Quantification of Myelinated Nerve Fraction and Degeneration in Spinal Cord Neuropil by SHIFT MRI.

BACKGROUND: Neurodegeneration is a complex cellular process linked to prompt changes in myelin integrity and gradual neuron loss. Current imaging techniques offer estimations of myelin volumes in lesions/remyelinated areas but are limited to detect subtle injury. PURPOSE: To investigate whether measurements detected by a signal hierarchically isolated as a function of time-to-echo (SHIFT) MRI technique can determine changes in myelin integrity and fiber axolemma. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Surgically demyelinated spinal cord (SC) injury model in rodents (n = 6). FIELD STRENGTH/SEQUENCE: Gradient-echo spin-echo at 3T. ASSESSMENT: Multicompartment T2 relaxations were computed by SHIFT MRI in 75-microns-resolution images of the SC injury penumbra region 2 weeks post-trauma. G-ratio and axolemma delamination were assessed by transmission electron microscopy (TEM) in intact and injured samples. SC myelinated nerve fraction was computed by SHIFT MRI prospectively and assessed histologically. STATISTICAL TESTS: Relations between SHIFT-isolated T2 -components and TEM measurements were studied using linear regression and t-tests. Pearson's correlation and significance were computed to determine the SHIFT's sensitivity to detect myelinated fibers ratio in gray matter. Regularized least-squares-based ranking analysis was employed to determine SHIFT MRI's ability to discern intact and injured myelinated nerves. RESULTS: Biexponential signals isolated by SHIFT MRI for intact vs. lesion penumbra exhibited changes in T2 , shifting from intermediate components (25 ± 2 msec) to long (43 ± 11 msec) in white matter, and similarly in gray matter regions-of-interest (31 ± 2 to 46 ± 16 msec). These changes correlated highly with TEM g-ratio and axon delamination measurements (P < 0.05). Changes in short T2 components were observed but not statistically significant (8.5 ± 0.5 to 7 ± 3 msec, P = 0.445, and 4.0 ± 0.9 to 7 ± 3 msec, P = 0.075, respectively). SHIFT MRI's ability to detect myelinated fibers within gray matter was confirmed (P < 0.001). DATA CONCLUSION: Changes detected by SHIFT MRI are associated with abnormal intermembrane spaces formed upon mild injury, directly correlated with early neuro integrity loss. Level of Evidence 1 Technical Efficacy Stage 2.

Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer.

The microRNA (miR)-200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial-mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future.

Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

We report potent radiosensitization of prostate cancers in vitro and in vivo using goserelin-conjugated gold nanorods. Progressive receptor-mediated internalization of conjugated nanorods over time increases the radiation interaction cross-section of cells and contributes to the effects observed in vitro. The low concentrations of gold required, the long interval between injection of nanoparticles and radiation, and the use of megavoltage radiation to generate radiosensitization in vivo foretell the possibility of eventual clinical translation of this approach. FROM THE CLINICAL EDITOR: The ability of gold nanoparticles (AuNPs) to enhance the effect of physical radiation dose on tumor cells is known. This radiosensitization effect is thought to result from an increased number of photoelectric absorption events and the increased number of electrons present in gold. The authors here sought to further increase the amount and specificity of gold accumulation in prostatic cancer cells by conjugating gold nanorods to goserelin, a synthetic luteinizing hormone releasing hormone (LHRH) analogue that would bind to the LHRH receptor overexpressed in prostate cancers. It was shown that tumour cells were more sensitive to megavoltage radiation therapy. It is hoped that there would be eventual clinical translation of this approach.

A novel minimally invasive and versatile kyphoplasty balloon-based model of porcine spinal cord injury.

Introduction: Spinal cord injury (SCI) animal models often utilize an open surgical laminectomy, which results in animal morbidity and also leads to changes in spinal canal diameter, spinal cord perfusion, cerebrospinal fluid flow dynamics, and spinal stability which may confound SCI research. Moreover, the use of open surgical laminectomy for injury creation lacks realism when considering human SCI scenarios. Methods: We developed a novel, image-guided, minimally invasive, large animal model of SCI which utilizes a kyphoplasty balloon inserted into the epidural space via an interlaminar approach without the need for open surgery. Results: The model was validated in 5 Yucatán pigs with imaging, neurofunctional, histologic, and electrophysiologic findings consistent with a mild compression injury. Discussion: Few large animal models exist that have the potential to reproduce the mechanisms of spinal cord injury (SCI) commonly seen in humans, which in turn limits the relevance and applicability of SCI translational research. SCI research relies heavily on animal models, which typically involve an open surgical, dorsal laminectomy which is inherently invasive and may have untoward consequences on animal morbidity and spinal physiology that limit translational impact. We developed a minimally invasive, large animal model of spinal cord injury which utilizes a kyphoplasty balloon inserted percutaneously into the spinal epidural space. Balloon inflation results in a targeted, compressive spinal cord injury with histological and electrophysiological features directly relevant to human spinal cord injury cases without the need for invasive surgery. Balloon inflation pressure, length of time that balloon remains inflated, and speed of inflation may be modified to achieve variations in injury severity and subtype.

