Publications by authors named "Rajiv Chopra"

125 Publications

A capillary-based microfluidic device enables primary high-throughput room-temperature crystallographic screening.

J Appl Crystallogr 2021 Aug 14;54(Pt 4):1034-1046. Epub 2021 Jun 14.

Department of Chemical Engineering, University of Massachusetts Amherst, Amherst, MA, USA.

A novel capillary-based microfluidic strategy to accelerate the process of small-molecule-compound screening by room-temperature X-ray crystallography using protein crystals is reported. The ultra-thin microfluidic devices are composed of a UV-curable polymer, patterned by cleanroom photolithography, and have nine capillary channels per chip. The chip was designed for ease of sample manipulation, sample stability and minimal X-ray background. 3D-printed frames and cassettes conforming to SBS standards are used to house the capillary chips, providing additional mechanical stability and compatibility with automated liquid- and sample-handling robotics. These devices enable an innovative crystal-soaking screening workflow, akin to high-throughput compound screening, such that quantitative electron density maps sufficient to determine weak binding events are efficiently obtained. This work paves the way for adopting a room-temperature microfluidics-based sample delivery method at synchrotron sources to facilitate high-throughput protein-crystallography-based screening of compounds at high concentration with the aim of discovering novel binding events in an automated manner.
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http://dx.doi.org/10.1107/S1600576721004155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366422PMC
August 2021

Alternating magnetic fields and antibiotics eradicate biofilm on metal in a synergistic fashion.

NPJ Biofilms Microbiomes 2021 08 12;7(1):68. Epub 2021 Aug 12.

Department of Internal Medicine, Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Hundreds of thousands of human implant procedures require surgical revision each year due to infection. Infections are difficult to treat with conventional antibiotics due to the formation of biofilm on the implant surface. We have developed a noninvasive method to eliminate biofilm on metal implants using heat generated by intermittent alternating magnetic fields (iAMF). Here, we demonstrate that heat and antibiotics are synergistic in biofilm elimination. For Pseudomonas aeruginosa biofilm, bacterial burden was reduced >3 log with iAMF and ciprofloxacin after 24 h compared with either treatment alone (p < 0.0001). This effect was not limited by pathogen or antibiotic as similar biofilm reductions were seen with iAMF and either linezolid or ceftriaxone in Staphylococcus aureus. iAMF and antibiotic efficacy was seen across various iAMF settings, including different iAMF target temperatures, dose durations, and dosing intervals. Initial mechanistic studies revealed membrane disruption as one factor important for AMF enhanced antibacterial activity in the biofilm setting. This study demonstrates the potential of utilizing a noninvasive approach to reduce biofilm off of metallic implants.
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http://dx.doi.org/10.1038/s41522-021-00239-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360946PMC
August 2021

Probing Cerebral Metabolism with Hyperpolarized C Imaging after Opening the Blood-Brain Barrier with Focused Ultrasound.

ACS Chem Neurosci 2021 08 22;12(15):2820-2828. Epub 2021 Jul 22.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

Transient disruption of the blood-brain barrier (BBB) with focused ultrasound (FUS) is an emerging clinical method to facilitate targeted drug delivery to the brain. The focal noninvasive disruption of the BBB can be applied to promote the local delivery of hyperpolarized substrates. In this study, we investigated the effects of FUS on imaging brain metabolism using two hyperpolarized C-labeled substrates in rodents: [1-C]pyruvate and [1-C]glycerate. The BBB is a rate-limiting factor for pyruvate delivery to the brain, and glycerate minimally passes through the BBB. First, cerebral imaging with hyperpolarized [1-C]pyruvate resulted in an increase in total C signals ( = 0.05) after disrupting the BBB with FUS. Significantly higher levels of both [1-C]lactate (lactate/total C signals, = 0.01) and [C]bicarbonate ( = 0.008) were detected in the FUS-applied brain region as compared to the contralateral FUS-unaffected normal-appearing brain region. The application of FUS without opening the BBB in a separate group of rodents resulted in comparable lactate and bicarbonate productions between the FUS-applied and the contralateral brain regions. Second, C imaging with hyperpolarized [1-C]glycerate after opening the BBB showed increased [1-C]glycerate delivery to the FUS-applied region ( = 0.04) relative to the contralateral side, and [1-C]lactate production was consistently detected from the FUS-applied region. Our findings suggest that FUS accelerates the delivery of hyperpolarized molecules across the BBB and provides enhanced sensitivity to detect metabolic products in the brain; therefore, hyperpolarized C imaging with FUS may provide new opportunities to study cerebral metabolic pathways as well as various neurological pathologies.
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http://dx.doi.org/10.1021/acschemneuro.1c00197DOI Listing
August 2021

AAPM Task Group 241: A medical physicist's guide to MRI-guided focused ultrasound body systems.

Med Phys 2021 Sep 29;48(9):e772-e806. Epub 2021 Jul 29.

