Discovery of Truncated Cyclic Peptides Targeting an Induced-Fit Pocket on PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDL-R) degradation. We previously identified and optimized 13-mer cyclic peptides that bind to a novel, induced-fit pocket adjacent to the binding interface of PCSK9 and LDL-R and effectively disrupted the PCSK9/LDL-R protein-protein interaction (PPI) both in vitro and in vivo. However this series of large cyclic peptides required charged groups for function and lacked oral bioavailability in rodents.

Alternating magnetic fields (AMF) and linezolid reduce Staphylococcus aureus biofilm in a large animal implant model.

Objectives: We aimed to evaluate the effectiveness of alternating magnetic fields (AMF) combined with antibiotics in reducing Staphylococcus aureus biofilm on metal implants in a large animal model, compared to antibiotics alone.

Methods: Metal plates were inoculated with a clinical MRSA strain and then implanted into thirty-three ewes divided into three groups: positive control, linezolid only, and a combination of linezolid and AMF. Animals had either titanium or cobalt-chrome plates and were sacrificed at 5 or 21 days post-implantation.

Intermittent alternating magnetic fields diminish metal-associated biofilm in vivo.

Prosthetic joint infection (PJI) is a complication of arthroplasty that results in significant morbidity. The presence of biofilm makes treatment difficult, and removal of the prosthesis is frequently required. We have developed a non-invasive approach for biofilm eradication from metal implants using intermittent alternating magnetic fields (iAMF) to generate targeted heating at the implant surface.

Improving tremor response to focused ultrasound thalamotomy.

MRI-guided high-intensity focused ultrasound thalamotomy is an incisionless therapy for essential tremor. To reduce adverse effects, the field has migrated to treating at 2 mm above the anterior commissure-posterior commissure plane. We perform MRI-guided high-intensity focused ultrasound with an advanced imaging targeting technique, four-tract tractography.

Focused ultrasound using a novel targeting method four-tract tractography for magnetic resonance-guided high-intensity focused ultrasound targeting.

Magnetic resonance-guided high-intensity focused ultrasound thalamotomy is a Food and Drug Administration-approved treatment for essential tremor. The target, the ventral intermediate nucleus of the thalamus, is not visualized on standard, anatomic MRI sequences. Several recent reports have used diffusion tensor imaging to target the dentato-rubro-thalamic-tract.

Physical Approaches to Prevent and Treat Bacterial Biofilm.

Prosthetic joint infection (PJI) presents several clinical challenges. This is in large part due to the formation of biofilm which can make infection eradication exceedingly difficult. Following an extensive literature search, this review surveys a variety of non-pharmacological methods of preventing and/or treating biofilm within the body and how they could be utilized in the treatment of PJI.

Quantifying the relationship between biofilm reduction and thermal tissue damage on metal implants exposed to alternating magnetic fields.

Aim: Metal implant infections are a devastating problem due to the formation of biofilm which impairs the effectiveness of antibiotics and leads to surgical replacement as definitive treatment. Biofilm on metal implants can be reduced using heat generated by alternating magnetic fields (AMF). In this study, the relationship between implant surface biofilm reduction and surrounding tissue thermal damage during AMF exposure is investigated through numerical simulations.

Feasibility of heating metal implants with alternating magnetic fields (AMF) in scaled up models.

Treatment of infected orthopedic implants remains a major medical challenge, involving prolonged antibiotic therapy and revision surgery, and adding a >$1 billion annual burden to the health care system in the US alone. Exposure of metallic implants to alternating magnetic fields (AMF) generates heat that can provide a noninvasive means to target biofilm adhered to the surface. In this study, an AMF system with a solenoid coil was constructed for targeting a metal plate surgically implanted in a sheep model.

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy.

Krabbe Disease (KD) is an autosomal metabolic disorder that affects both the central and peripheral nervous systems. It is caused by a functional deficiency of the lysosomal enzyme, galactocerebrosidase (GALC), resulting in an accumulation of the toxic metabolite, psychosine. Psychosine accumulation affects many different cellular pathways, leading to severe demyelination.

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

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.

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

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).

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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.

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.

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

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.

Advanced MRI techniques for transcranial high intensity focused ultrasound targeting.

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.

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

[This corrects the article DOI: 10.18632/oncotarget.26215.

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.

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.

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

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.

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

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.

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

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.).