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      Nerve-targeted probes for fluorescence-guided intraoperative imaging

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          Abstract

          A fundamental goal of many surgeries is nerve preservation, as inadvertent injury can lead to patient morbidity including numbness, pain, localized paralysis and incontinence. Nerve identification during surgery relies on multiple parameters including anatomy, texture, color and relationship to surrounding structures using white light illumination. We propose that fluorescent labeling of nerves can enhance the contrast between nerves and adjacent tissue during surgery which may lead to improved outcomes.

          Methods: Nerve binding peptide sequences including HNP401 were identified by phage display using selective binding to dissected nerve tissue. Peptide dye conjugates including FAM-HNP401 and structural variants were synthesized and screened for nerve binding after topical application on fresh rodent and human tissue and in-vivo after systemic IV administration into both mice and rats. Nerve to muscle contrast was quantified by measuring fluorescent intensity after topical or systemic administration of peptide dye conjugate.

          Results: Peptide dye conjugate FAM-HNP401 showed selective binding to human sural nerve with 10.9x fluorescence signal intensity (1374.44 ± 425.96) compared to a previously identified peptide FAM-NP41 (126.17 ± 61.03). FAM-HNP401 showed nerve-to-muscle contrast of 3.03 ± 0.57. FAM-HNP401 binds and highlight multiple human peripheral nerves including lower leg sural, upper arm medial antebrachial as well as autonomic nerves isolated from human prostate.

          Conclusion: Phage display has identified a novel peptide that selectively binds to ex-vivo human nerves and in-vivo using rodent models. FAM-HNP401 or an optimized variant could be translated for use in a clinical setting for intraoperative identification of human nerves to improve visualization and potentially decrease the incidence of intra-surgical nerve injury.

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          Most cited references 37

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          Indocyanine green: observations on its physical properties, plasma decay, and hepatic extraction.

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            Current concepts in neuroanatomical tracing.

            The development of new axonal tract tracing and cell labelling methods has revolutionised neurobiology in the last 30 years. The aim of this review is to consider some of the key methods of neuroanatomical tracing that are currently in use and have proved invaluable in charting the complex interconnections of the central nervous system. The review begins with a short overview of the most frequently used tracers, including enzymes, peptides, biocytin, latex beads, plant lectins and the ever-increasing number of fluorescent dyes. This is followed by a more detailed consideration of both well established and more recently introduced neuroanatomical tracing methods. Technical aspects of the application, uptake mechanisms, intracellular transport of tracers, and the problems of subsequent signal detection, are also discussed. The methods that are presented and discussed in detail include: (1) anterograde and retrograde neuroanatomical labelling with fluorescent dyes in vivo, (2) labelling of post mortem tissue, (3) developmental studies, (4) transcellular tracing (phagocytosis-dependent staining of glial cells), (5) electrophysiological mapping combined with neuronal tract tracing, and (6) simultaneous detection of more than one axonal tracer. (7) Versatile protocols for three-colour labelling have been developed to study complex patterns of connections. It is envisaged that this review will be used to guide the readers in their selection of the most appropriate techniques to apply to their own particular area of interest.
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              Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study.

              Patients with prostate cancer and their physicians need knowledge of treatment options and their potential complications, but limited data on complications are available in unselected population-based cohorts of patients. To measure changes in urinary and sexual function in men who have undergone radical prostatectomy for clinically localized prostate cancer. The Prostate Cancer Outcomes Study, a population-based longitudinal cohort study with up to 24 months of follow-up. Population-based cancer registries in 6 geographic regions of the United States. A total of 1291 black, white, and Hispanic men aged 39 to 79 years who were diagnosed as having primary prostate cancer between October 1, 1994, and October 31, 1995, and who underwent radical prostatectomy within 6 months of diagnosis for clinically localized disease. Distribution of and change in urinary and sexual function measures reported by patients at baseline and 6, 12, and 24 months after diagnosis. At 18 or more months following radical prostatectomy, 8.4% of men were incontinent and 59.9% were impotent. Among men who were potent before surgery, the proportion of men reporting impotence at 18 or more months after surgery varied according to whether the procedure was nerve sparing (65.6% of non-nerve-sparing, 58.6% of unilateral, and 56.0% of bilateral nerve-sparing). At 18 or more months after surgery, 41.9% reported that their sexual performance was a moderate-to-large problem. Both sexual and urinary function varied by age (39.0% of men aged or =18 months [P or =18 months [P = .03]), and sexual function also varied by race (38.4% of black men reported firm erections at > or =18 months vs 25.9% of Hispanic and 21.3% of white men; P = .001). Our study suggests that radical prostatectomy is associated with significant erectile dysfunction and some decline in urinary function. These results may be particularly helpful to community-based physicians and their patients with prostate cancer who face difficult treatment decisions.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2018
                30 July 2018
                : 8
                : 15
                : 4226-4237
                Affiliations
                [1 ]Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of California at San Diego, La Jolla, California, USA
                [2 ]Department of Pharmacology, University of California at San Diego, La Jolla, California, USA.
                [3 ]Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California, USA
                [4 ]Department of Urology, UC San Diego Health System, La Jolla, California, USA.
                [5 ]Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
                Author notes
                ✉ Corresponding author: Quyen T. Nguyen MD/PhD, UC San Diego MC 0647, 9500 Gilman Drive, La Jolla, CA 92093-0647. q1nguyen@ 123456ucsd.edu ; Fax: (858)534-5270

                *Authors contributed equally

                # Author is deceased

                Competing interests: Dr. Quyen T Nguyen and Dr. Michael A Whitney are founders of Alume Biosciences, Inc. which is currently licensing technology from UC San Diego.

                Article
                thnov08p4226
                10.7150/thno.23084
                6096382
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                Categories
                Research Paper

                Molecular medicine

                human nerve, fluorescence imaging, nerve targeting, translational

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