National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a completely non-invasive technology that has been approved by FDA to treat several diseases. This report, prepared by the American Association of Physicist in Medicine (AAPM) Task Group 241, provides background on MRgFUS technology with a focus on clinical body MRgFUS systems. The report addresses the issues of interest to the medical physics community, specific to the body MRgFUS system configuration, and provides recommendations on how to successfully implement and maintain a clinical MRgFUS program. The following sections describe the key features of typical MRgFUS systems and clinical workflow and provide key points and best practices for the medical physicist. Commonly used terms, metrics and physics are defined and sources of uncertainty that affect MRgFUS procedures are described. Finally, safety and quality assurance procedures are explained, the recommended role of the medical physicist in MRgFUS procedures is described, and regulatory requirements for planning clinical trials are detailed. Although this report is limited in scope to clinical body MRgFUS systems that are approved or currently undergoing clinical trials in the United States, much of the material presented is also applicable to systems designed for other applications.
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http://dx.doi.org/10.1002/mp.15076DOI Listing
September 2021

Pulsed Focal Ultrasound as a Non-Invasive Method to Deliver Exosomes in the Brain/Stroke.

J Biomed Nanotechnol 2021 Jun;17(6):1170-1183

Georgia Cancer Center, Augusta University, Augusta, 30912, GA.

Exosomes, a component of extracellular vesicles, are shown to carry important small RNAs, mRNAs, protein, and bioactive lipid from parent cells and are found in most biological fluids. Investigators have demonstrated the importance of mesenchymal stem cells derived exosomes in repairing stroke lesions. However, exosomes from endothelial progenitor cells have not been tested in any stroke model, nor has there been an evaluation of whether these exosomes target/home to areas of pathology. Targeted delivery of intravenous administered exosomes has been a great challenge, and a targeted delivery system is lacking to deliver naïve () exosomes from endothelial progenitor cells to the site of interest. Pulsed focused ultrasound is being used for therapeutic and experimental purposes. There has not been any report showing the use of low-intensity pulsed focused ultrasound to deliver exosomes to the site of interest in stroke models. In this proof of principle study, we have shown different parameters of pulsed focused ultrasound to deliver exosomes in the intact and stroke brain with or without intravenous administration of nanobubbles. The study results showed that administration of nanobubbles is detrimental to the brain structures (micro bleeding and white matter destruction) at peak negative pressure of >0.25 megapascal, despite enhanced delivery of intravenous administered exosomes. However, without nanobubbles, pulsed focused ultrasound enhances the delivery of exosomes in the stroke area without altering the brain structures.
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http://dx.doi.org/10.1166/jbn.2021.3091DOI Listing
June 2021

3D optical/CT as a preclinical companion imaging platform for glioblastoma drug development.

Drug Deliv 2020 Dec;27(1):1686-1694

Columbia University PET Center, Department of Radiology, Columbia University Medical Center, New York, NY, USA.

Multimodality 3D Optical Imaging (OI)/CT has the potential to play a major role in drug development for glioblastomas (GBM), as it is an accessible preclinical method. To demonstrate the potential of 3D OI/CT to visualize orthotopic GBM implantation, we labeled GBM cells with Cy7 and imaged their location using 3D OI/CT. To confirm the accuracy of the spatial localization and demonstrate the ability to image locoregionally delivered therapies, we labeled mouse albumin with Cy7 (Cy7ALB) and delivered it via locoregional infusion 1 mm or 3 mm into the brain and demonstrated correlation of signal between the 3D OI/CT and post necropsy brain slices. In addition, we demonstrated the potential of systemically delivered Cy7ALB contrast to detect blood-brain barrier (BBB) permeability caused by orthotopic GBMs using 3D OI/CT. We also tested the potential of 3D OI/CT to assess focal BBB permeability induced by high intensity focused ultrasound (HIFU), a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. We demonstrated the ability of systemic Cy7ALB contrast together with 3D OI/CT to accurately assess real-time HIFU-induced BBB permeability, which correlated to post necropsy imaging of brains. Furthermore, we demonstrated that 3D OI/CT can also image the therapeutic distribution of a Cy7-labeled anti-PD-1 antibody, a prototype translational antibody therapy. We successfully imaged real-time antibody distribution after HIFU-induced BBB permeability, which correlated with post necropsy Cy7 signal and translational PET imaging after injection of [Zr] anti-PD-1 antibody. Thus, we demonstrated the broad potential of using 3D OI/CT as an accessible preclinical tool to develop anti-GBM therapies.
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http://dx.doi.org/10.1080/10717544.2020.1833381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717859PMC
December 2020

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy.

Cancer Immunol Res 2021 01 11;9(1):34-49. Epub 2020 Nov 11.

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. IFNγ functioned by stimulating the expression of T-cell killing-related molecules in a cell type-specific manner. By assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Proper fucosylation of CD123 was required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T-cell-engaging CD3-bispecific antibody therapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601150PMC
January 2021

Consistent opening of the blood brain barrier using focused ultrasound with constant intravenous infusion of microbubble agent.

Sci Rep 2020 10 6;10(1):16546. Epub 2020 Oct 6.

