Browsing by Author "Sun, Yan"

Now showing 1 - 8 of 8
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    3D Image Segmentation Implementation on FPGA Using EM/MPM Algorithm
    (2010-12) Sun, Yan; Christopher, Lauren; Rizkalla, Maher E.; Salama, Paul
    In this thesis, 3D image segmentation is targeted to a Xilinx Field Programmable Gate Array (FPGA), and verified with extensive simulation. Segmentation is performed using the Expectation-Maximization with Maximization of the Posterior Marginals (EM/MPM) Bayesian algorithm. This algorithm segments the 3D image using neighboring pixels based on a Markov Random Field (MRF) model. This iterative algorithm is designed, synthesized and simulated for the Xilinx FPGA, and greater than 100 times speed improvement over standard desktop computer hardware is achieved. Three new techniques were the key to achieving this speed: Pipelined computational cores, sixteen parallel data paths and a novel memory interface for maximizing the external memory bandwidth. Seven MPM segmentation iterations are matched to the external memory bandwidth required of a single source file read, and a single segmented file write, plus a small amount of latency.
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    Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice
    (Elsevier, 2022-05) Mah, Kar Men; Wu, Wei; Al-Ali, Hassan; Sun, Yan; Han, Qi; Ding, Ying; Muñoz, Melissa; Xu, Xiao-Ming; Lemmon, Vance P.; Bixby, John L.; Neurological Surgery, School of Medicine
    Recovery from spinal cord injury (SCI) and other central nervous system (CNS) trauma is hampered by limits on axonal regeneration in the CNS. Regeneration is restricted by the lack of neuron-intrinsic regenerative capacity and by the repressive microenvironment confronting damaged axons. To address this challenge, we have developed a therapeutic strategy that co-targets kinases involved in both extrinsic and intrinsic regulatory pathways. Prior work identified a kinase inhibitor (RO48) with advantageous polypharmacology (co-inhibition of targets including ROCK2 and S6K1), which promoted CNS axon growth in vitro and corticospinal tract (CST) sprouting in a mouse pyramidotomy model. We now show that RO48 promotes neurite growth from sensory neurons and a variety of CNS neurons in vitro, and promotes CST sprouting and/or regeneration in multiple mouse models of spinal cord injury. Notably, these in vivo effects of RO48 were seen in several independent experimental series performed in distinct laboratories at different times. Finally, in a cervical dorsal hemisection model, RO48 not only promoted growth of CST axons beyond the lesion, but also improved behavioral recovery in the rotarod, gridwalk, and pellet retrieval tasks. Our results provide strong evidence for RO48 as an effective compound to promote axon growth and regeneration. Further, they point to strategies for increasing robustness of interventions in pre-clinical models.
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    Disrupting nNOS–PSD95 Interaction Improves Neurological and Cognitive Recoveries after Traumatic Brain Injury
    (Oxford University Press, 2020-06) Qu, Wenrui; Liu, Nai-Kui; Wu, Xiangbing; Wang, Ying; Xia, Yongzhi; Sun, Yan; Lai, Yvonne; Li, Rui; Shekhar, Anantha; Xu, Xiao-Ming; Psychiatry, School of Medicine
    Excessive activation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation plays a crucial role in the pathogenesis of traumatic brain injury (TBI). However, directly inhibiting NMDARs or nNOS produces adverse side effects because they play key physiological roles in the normal brain. Since interaction of nNOS–PSD95 is a key step in NMDAR-mediated excitotoxicity, we investigated whether disrupting nNOS–PSD95 interaction with ZL006, an inhibitor of nNOS–PSD95 interaction, attenuates NMDAR-mediated excitotoxicity. In cortical neuronal cultures, ZL006 treatment significantly reduced glutamate-induced neuronal death. In a mouse model of controlled cortical impact (CCI), administration of ZL006 (10 mg/kg, i.p.) at 30 min postinjury significantly inhibited nNOS–PSD95 interaction, reduced TUNEL- and phospho-p38-positive neurons in the motor cortex. ZL006 treatment also significantly reduced CCI-induced cortical expression of apoptotic markers active caspase-3, PARP-1, ratio of Bcl-2/Bax, and phosphorylated p38 MAPK (p-p38). Functionally, ZL006 treatment significantly improved neuroscores and sensorimotor performance, reduced somatosensory and motor deficits, reversed CCI-induced memory deficits, and attenuated cognitive impairment. Histologically, ZL006 treatment significantly reduced the brain lesion volume. These findings collectively suggest that blocking nNOS–PSD95 interaction represents an attractive strategy for ameliorating consequences of TBI and that its action is mediated via inhibiting neuronal apoptosis and p38 MAPK signaling.
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    Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism A Randomized Clinical Trial
    (AMA, 2017-01) Block, Geoffrey A.; Bushinsky, David A.; Cheng, Sunfa; Cunningham, John; Dehmel, Bastian; Drueke, Tilman B.; Ketteler, Markus; Kewalramani, Reshma; Martin, Kevin J.; Moe, Sharon M.; Patel, Uptal D.; Silver, Justin; Sun, Yan; Wang, Hao; Chertow, Glenn M.; Department of Medicine, School of Medicine
    Importance Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects. Objective To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet. Design, Setting, and Participants A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015. Interventions Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily. Main Outcomes and Measures The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting. Results The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was −10.5% (95% CI, −17.5% to −3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%). Conclusions and Relevance Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety.
