Bio

Clinical Focus


  • Diagnostic Radiology
  • Interventional Radiology

Academic Appointments


Professional Education


  • Residency:Stanford University School of Medicine (2010) CA
  • Board Certification: Vascular and Interventional Radiology, American Board of Radiology (2012)
  • Fellowship:University of Pennsylvania Health System (2011) PA
  • Board Certification: Diagnostic Radiology, American Board of Radiology (2010)
  • Internship:Scripps Mercy Hospital (2006) CA
  • Medical Education:Stanford University School of Medicine (2005) CA
  • BA & BS, Stanford University, Economics & Biological Sciences (1999)

Community and International Work


  • Pacific Free Clinic

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Research & Scholarship

Clinical Trials


  • Pulmonary Embolism Response to Fragmentation, Embolectomy, & Catheter Thrombolysis: PERFECT Recruiting

    A prospective observational study to evaluate the safety and effectiveness data of catheter-directed therapy (CDT) including percutaneous mechanical thrombectomy (PMT) for treatment of acute pulmonary embolism (PE)

    View full details

Publications

Journal Articles


  • A titratable two-step transcriptional amplification strategy for targeted gene therapy based on ligand-induced intramolecular folding of a mutant human estrogen receptor. Molecular imaging and biology Chen, I. Y., Paulmurugan, R., Nielsen, C. H., Wang, D. S., Chow, V., Robbins, R. C., Gambhir, S. S. 2014; 16 (2): 224-234

    Abstract

    The efficacy and safety of cardiac gene therapy depend critically on the level and the distribution of therapeutic gene expression following vector administration. We aimed to develop a titratable two-step transcriptional amplification (tTSTA) vector strategy, which allows modulation of transcriptionally targeted gene expression in the myocardium.We constructed a tTSTA plasmid vector (pcTnT-tTSTA-fluc), which uses the cardiac troponin T (cTnT) promoter to drive the expression of the recombinant transcriptional activator GAL4-mER(LBD)-VP2, whose ability to transactivate the downstream firefly luciferase reporter gene (fluc) depends on the binding of its mutant estrogen receptor (ERG521T) ligand binding domain (LBD) to an ER ligand such as raloxifene. Mice underwent either intramyocardial or hydrodynamic tail vein (HTV) injection of pcTnT-tTSTA-fluc, followed by differential modulation of fluc expression with varying doses of intraperitoneal raloxifene prior to bioluminescence imaging to assess the kinetics of myocardial or hepatic fluc expression.Intramyocardial injection of pcTnT-tTSTA-fluc followed by titration with intraperitoneal raloxifene led to up to tenfold induction of myocardial fluc expression. HTV injection of pcTnT-tTSTA-fluc led to negligible long-term hepatic fluc expression, regardless of the raloxifene dose given.The tTSTA vector strategy can effectively modulate transgene expression in a tissue-specific manner. Further refinement of this strategy should help maximize the benefit-to-risk ratio of cardiac gene therapy.

    View details for DOI 10.1007/s11307-013-0673-4

    View details for PubMedID 23955099

  • Ultrasound and microbubble-mediated gene delivery in cancer: progress and perspectives. Investigative radiology Panje, C. M., Wang, D. S., Willmann, J. K. 2013; 48 (11): 755-769

    Abstract

    Ultrasound-mediated gene delivery with microbubbles has emerged as an attractive nonviral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents, particularly in the presence of microbubbles, by increasing vascular and cell membrane permeability. Several preclinical studies have reported successful gene delivery into solid tumors with significant therapeutic effects using this novel approach. This review provides background information on gene therapy and ultrasound bioeffects and discusses the current progress and overall perspectives on the application of ultrasound and microbubble-mediated gene delivery in cancer.

    View details for DOI 10.1097/RLI.0b013e3182982cc1

    View details for PubMedID 23697924

  • Noninvasive imaging of hypoxia-inducible factor-1a gene therapy for myocardial ischemia. Human gene therapy methods Chen, I. Y., Gheysens, O., Li, Z., Rasooly, J. A., Wang, Q., Paulmurugan, R., Rosenberg, J., Rodriguez-Porcel, M., Willmann, J. K., Wang, D. S., Contag, C. H., Robbins, R. C., Wu, J. C., Gambhir, S. S. 2013; 24 (5): 279-288

    Abstract

    Abstract Hypoxia-inducible factor-1 alpha (HIF-1α) gene therapy holds great promise for the treatment of myocardial ischemia. Both preclinical and clinical evaluations of this therapy are underway and can benefit from a vector strategy that allows noninvasive assessment of HIF-1α expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1α-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1α gene (HIF-1α-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1α-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1α-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1α-dependent vascular endothelial growth factor expression (r(2)=0.88). Intramyocardial delivery of pcTnT-HIF-1α-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1α-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1α therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1α-VP2 therapy in preclinical models of myocardial ischemia.