Focused Ultrasound Laboratory, Department of Radiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

The blood brain barrier (BBB) is a major obstacle to the delivery of therapeutics to the brain. Focused ultrasound (FUS) in combination with microbubbles can non-invasively open the BBB in a targeted manner. Bolus intravenous injections of microbubbles are standard practice, but dynamic influx and clearance mechanisms prevent delivery of a uniform dose with time. When multiple targets are selected for sonication in a single treatment, uniform serum concentrations of microbubbles are important for consistent BBB opening. Herein, we show that bubble infusions were able to achieve consistent BBB opening at multiple target sites. FUS exposures were conducted with different Definity microbubble concentrations at various acoustic pressures. To quantify the effects of infusion on BBB opening, we calculated the MRI contrast enhancement rate. When infusions were performed at rates of 7.2 µl microbubbles/kg/min or below, we were able to obtain consistent BBB opening without injury at all pressures. However, when infusion rates exceeded 20 µl/kg/min, signs of injury occurred at pressures from 0.39 to 0.56 MPa. When compared to bolus injections, a bubble infusion offers a more controlled and consistent approach to multi-target BBB disruption.
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http://dx.doi.org/10.1038/s41598-020-73312-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538995PMC
October 2020

The effect of injected dose on localized tumor accumulation and cardiac uptake of doxorubicin in a Vx2 rabbit tumor model using MR-HIFU mild hyperthermia and thermosensitive liposomes.

Int J Hyperthermia 2020 ;37(1):1052-1059

Department of Radiology, UT Southwestern Medical Center, Dallas, TX, USA.

Purpose: When doxorubicin (DOX) is administered lyso-thermosensitive liposomes (LTLD), mild hyperthermia enhances localized delivery to heated vs. unheated tumors. The optimal LTLD dose and the impact of different doses on systemic drug distribution are unknown.

In this study, we evaluated local and systemic DOX delivery with three LTLD doses (0.1, 0.5, and 2.5 mg/kg) in a Vx2 rabbit tumor model. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the intended heating duration (40 min).

DOX concentration in tissues delivered from LTLD combined with MR-HIFU mild hyperthermia are dose-dependent, including heated/unheated tumor, heart, and other healthy organs. Higher DOX accumulation and tumor-to-heart drug concentration ratio, defined as the ratio of DOX delivered into the tumor vs the heart, were observed in heated tumors compared to unheated tumors in all three tested doses. The DOX uptake efficiency for each mg/kg of LTLD injected IV of heated tumor was significantly higher than that of unheated tumor and heart within the tested dose range (0.1-2.5 mg/kg). The DOX uptake for the heart linearly scaled up as a function of dose while that for the heated tumor showed some evidence of saturation at the high dose of 2.5 mg/kg.

These results provide guidance on clinical protocol design of hyperthermia-triggered drug delivery.
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http://dx.doi.org/10.1080/02656736.2020.1812737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727403PMC
June 2021

Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake .

Theranostics 2020 9;10(18):8143-8161. Epub 2020 Jul 9.

Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with "microbubble" ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. : To monitor the therapeutic efficacy of sonopermeation we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted along with associated vascular changes. : In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment . Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. : Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by qCEUS imaging and analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.
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http://dx.doi.org/10.7150/thno.45903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381728PMC
May 2021

Advanced MRI techniques for transcranial high intensity focused ultrasound targeting.

Brain 2020 09;143(9):2664-2672

Department of Radiology, University of Texas Southwestern, Dallas, TX 75390, USA.

Magnetic resonance guided high intensity focused ultrasound is a novel, non-invasive, image-guided procedure that is able to ablate intracranial tissue with submillimetre precision. It is currently FDA approved for essential tremor and tremor dominant Parkinson's disease. The aim of this update is to review the limitations of current landmark-based targeting techniques of the ventral intermediate nucleus and demonstrate the role of emerging imaging techniques that are relevant for both magnetic resonance guided high intensity focused ultrasound and deep brain stimulation. A significant limitation of standard MRI sequences is that the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei cannot be clearly identified. This paper provides original, annotated images demarcating the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei on advanced MRI sequences such as fast grey matter acquisition T1 inversion recovery, quantitative susceptibility mapping, susceptibility weighted imaging, and diffusion tensor imaging tractography. Additionally, the paper reviews clinical efficacy of targeting with these novel MRI techniques when compared to current established landmark-based targeting techniques. The paper has widespread applicability to both deep brain stimulation and magnetic resonance guided high intensity focused ultrasound.
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http://dx.doi.org/10.1093/brain/awaa107DOI Listing
September 2020

Quantifying differences in femoral head and neck asphericity in CAM type femoroacetabular impingement and hip dysplasia versus controls using radial 3DCT imaging and volumetric segmentation.

Br J Radiol 2020 Jun 18;93(1110):20190039. Epub 2020 Mar 18.

Radiology Department, UT Southwestern Medical Center, Dallas, Texas, USA.

Objective: Femoroacetabular impingement (FAI) and hip dysplasia are the most common causes of groin pain originating from the hip joint. To date, there is controversy over cut-off values for the evaluation of abnormal femoral head-neck anatomy with significant overlap between the normal and abnormal hips. Our aim was to perform three-dimensional CT analysis of femoral head and bump anatomy to quantify common hip pathologies (FAI and hip dysplasia) controls.

Methods: Consecutive patients who underwent three-dimensional CT imaging for hip dysplasia or CAM type FAI were compared to asymptomatic controls. α angles on radial CT and 3D volumetric femoral head and bump segmentations were performed by two readers. Inter- and intrapatient comparisons were performed including interreader and receiver operating characteristic analyses.

