Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

In vitro and in vivo release of nerve growth factor from biodegradable poly-lactic-co-glycolic-acid microspheres

Regeneration of peripheral nerves after injury is suboptimal. We now report the long term delivery of nerve growth factor (NGF) by biodegradable poly-lactic-co-glycolic acid (PLGA) microspheres in vitro and in vivo. Lactic to glycolic acid ratios of 50:50 and 85:15 were fabricated using the double emulsion solvent, evaporation technique. Three different inherent viscosities (0.1 dL g(-1):1A 0.4 dL g(-1):4A, 0.7 dL g(-1):7A) were analyzed. In vitro, release of NGF for 23 days was measured. Electron microscopy demonstrated intact spheres for at least 7 days (50:50 1A), 14 days (50:50 4A), or 35 days (50:50 7A and 85:15 7A). In vitro release kinetics was characterized by burst release, followed by release of NGF at a rate of 0.6-1.6% a day. Release curves for 50:50 1A and 85:15 7A differed significantly from other compositions (p < 0.01). In vivo, release was characterized by a novel radionuclide tracking assay. Release rates varied from 0.9 to 2.2% per day with linear kinetics. All but the 85:15 type of spheres showed different release profiles in vivo compared to in vitro conditions. On the basis of the surface morphology and release profiles, we found microspheres fabricated from 50:50 4A PLGA to be best suited for the use in a rat sciatic nerve injury model. (C) 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 95A: 1067-1073,2010

In vitro and in vivo release of nerve growth factor from biodegradable poly-lactic-co-glycolic-acid microspheres

Regeneration of peripheral nerves after injury is suboptimal. We now report the long term delivery of nerve growth factor (NGF) by biodegradable poly-lactic-co-glycolic acid (PLGA) microspheres in vitro and in vivo. Lactic to glycolic acid ratios of 50:50 and 85:15 were fabricated using the double emulsion solvent, evaporation technique. Three different inherent viscosities (0.1 dL g(-1):1A 0.4 dL g(-1):4A, 0.7 dL g(-1):7A) were analyzed. In vitro, release of NGF for 23 days was measured. Electron microscopy demonstrated intact spheres for at least 7 days (50:50 1A), 14 days (50:50 4A), or 35 days (50:50 7A and 85:15 7A). In vitro release kinetics was characterized by burst release, followed by release of NGF at a rate of 0.6-1.6% a day. Release curves for 50:50 1A and 85:15 7A differed significantly from other compositions (p < 0.01). In vivo, release was characterized by a novel radionuclide tracking assay. Release rates varied from 0.9 to 2.2% per day with linear kinetics. All but the 85:15 type of spheres showed different release profiles in vivo compared to in vitro conditions. On the basis of the surface morphology and release profiles, we found microspheres fabricated from 50:50 4A PLGA to be best suited for the use in a rat sciatic nerve injury model. (C) 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 95A: 1067-1073,2010.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

The Translesional Spinal Network and Its Reorganization after Spinal Cord Injury

© The Author(s) 2020. Evidence from preclinical and clinical research suggest that neuromodulation technologies can facilitate the sublesional spinal networks, isolated from supraspinal commands after spinal cord injury (SCI), by reestablishing the levels of excitability and enabling descending motor signals via residual connections. Herein, we evaluate available evidence that sublesional and supralesional spinal circuits could form a translesional spinal network after SCI. We further discuss evidence of translesional network reorganization after SCI in the presence of sensory inputs during motor training. In this review, we evaluate potential mechanisms that underlie translesional circuitry reorganization during neuromodulation and rehabilitation in order to enable motor functions after SCI. We discuss the potential of neuromodulation technologies to engage various components that comprise the translesional network, their functional recovery after SCI, and the implications of the concept of translesional network in development of future neuromodulation, rehabilitation, and neuroprosthetics technologies

Controlling dispersion of axonal regeneration using a multichannel collagen nerve conduit