Quantification of Skeletal Muscle Perfusion in Peripheral Artery Disease Using 18F-Sodium Fluoride Positron Emission Tomography Imaging.

BACKGROUND: Perfusion deficits contribute to symptom severity, morbidity, and death in peripheral artery disease (PAD); however, no standard method for quantifying absolute measures of skeletal muscle perfusion exists. This study sought to preclinically test and clinically translate a positron emission tomography (PET) imaging approach using an atherosclerosis-targeted radionuclide, fluorine-18-sodium fluoride (18F-NaF), to quantify absolute perfusion in PAD. METHODS AND RESULTS: Eight Yorkshire pigs underwent unilateral femoral artery ligation and dynamic 18F-NaF PET/computed tomography imaging on the day of and 2 weeks after occlusion. Following 2-week imaging, calf muscles were harvested to quantify microvascular density. PET methodology was validated with microspheres in 4 additional pig studies and translated to patients with PAD (n=39) to quantify differences in calf perfusion across clinical symptoms/stages and perfusion responses in a case of revascularization. Associations between PET perfusion, ankle-brachial index, toe-brachial index, and toe pressure were assessed in relation to symptoms. 18F-NaF PET/computed tomography quantified significant deficits in calf perfusion in pigs following arterial occlusion and perfusion recovery 2 weeks after occlusion that coincided with increased muscle microvascular density. Additional studies confirmed that PET-derived perfusion measures agreed with microsphere-derived perfusion measures. Translation of imaging methods demonstrated significant decreases in calf perfusion with increasing severity of PAD and quantified perfusion responses to revascularization. Perfusion measures were also significantly associated with symptom severity, whereas traditional hemodynamic measures were not. CONCLUSIONS: 18F-NaF PET imaging quantifies perfusion deficits that correspond to clinical stages of PAD and represents a novel perfusion imaging strategy that could be partnered with atherosclerosis-targeted 18F-NaF PET imaging using a single radioisotope injection. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03622359.

Transplantable human motor networks as a neuron-directed strategy for spinal cord injury.

To repair neural circuitry following spinal cord injury (SCI), neural stem cell (NSC) transplantation has held a primary focus; however, stochastic outcomes generate challenges driven in part by NSC differentiation and tumor formation. The recent ability to generate regionally specific neurons and their support cells now allows consideration of directed therapeutic approaches with pre-differentiated and networked spinal neural cells. Here, we form encapsulated, transplantable neuronal networks of regionally matched cervical spinal motor neurons, interneurons, and oligodendrocyte progenitor cells derived through trunk-biased neuromesodermal progenitors. We direct neurite formation in alginate-based neural ribbons to generate electrically active, synaptically connected networks, characterized by electrophysiology and calcium imaging before transplantation into rodent models of contused SCI for evaluation at 10-day and 6-week timepoints. The in vivo analyses demonstrate viability and retention of interconnected synaptic networks that readily integrate with the host parenchyma to advance goals of transplantable neural circuitry for SCI treatment.

Nanochannel Implants for Minimally-Invasive Insertion and Intratumoral Delivery.

Novel approaches to achieve local, intratumoral drug delivery have the dual benefit of reducing systemic toxicity while enhancing efficacy for malignant cells. We have developed a new implantable system combining a next-generation BioNEMS nanofluidic membrane with parallel nanochannels that offers controlled release of biomolecules. Based on concentration-driven diffusive transport, nanochannel membranes provide a "drug agnostic" delivery mechanism. Integrating this nanotechnology within a small implantable capsule permits multipurpose functionality and compatibility with different therapeutic approaches as well as diagnostic imaging capability. A minimally-invasive, percutaneous trocar delivery mechanism enables serial implantation throughout a target tissue volume. In this manuscript, we demonstrate that this platform is capable of sustained delivery for chemotherapy, radiosensitization, immunomodulation, and imaging contrast, among others. This platform's utility was established through release of doxorubicin, OX86, FGK45, and Magnevist. Further proof-of-concept experiments demonstrated successful in vivo implantation and intratumoral release of antibodies and contrast agents, as well as the platform's MR-compatibility and capability as a radiopaque fiducial. These results provide strong evidence for a flexible, multifunctional nanofluidic implant capable of broadening local delivery utility in the clinic.

Convergence of nanotechnology with radiation therapy-insights and implications for clinical translation.

Improvements in accuracy and efficacy in treating tumors with radiation therapy (RT) over the years have been fueled by parallel technological and conceptual advances in imaging and image-guidance techniques, radiation treatment machines, computational methods, and the understanding of the biology of tumor response to RT. Recent advances in our understanding of the hallmarks of cancer and the emergence of strategies to combat these traits of cancer have resulted in an expanding repertoire of targeted therapeutics, many of which can be exploited for enhancing the efficacy of RT. Complementing this advent of new treatment options is the evolution of our knowledge of the interaction between nanoscale materials and human tissues (nanomedicine). As with the changes in RT paradigms when the field has encountered newer and maturing disciplines, the incorporation of nanotechnology innovations into radiation oncology has the potential to refine or redefine its principles and revolutionize its practice. This review provides a summary of the principles, applications, challenges and outlook for the use of metallic nanoparticles in RT.