Results: 25 FAI patients, 16 hip dysplasia patients and 38 controls were included. FAI and dysplasia patients exhibited higher α angles and higher bump-head volume ratios than the controls ( < 0.05). Larger bump volumes were found among FAI than dysplasia patients and contralateral hips of FAI patients were also different than the controls. α angle at 2 o'clock and bump to head ratio showed the highest area under the curve for patients controls. The interreader reliability was better for volumetric segmentation (intraclass correlation coefficient = 0.35-0.84) as compared to the α angles (intraclass correlation coefficient = 0.11-0.44).

Conclusion: Patients with FAI and dysplasia exhibit different femoral head anatomy than asymptomatic controls. Volumetric segmentation of femoral head and bump is more reliable and better demonstrates the bilateral femoral head anatomy differences in hip patients controls.

Advances In Knowledge: Utilizing information from 3D volumetric bump assessment in patients with FAI and dysplasia, the physicians may be able to more objectively and reliably evaluate the altered anatomy for better pre-surgical evaluation.
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http://dx.doi.org/10.1259/bjr.20190039DOI Listing
June 2020

The effect of transcranial focused ultrasound target location on the acoustic feedback control performance during blood-brain barrier opening with nanobubbles.

Sci Rep 2019 12 27;9(1):20020. Epub 2019 Dec 27.

Department of Radiology, UT Southwestern Medical Center, Dallas, TX, USA.

Real-time acoustic feedback control based on harmonic emissions of stimulated microbubbles may be important for facilitating the clinical adoption of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening, both to ensure safe acoustic exposures, and to achieve repeatable and consistent opening. Previously our group demonstrated that successful BBB opening was achievable with both commercially available microbubbles and custom-made nanobubbles under acoustic feedback control. In a recent study, we demonstrated the acoustic control performance was not sensitive to the nanobubble concentration within 10-10 bubbles/ml. The goal of this study was to examine the effect of the ultrasound target location in the rat brain on the acoustic control quality during BBB opening with nanobubbles. Temporal analysis of the received acoustic signals during each ultrasound pulse indicated that stable nanobubble oscillation was present throughout the entire 10 ms ultrasound exposure. The acoustic feedback control signals were very sensitive to the brain spatial location in rats. There appears to be a shared pattern of acoustic control stability in the brain across different animals, suggesting anatomical features are an underlying cause. The findings emphasize the importance of tuning acoustic feedback control algorithms for specific rodent brain regions of interest to ensure optimal performance.
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http://dx.doi.org/10.1038/s41598-019-55629-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934715PMC
December 2019

Breath-hold MR-HIFU hyperthermia: phantom and feasibility.

Int J Hyperthermia 2019 ;36(1):1084-1097

Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

The use of magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) to deliver mild hyperthermia requires stable temperature mapping for long durations. This study evaluates the effects of respiratory motion on MR thermometry precision in pediatric subjects and determines the feasibility of circumventing breathing-related motion artifacts by delivering MR thermometry-controlled HIFU mild hyperthermia during repeated forced breath holds. Clinical and preclinical studies were conducted. Clinical studies were conducted without breath-holds. In phantoms, breathing motion was simulated by moving an aluminum block towards the phantom along a sinusoidal trajectory using an MR-compatible motion platform. experiments were performed in ventilated pigs. MR thermometry accuracy and stability were evaluated. Clinical data confirmed acceptable MR thermometry accuracy (0.12-0.44 °C) in extremity tumors, but not in the tumors in the chest/spine and pelvis. In phantom studies, MR thermometry accuracy and stability improved to 0.37 ± 0.08 and 0.55 ± 0.18 °C during simulated breath-holds. MR thermometry accuracy and stability in porcine back muscle improved to 0.64 ± 0.22 and 0.71 ± 0.25 °C during breath-holds. MR-HIFU hyperthermia delivered during intermittent forced breath holds over 10 min duration heated an 18-mm diameter target region above 41 °C for 10.0 ± 1.0 min, without significant overheating. For a 10-min mild hyperthermia treatment, an optimal treatment effect (TIR > 9 min) could be achieved when combining 36-60 s periods of forced apnea with 60-155.5 s free-breathing. MR-HIFU delivery during forced breath holds enables stable control of mild hyperthermia in targets adjacent to moving anatomical structures.
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http://dx.doi.org/10.1080/02656736.2019.1679893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873809PMC
April 2020

Influence of Nanobubble Concentration on Blood-Brain Barrier Opening Using Focused Ultrasound Under Real-Time Acoustic Feedback Control.

Ultrasound Med Biol 2019 08 7;45(8):2174-2187. Epub 2019 May 7.

Department of Radiology, UT Southwestern Medical Center, Dallas, TX, USA; Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA.

Real-time acoustic feedback control based on harmonic emissions of stimulated microbubbles may serve as a way to achieve reliable blood-brain barrier (BBB) opening with focused ultrasound in the brain. Previously, we demonstrated BBB opening was possible using sub-micron bubbles (aka nanobubbles) and produced comparable results to commercially available microbubbles (Optison, Definity, etc.). The harmonic emissions and acoustic control were observed to be more consistent using nanobubbles, which warrants further study of BBB opening using these agents. This study examined the stimulated acoustic emissions of nanobubbles at different concentrations both in vitro and in vivo and evaluated BBB opening under real-time acoustic feedback control across concentrations. Original nanobubbles (10 bubbles/mL) have long in vitro persistence (7.3 ± 3.3 min) and circulation time in rats (approximately 10 min) under exposures in this study, and both degraded with dilutions. With all three tested dilutions (1:1, 1:10 and 1:100), successful BBB opening was reliably achieved under real-time feedback control.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2019.03.016DOI Listing
August 2019

Cam-type femoroacetabular impingement-correlations between alpha angle versus volumetric measurements and surgical findings.

