinearity, with the HS pair giving rise to a multistability, with up to eight coexisting stable multipeak patterns, symmetric and antisymmetric ones. The system without the self-interaction, the nonlinearity being represented only by the local cubic loss, is investigated too. This case is similar to those with the self-focusing or defocusing nonlinearity, if the linear potential of the HS is, respectively, attractive or repulsive. An additional feature of the former setting is the coexistence of the stable fundamental modes with robust breathers.

Design and operation of microelectrochemical gates and integrated circuits.

Here we report a simple design philosophy, based on the principles of bipolar electrochemistry, for the operation of microelectrochemical integrated circuits. The inputs for these systems are simple voltage sources, but because they do not require much power they could be activated by chemical or biological reactions. Device output is an optical signal arising from electrogenerated chemiluminescence. Individual microelectrochemical logic gates are described first, and then multiple logic circuits are integrated into a single microfluidic channel to yield an integrated circuit that can perform parallel logic functions. AND, OR, NOR, and NAND gates are described. Eventually, systems such as those described here could provide on-chip data processing functions for lab-on-a-chip devices.

Bipolar electrodes: a useful tool for concentration, separation, and detection of analytes in microelectrochemical systems.

Over the past decade, bipolar electrochemistry has emerged from relative obscurity to provide a promising new means for integrating electrochemistry into lab-on-a-chip systems. This article describes the fundamental operating principles of bipolar electrodes, as well as several interesting applications.