Single channel conduits are used clinically in nerve repair as an alternative to the autologous nerve graft. Axons regenerating across single channel tubes, however, may disperse resulting in inappropriate target reinnervation. This dispersion may be limited by multichannel nerve conduits as they resemble the structure of nerve multiple basal lamina tubes. In this study, we investigated the influence of channel number on the axonal regeneration using a series of 1-, 2-, 4-, and 7-channel collagen conduits and commercial (NeuraGen (R)) single channel conduits. Nerve conduits were implanted in rats with a 1 cm gap of sciatic nerve. After four months, quantitative results of regeneration were evaluated with nerve morphometry and the accuracy of regeneration was assessed using retrograde tracing: two tracers being applied simultaneously to tibial and peroneal nerves to determine the percentage of motor neurons with double projections. Recovery of function was investigated with compound muscle action potential recordings and ankle motion analysis. We showed that the fabricated 1-channel and 4-channel conduits are superior to other types of conduits in axonal regeneration. Simultaneous tracing showed a significantly lower percentage of motor neurons with double projections after 2- and 4-channel compared with 1-channel conduit repair. This study shows the potential influence of multichannel guidance on limiting dispersion without decreasing quantitative results of regeneration. (C) 2010 Elsevier Ltd. All rights reserved.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

RAT SCIATIC NERVE REPAIR WITH A POLY-LACTIC-co-GLYCOLIC ACID SCAFFOLD AND NERVE GROWTH FACTOR RELEASING MICROSPHERES

The effect of microsphere delivered Nerve Growth Factor (NGF) in a poly-lactic-co-glycolic-acid (PLGA) 85/15 nerve conduit bridging a 10 mm rat sciatic nerve gap was assessed, comparing nine groups (n = 6): PLGA conduits filled with saline, saline and NGF, saline with blank microspheres; four different NGF microspheres (5, 20, 50, and 100 mg/ml); an autologous graft and sciatic nerve gap. Histomorphometry, retrograde tracing, electrophysiology, and functional outcomes were evaluated up to 16 weeks. The autologous graft showed the largest fascicular area (0.65 mm(2)) and had a significantly greater number of myelinated fibers (P < 0.0001). Electrophysiology showed Compound Muscle Action Potential (CMAP) recordings for the autologous graft returning at 6 weeks after nerve transection, reaching their highest amplitude of 3.6 mV at endpoint. No significant differences were found in functional evaluation between groups or between conduits with microspheres and the saline filled conduit. A PLGA 85/15 nerve conduit is capable of sustaining nerve regeneration. The microsphere delivery system does not interfere with regeneration. (C) 2011 Wiley-Liss, Inc. Microsurgery 31:293-302, 2011.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Short- and long-term peripheral nerve regeneration using a poly-lactic-co-glycolic-acid scaffold containing nerve growth factor and glial cell line-derived neurotrophic factor releasing microspheres

Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Segment-Specific Orientation of the Dorsal and Ventral Roots for Precise Therapeutic Targeting of Human Spinal Cord

Objective: To provide precise description of the dorsal and ventral roots orientation along with the main spinal cord anatomical measurements and their segment-specific variations. Patients and Methods: We collected and analyzed the measurements of the spines, spinal cords, and dorsal and ventral roots (C2-L5) of nine adult cadavers (five males and four females). Results: This study for the first time provides analysis of the dorsal and ventral roots orientation along with spinal cord anatomical measurements and their segment-specific distribution. The results of this study showed less variability in rostral root angles compared with the caudal. Dorsal and ventral rootlets were oriented mostly perpendicular to the spinal cord at the cervical level and had more parallel orientation to the spinal cord at the thoracic and lumbar segments. The number of rootlets per root was greatest at dorsal cervical and lumbar segments. Spinal cord transverse diameter and width of the dorsal columns were largest at cervical segments. The strongest correlation between the spinal cord and vertebrae structures was found between the length of intervertebral foramen to rostral rootlet distance and vertebral bone length. Conclusion: These results demonstrate consistent variation in spinal cord anatomical features across all tested subjects. The results of this study can be used to locate spinal roots and main spinal cord landmarks based on bone marks on computed tomography or X-rays. These results could improve stereotactic surgical procedures and electrode positioning for neuromodulation procedures