Eur Radiol 2019 Jul 11;29(7):3431-3440. Epub 2019 Feb 11.

Department of Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Aim: Determine correlations of 3DCT cam-type femoroacetabular impingement (FAI) measurements with surgical findings of labral tear and cartilage loss.

Methods: Digital search of symptomatic cam-type FAI from July 2013 to August 2016 yielded 43 patients. Two readers calculated volumes of femoral head, bump, and alpha angles on 3DCT images. Correlations between CT and surgical findings, inter-, and intra-reader reliabilities were assessed using Spearman rank correlation and intraclass correlation coefficients (ICC).

Results: Thirteen men and 14 women aged 37 ± 10 (mean ± SD) years were included. Most common clinical finding was positive flexion-adduction-internal rotation (70.4%). Twenty-seven labral tears and 20 cartilage defects were surgically detected. Significant correlations existed between femoral bump, head volumes, and extent of the labral tear (p = 0.008 and 0.003). No significant correlations were found between the alpha angles at 12 to 3 o'clock and the extent of labral tear (p = 0.2, 0.8, 0.9, and 0.09) or any measurement with the cartilage loss (p values for alpha 12 to 3, bump, and head volumes = 0.7, 0.3, 0.9, 0.9, 0.07, and 0.2). Inter- and intra-reader reliabilities were excellent to moderate for femoral head and bump volumes (ICC = 0.85, 0.52, and 0.8, 0.5) and moderate to poor for alpha angles (ICC = 0.48, 0.40, 0.05, 0.25 and 0.3, 0.24, 0.29, 0.49).

Conclusion: Three dimensional volumetric measurements of cam-type FAI significantly correlate with the extent of intraoperative labral tears. Superior inter- and intra-reader reliability to that of alpha angles renders it a more clinically relevant measurement for quantifying cam morphology.

Key Points: • The 3DCT bump volume and femoral head volume showed significant correlations with the extent of labral tear (p values = 0.008 and 0.003). • No significant correlations were seen between alpha angles and the extent of labral tear (p values > 0.05). • Inter- and intra-reader reliability was excellent to moderate (ICC = 0.85 and 0.52, 0.8, and 0.5) for femoral head and bump volumes while inter- and intra-reader reliability was fair to poor (ICC = 0.48, 0.40, 0.05, 0.25 and 0.3, 0.24, 0.29, 0.49) for alpha angles.
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http://dx.doi.org/10.1007/s00330-018-5968-zDOI Listing
July 2019

Longer heating duration increases localized doxorubicin deposition and therapeutic index in Vx2 tumors using MR-HIFU mild hyperthermia and thermosensitive liposomal doxorubicin.

Int J Hyperthermia 2019 12;36(1):196-203. Epub 2018 Dec 12.

a Department of Radiology , UT Southwestern Medical Center , Dallas , TX , USA.

Thermosensitive liposomal doxorubicin (LTSL-Dox) combined with mild hyperthermia enhances the localized delivery of doxorubicin (Dox) within a heated region. The optimal heating duration and the impact of extended heating on systemic drug distribution are unknown. Here we evaluated local and systemic Dox delivery with two different mild hyperthermia durations (42 °C for 10 or 40 minutes) in a Vx2 rabbit tumor model. We hypothesized that longer duration of hyperthermia would increase Dox concentration in heated tumors without increasing systemic exposure. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the prescribed heating durations. Forty-minutes of heating resulted in a nearly 6-fold increase in doxorubicin concentration in heated vs unheated tumors in the same animals. Therapeutic ratio, defined as the ratio of Dox delivered into the heated tumor vs the heart, increased from 1.9-fold with 10 minutes heating to 4.4-fold with 40 minutes heating. MR-HIFU can be used to guide, deliver and monitor mild hyperthermia of a Vx2 tumor model in a rabbit model, and an increased duration of heating leads to higher Dox deposition from LTSL-Dox in a target tumor without a concomitant increase in systemic exposure. Results from this preclinical study can be used to help establish clinical treatment protocols for hyperthermia mediated drug delivery.
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http://dx.doi.org/10.1080/02656736.2018.1550815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430695PMC
January 2020

The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models.

Oncotarget 2018 Oct 16;9(81):35226-35240. Epub 2018 Oct 16.

Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, MA, USA.

Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is associated with robust antitumor activity. Ribociclib (LEE011) is an orally bioavailable CDK4/6 inhibitor that is approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, in combination with an aromatase inhibitor, and is currently being evaluated in several additional trials. Here, we report the preclinical profile of ribociclib. When tested across a large panel of kinase active site binding assays, ribociclib and palbociclib were highly selective for CDK4, while abemaciclib showed affinity to several other kinases. Both ribociclib and abemaciclib showed slightly higher potency in -dependent cells than in -dependent cells, while palbociclib did not show such a difference. Profiling CDK4/6 inhibitors in large-scale cancer cell line screens confirmed that loss of function is a negative predictor of sensitivity. We also found that routinely used cellular viability assays measuring adenosine triphosphate levels as a proxy for cell numbers underestimated the effects of CDK4/6 inhibition, which contrasts with assays that assess cell number more directly. Robust antitumor efficacy and combination benefit was detected when ribociclib was added to encorafenib, nazartinib, or endocrine therapies in patient-derived xenografts.
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http://dx.doi.org/10.18632/oncotarget.26215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219668PMC
October 2018

Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition.

Nat Commun 2018 10 30;9(1):4508. Epub 2018 Oct 30.

Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.

Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099. SHP2 adopts an open conformation but can be restored to the closed, autoinhibited conformation, near-identical to the unoccupied wild-type enzyme, when complexed with SHP099. SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer.
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http://dx.doi.org/10.1038/s41467-018-06823-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207684PMC
October 2018

Author Correction: Acylated-acyl carrier protein stabilizes the Pseudomonas aeruginosa WaaP lipopolysaccharide heptose kinase.

Sci Rep 2018 Oct 23;8(1):15907. Epub 2018 Oct 23.

Infectious Diseases, Novartis Institutes for Biomedical Research, Emeryville, CA, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-34070-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198010PMC
October 2018

Acylated-acyl carrier protein stabilizes the Pseudomonas aeruginosa WaaP lipopolysaccharide heptose kinase.

Sci Rep 2018 09 20;8(1):14124. Epub 2018 Sep 20.

Infectious Diseases, Novartis Institutes for Biomedical Research, Emeryville, CA, USA.

Phosphorylation of Pseudomonas aeruginosa lipopolysaccharide (LPS) is important for maintaining outer membrane integrity and intrinsic antibiotic resistance. We solved the crystal structure of the LPS heptose kinase WaaP, which is essential for growth of P. aeruginosa. WaaP was structurally similar to eukaryotic protein kinases and, intriguingly, was complexed with acylated-acyl carrier protein (acyl-ACP). WaaP produced by in vitro transcription-translation was insoluble unless acyl-ACP was present. WaaP variants designed to perturb the acyl-ACP interaction were less stable in cells and exhibited reduced kinase function. Mass spectrometry identified myristyl-ACP as the likely physiological binding partner for WaaP in P. aeruginosa. Together, these results demonstrate that acyl-ACP is required for WaaP protein solubility and kinase function. To the best of our knowledge, this is the first report describing acyl-ACP in the role of a cofactor necessary for the production and stability of a protein partner.
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http://dx.doi.org/10.1038/s41598-018-32379-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147952PMC
September 2018

3D CT segmentation of CAM type femoroacetabular impingement-reliability and relationship of CAM lesion with anthropomorphic features.

Br J Radiol 2018 Dec 12;91(1092):20180371. Epub 2018 Sep 12.

1 Department of Radiology, University of Texas Southwestern Medical Center , Dallas, TX , USA.

Objective:: Evaluate feasibility and reliability of 3DCT semi-automatic segmentation and volumetrics of CAM lesions in femoroacetabular impingement and determine correlations with anthropometrics.

Methods:: A consecutive series of 43 patients with CAM type FAI underwent 3DCT. 20 males and 23 females (30 unilateral and 13 bilateral symptomatic hips) were included. 56 CAM lesions and femoral heads were segmented by two readers. Radial images were obtained for alpha angles. Pearson and ICC correlations were used for analysis.

Results:: In 43 patients (male: female = 1 : 1.15), mean ± SD of age, height, BMI were 36.6 ± 11.47 years, 1.72 ± 0.10 meters and 26.25 ± 4.31  kg m². Femoral head and bumps were segmented in 4  min. Inter reader reliability was good to excellent for volumetrics and poor for alpha angles. Mean ± SD of CAM lesion and femoral head volumes were significantly larger (6.7 ± 2.5 cc and 62.9 ± 10.8 cc) for males than females (p < 0.001) and these increased with increasing patient height (Pearson correlation and p-values = 0.45, 0.0006; 0.82, < 0.0001 respectively).

Conclusion:: Volumetric analysis of CAM lesion shows better inter reader reliability than alpha angle measurements. CAM and femoral head volumes exhibit significant positive correlations with patient heights and male gender that may aid in pre-operative planning for femoroplasty.

Advances In Knowledge:: Femoral head & CAM volumes are segmented three times faster than alpha angles with superior inter reader reliability than alpha angles. Femoral head & CAM volumes are significantly larger in males and positively correlate with patients' heights.
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http://dx.doi.org/10.1259/bjr.20180371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319838PMC
December 2018

Multiparametric MRI Characterization of Funaki Types of Uterine Fibroids Considered for MR-Guided High-Intensity Focused Ultrasound (MR-HIFU) Therapy.

Acad Radiol 2019 04 29;26(4):e9-e17. Epub 2018 Jul 29.

UT Southwestern Medical Center, Dallas, Texas.

Rationale And Objectives: To compare quantitative multiparametric magnetic resonance imaging (mpMRI) data of symptomatic uterine fibroids being considered for MR-guided high-intensity focused ultrasound ablation with fibroid characterization based on the Funaki Classification scheme.