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    Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis
    (Oxford University Press, 2019-04-26) Wolf, Myles; Block, Geoffrey A.; Chertow, Glenn M.; Cooper, Kerry; Fouqueray, Bruno; Moe, Sharon M.; Sun, Yan; Tomlin, Holly; Vervloet, Marc; Oberbauer, Rainer; Medicine, School of Medicine
    Background: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown. Methods: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide. Results: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P < 0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide. Conclusion: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium.
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    An In Vivo Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury
    (Journal of Visualized Experiments, 2017-12-31) Chen, Chen; Zhang, Yi Ping; Sun, Yan; Xiong, Wenhui; Shields, Lisa B. E.; Shields, Christopher B.; Jin, Xiaoming; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
    Spinal cord injury (SCI) causes significant vascular disruption at the site of injury. Vascular pathology occurs immediately after SCI and continues throughout the acute injury phase. In fact, endothelial cells appear to be the first to die after a contusive SCI. The early vascular events, including increased permeability of the blood-spinal cord barrier (BSCB), induce vasogenic edema and contribute to detrimental secondary injury events caused by complex injury mechanisms. Targeting the vascular disruption, therefore, could be a key strategy to reduce secondary injury cascades that contribute to histological and functional impairments after SCI. Previous studies were mostly performed on postmortem samples and were unable to capture the dynamic changes of the vascular network. In this study, we have developed an in vivo duo-color two-photon imaging method to monitor acute vascular dynamic changes following contusive SCI. This approach allows detecting blood flow, vessel diameter, and other vascular pathologies at various sites of the same rat pre- and post-injury. Overall, this method provides an excellent venue for investigating vascular dynamics.
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    Lipocalin 2: could it be a new biomarker in pediatric pulmonary hypertension associated with congenital heart disease?
    (IMR Press, 2021) Zhang, Hongju; Sun, Tao; Yang, Jiao; Sun, Yan; Liu, Guowen; Krittanawong, Chayakrit; El-Am, Edward A.; Bou Chaaya, Rody G.; Xu, Liyuan; Ye, Zankai; Li, Zhiqiang; Ma, Ning; Medicine, School of Medicine
    The role of lipocalin 2 (LCN2) in pulmonary hypertension (PH) in pediatric patients with congenital heart disease (CHD) remains unclear. We sought to investigate whether LCN2 could be a potential biomarker for PH in pediatric patients who underwent surgery for CHD. From December 2018 to February 2020, patients undergoing surgical repair for congenital defects with and without PH were identified. Healthy children without CHD and PH served as controls. A mean pulmonary artery pressure (mPAP) >20 mmHg was used as the definition of PH. Blood samples and echocardiograms were obtained in all patients and right heart catheterization was performed in 79 patients. Multivariable logistic regression analysis was used to determine potential predictors for PH. Among 102 patients, the median age was 10 [Interquartile range (IQR) 7.0-13] months, and 37.5% were female. Compared to non-PH patients and controls, PH patients showed elevated levels of LCN2 (P < 0.001). In addition, LCN2 levels positively correlated with the invasive haemodynamic indices of PH. In univariate regression, LCN2 (odds ratio = 2.69 [1.06-5.31], P < 0.001), N-Terminal pro Brain Natriuretic Peptide (NT-proBNP) (OR = 1.91 [1.21-7.56], P = 0.03) and high-sensitive troponin T (hsTnT) (OR = 1.36 [1.01-3.57], P = 0.01) were associated with PH; however, only LCN2 (OR = 1.68 [1.04-4.52], P = 0.03) was significantly associated with PH on multivariate analysis. In conclusion, children with PH had increased LCN2 expression. LCN2 levels positively correlated with invasive indices of PH. These results indicate LCN2 could be a useful biomarker for prediction of PH in pediatric CHD cases.
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    The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury
    (Society for Neuroscience, 2017-07-26) Al-Ali, Hassan; Ding, Ying; Slepak, Tatiana; Wu, Wei; Sun, Yan; Martinez, Yania; Xu, Xiao-Ming; Lemmon, Vance P.; Bixby, John L.; Neurological Surgery, School of Medicine
    The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3 mm beyond the injury site at 8 weeks after injury. Concomitantly, treatment with PF-4708671 produced significant locomotor recovery. Pharmacological targeting of S6K1 may therefore constitute an attractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.SIGNIFICANCE STATEMENT Despite mTOR's well-established function in promoting axon regeneration, the role of its downstream target, S6 kinase 1 (S6K1), has been unclear. We used cellular assays with primary neurons to demonstrate that S6K1 is a negative regulator of neurite outgrowth, and a spinal cord injury model to show that it is a viable pharmacological target for inducing axon regeneration. We provide mechanistic evidence that S6K1's negative feedback to PI3K signaling is involved in axon growth inhibition, and show that phosphorylation of S6K1 is a more appropriate regeneration indicator than is S6 phosphorylation.