Materials And Methods: This was a prospective, Institutional Review Board -approved, Health Insurance Portability, and Accountability Act-compliant study. Informed consent was obtained. From December 2013 to April 2015, 48 women with symptomatic fibroids underwent screening with mpMRI protocol including sagittal/axial T2-weighted fast spin-echo, sagittal diffusion-weighted, and sagittal dynamic contrast-enhanced 3D T1-weighted gradient echo imaging on a 3T magnet. All fibroids were assigned Funaki type 1, 2, or 3 based on T2-weighted imaging. Differences in size, perfusion, and diffusion/intravoxel incoherent motion parameters among the three Funaki types were determined using linear mixed model. A logistic regression analysis was performed to select the best model in predicting type 3 fibroids.

Results: A total of 100 fibroids were assessed (20 type 1, 66 type 2, and 14 type 3). Apparent diffusion coefficient and D of type 3 fibroids were significantly higher than those of type 1 (P < 0.0001, P < 0.0001) and 2 fibroids (P = 0.004, P < 0.0001) respectively. Transfer constant of type 3 fibroids was significantly higher than type 1 (P = 0.0357), but not than type 2 (P = 0.0752). A cutoff value of D = 1 × 10 mm/s offers an accuracy, sensitivity, and specificity of 76%, 71%, and 77%, respectively, for the diagnosis of Funaki 3 fibroids.

Conclusion: mpMRI-derived quantitative parameters may enable a more objective selection of patients prior to MR-guided high-intensity focused ultrasound therapy.
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http://dx.doi.org/10.1016/j.acra.2018.05.012DOI Listing
April 2019

Characterization of different bubble formulations for blood-brain barrier opening using a focused ultrasound system with acoustic feedback control.

Sci Rep 2018 05 22;8(1):7986. Epub 2018 May 22.

Department of Radiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

Focused ultrasound combined with bubble-based agents serves as a non-invasive way to open the blood-brain barrier (BBB). Passive acoustic detection was well studied recently to monitor the acoustic emissions induced by the bubbles under ultrasound energy, but the ability to perform reliable BBB opening with a real-time feedback control algorithm has not been fully evaluated. This study focuses on characterizing the acoustic emissions of different types of bubbles: Optison, Definity, and a custom-made nanobubble. Their performance on reliable BBB opening under real-time feedback control based on acoustic detection was evaluated both in-vitro and in-vivo. The experiments were conducted using a 0.5 MHz focused ultrasound transducer with in-vivo focal pressure ranges from 0.1-0.7 MPa. Successful feedback control was achieved with all three agents when combining with infusion injection. Localized opening was confirmed with Evans blue dye leakage. Microscopic images were acquired to review the opening effects. Under similar total gas volume, nanobubble showed a more reliable opening effect compared to Optison and Definity (p < 0.05). The conclusions obtained from this study confirm the possibilities of performing stable opening using a feedback control algorithm combined with infusion injection. It also opens another potential research area of BBB opening using sub-micron bubbles.
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http://dx.doi.org/10.1038/s41598-018-26330-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964106PMC
May 2018

Remote acoustic sensing as a safety mechanism during exposure of metal implants to alternating magnetic fields.

PLoS One 2018 10;13(5):e0197380. Epub 2018 May 10.

Department of Radiology, UT Southwestern Medical Center, Dallas TX, United States of America.

Treatment of prosthetic joint infections often involves multiple surgeries and prolonged antibiotic administration, resulting in a significant burden to patients and the healthcare system. We are exploring a non-invasive method to eradicate biofilm on metal implants utilizing high-frequency alternating magnetic fields (AMF) which can achieve surface induction heating. Although proof-of-concept studies demonstrate the ability of AMF to eradicate biofilm in vitro, there is a legitimate safety concern related to the potential for thermal damage to surrounding tissues when considering heating implanted metal objects. The goal of this study was to explore the feasibility of detecting acoustic emissions associated with boiling at the interface between a metal implant and surrounding soft tissue as a wireless safety sensing mechanism. Acoustic emissions generated during in vitro and in vivo AMF exposures were captured with a hydrophone, and the relationship with surface temperature analyzed. The effect of AMF exposure power, surrounding media composition, implant location within the AMF transmitter, and implant geometry on acoustic detection during AMF therapy was also evaluated. Acoustic emissions were reliably identified in both tissue-mimicking phantom and mouse studies, and their onset coincided with the implant temperature reaching the boiling threshold. The viscosity of the surrounding medium did not impact the production of acoustic emissions; however, emissions were not present when the medium was oil due to the higher boiling point. Results of simulations and in vivo studies suggest that short-duration, high-power AMF exposures combined with acoustic sensing can be used to minimize the amount of thermal damage in surrounding tissues. These studies support the hypothesis that detection of boiling associated acoustic emissions at a metal/tissue interface could serve as a real-time, wireless safety indicator during AMF treatment of biofilm on metallic implants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944992PMC
December 2018

Correcting B Field Distortions in MRI Caused by Stainless Steel Orthodontic Appliances at 1.5 T Using Permanent Magnets - A Head Phantom Study.

Sci Rep 2018 04 9;8(1):5706. Epub 2018 Apr 9.

Department of Radiology, Children's Health, Dallas, Texas, USA.

Susceptibility artifacts caused by stainless steel orthodontic appliances (braces) pose significant challenges in clinical brain MRI examinations. We introduced field correction device (FCD) utilizing permanent magnets to cancel the induced B inhomogeneity and mitigate geometric distortions in MRI. We evaluated a prototype FCD using a 3D-printed head phantom in this proof of concept study. The phantom was compartmented into anterior frontal lobe, temporal lobe, fronto-parieto-occipital lobe, basal ganglia and thalami, brain stem, and cerebellum and had built-in orthogonal gridlines to facilitate the quantification of geometric distortions and volume obliterations. Stainless steel braces were mounted on dental models of three different sizes with total induced magnetic moment 0.15 to 0.17 A·m. With braces B standard deviation (SD) ranged from 2.8 to 3.7 ppm in the temporal and anterior frontal lobes vs. 0.2 to 0.3 ppm without braces. The volume of brain regions in diffusion weighted imaging was obliterated by 32-38% with braces vs. 0% without braces in the cerebellum. With the FCD the SD of B ranged from 0.3 to 1.2 ppm, and obliterated volume ranged from 0 to 6% in the corresponding brain areas. These results showed that FCD can effectively decrease susceptibility artifacts from orthodontic appliances.
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http://dx.doi.org/10.1038/s41598-018-23890-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890254PMC
April 2018

Introduction to the special issue on thermal therapy and infectious diseases.

Int J Hyperthermia 2018 03;34(2):133-134

d Microbiology and Immunology , University of Arkansas for Medical Sciences , Little Rock , AR , USA.

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http://dx.doi.org/10.1080/02656736.2018.1424947DOI Listing
March 2018

Temperature-sensitive liposomal ciprofloxacin for the treatment of biofilm on infected metal implants using alternating magnetic fields.

Int J Hyperthermia 2018 03;34(2):189-200

a Department of Radiology , University of Texas Southwestern Medical Center , Dallas , TX , USA.

Implants are commonly used as a replacement for damaged tissue. Many implants, such as pacemakers, chronic electrode implants, bone screws, and prosthetic joints, are made of or contain metal. Infections are one of the difficult to treat complications associated with metal implants due to the formation of biofilm, a thick aggregate of extracellular polymeric substances (EPS) produced by the bacteria. In this study, we treated a metal prosthesis infection model using a combination of ciprofloxacin-loaded temperature-sensitive liposomes (TSL) and alternating magnetic fields (AMF). AMF heating is used to disrupt the biofilm and release the ciprofloxacin-loaded TSL. The three main objectives of this study were to (1) investigate low- and high-temperature-sensitive liposomes (LTSLs and HTSLs) containing the antimicrobial agent ciprofloxacin for temperature-mediated antibiotic release, (2) characterise in vitro ciprofloxacin release and stability and (3) study the efficacy of combining liposomal ciprofloxacin with AMF against Pseudomonas aeruginosa biofilms grown on metal washers. The release of ciprofloxacin from LTSL and HTSL was assessed in physiological buffers. Results demonstrated a lower transition temperature for both LTSL and HTSL formulations when incubated in serum as compared with PBS, with a more pronounced impact on the HTSLs. Upon combining AMF with temperature-sensitive liposomal ciprofloxacin, a 3 log reduction in CFU of Pseudomonas aeruginosa in biofilm was observed. Our initial studies suggest that AMF exposure on metal implants can trigger release of antibiotic from temperature sensitive liposomes for a potent bactericidal effect on biofilm.
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http://dx.doi.org/10.1080/02656736.2017.1422028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034688PMC
March 2018

Prototype volumetric ultrasound tomography image guidance system for prone stereotactic partial breast irradiation: proof-of-concept.

Phys Med Biol 2018 03 1;63(5):055004. Epub 2018 Mar 1.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. Tsuicheng Chiu and David Parsons contributed equally to this study.

Accurate dose delivery in stereotactic partial breast irradiation (S-PBI) is challenging because of the target position uncertainty caused by breast deformation, the target volume changes caused by lumpectomy cavity shrinkage, and the target delineation uncertainty on simulation computed tomography (CT) images caused by poor soft tissue contrast. We have developed a volumetric ultrasound tomography (UST) image guidance system for prone position S-PBI. The system is composed of a novel 3D printed rotation water tank, a patient-specific resin breast immobilization cup, and a 1D array ultrasound transducer. Coronal 2D US images were acquired in 5° increments over a 360° range, and planes were acquired every 2 mm in elevation. A super-compounding technique was used to reconstruct the image volume. The image quality of UST was evaluated with a BB-1 breast phantom and BioZorb surgical marker, and the results revealed that UST offered better soft tissue contrast than CT and similar image quality to MR. In the evaluated plane, the size and location of five embedded objects were measured and compared to MR, which is considered as the ground truth. Objects' diameters and the distances between objects in UST differ by approximately 1 to 2 mm from those in MR, which showed that UST offers the image quality required for S-PBI. In future work we will develop a robotic system that will be ultimately implemented in the clinic.
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http://dx.doi.org/10.1088/1361-6560/aaad1fDOI Listing
March 2018
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