    View details for DOI 10.1089/hgtb.2013.028

    View details for PubMedID 23937265

  • Prophylactic Topically Applied Ice to Prevent Cutaneous Complications of Nontarget Chemoembolization and Radioembolization JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Wang, D. S., Louie, J. D., Kothary, N., Shah, R. P., Sze, D. Y. 2013; 24 (4): 596-600

    Abstract

    Cutaneous complications can result from nontarget deposition during transcatheter arterial chemoembolization or radioembolization. Liver tu"TACE" because of its inconsistent use in the literature (ie, to abbreviate different terms). Please note that "TACE" has been replaced with "transcatheter arterial chemoembolization" or simply "chemoembolization" as appropriate throughout the manuscript. Please verify these changes.-->mors may receive blood supply from parasitized extrahepatic arteries (EHAs) that also perfuse skin or from hepatic arteries located near the origin of the falciform artery (FA), which perfuses the anterior abdominal wall. To vasoconstrict cutaneous vasculature and prevent nontarget deposition, ice packs were topically applied to at-risk skin in nine chemoembolization treatments performed via 14 parasitized EHAs, seven chemoembolization treatments near the FA origin, and five radioembolization treatments in cases in which the FA could not be prophylactically coil-embolized. No postprocedural cutaneous complications were encountered.

    View details for DOI 10.1016/j.jvir.2012.12.020

    View details for Web of Science ID 000316828000022

    View details for PubMedID 23522163

  • Intra-arterial therapies for metastatic colorectal cancer. Seminars in Interventional Radiology Wang, D. S., Louie, J. D., Sze, D. Y. 2013; 30 (1): 12-20
  • Heparin-induced thrombocytopenia (HIT) causing portosplenic, superior mesenteric, and splenic vein thrombosis resulting in splenic rupture and pulmonary emboli formation CLINICAL IMAGING Lammering, J. C., Wang, D. S., Shin, L. K. 2012; 36 (6): 865-868

    Abstract

    Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin administration. Of the few reported cases of HIT-associated intra-abdominal thrombosis, none to our knowledge provide multidetector-row computed tomography (MDCT) imaging findings or emphasize its utility in diagnosis. We describe a case of HIT with MDCT images demonstrating extensive intra-abdominal thrombosis and end-organ complications including splenic rupture and pulmonary emboli. This case emphasizes the potential role of MDCT in the rapid detection of HIT-related thromboembolic complications in patients with nonspecific abdominal pain.

    View details for DOI 10.1016/j.clinimag.2012.01.011

    View details for Web of Science ID 000311533800037

    View details for PubMedID 23154026

  • Cationic versus Neutral Microbubbles for Ultrasound-mediated Gene Delivery in Cancer RADIOLOGY Wang, D. S., Panje, C., Pysz, M. A., Paulmurugan, R., Rosenberg, J., Gambhir, S. S., Schneider, M., Willmann, J. K. 2012; 264 (3): 721-732

    Abstract

    To test whether plasmid-binding cationic microbubbles (MBs) enhance ultrasound-mediated gene delivery efficiency relative to control neutral MBs in cell culture and in vivo tumors in mice.Animal studies were approved by the institutional animal care committee. Cationic and neutral MBs were characterized in terms of size, charge, circulation time, and DNA binding. Click beetle luciferase (CBLuc) reporter plasmids were mixed with cationic or neutral MBs. The ability of cationic MBs to protect bound plasmids from nuclease degradation was tested by means of a deoxyribonuclease (DNase) protection assay. Relative efficiencies of ultrasound-mediated transfection (ultrasound parameters: 1 MHz, 1 W/cm(2), 20% duty cycle, 1 minute) of CBLuc to endothelial cells by using cationic, neutral, or no MBs were compared in cell culture. Ultrasound-mediated gene delivery to mouse hind limb tumors was performed in vivo (n = 24) with insonation (1 MHz, 2 W/cm(2), 50% duty cycle, 5 minutes) after intravenous administration of CBLuc with cationic, neutral, or no MBs. Tumor luciferase activity was assessed by means of serial in vivo bioluminescence imaging and ex vivo analysis. Results were compared by using analysis of variance.Cationic MBs (+15.8 mV; DNA binding capacity, 0.03 pg per MB) partially protected bound DNA from DNase degradation. Mean CBLuc expression of treated endothelial cells in culture was 20-fold higher with cationic than with neutral MBs (219.0 relative light units [RLUs]/µg protein ± 92.5 [standard deviation] vs 10.9 RLUs/µg protein ± 2.7, P = .001) and was significantly higher (P < .001) than that in the no MB and no ultrasound control groups. Serial in vivo bioluminescence of mouse tumors was significantly higher with cationic than with neutral MBs ([5.9 ± 2.2] to [9.3 ± 5.2] vs [2.4 ± 0.8] to [2.9 ± 1.1] × 10(4) photons/sec/cm(2)/steradian, P < .0001) and versus no MB and no ultrasound controls (P < .0001). Results of ex vivo analysis confirmed these results (? = 0.88, P < .0001).Plasmid-binding cationic MBs enhance ultrasound-mediated gene delivery efficiency relative to neutral MBs in both cell culture and mouse hind limb tumors.

    View details for DOI 10.1148/radiol.12112368

    View details for Web of Science ID 000308645500013

    View details for PubMedID 22723497

  • Ultrasound-Mediated Gene Delivery with Cationic Versus Neutral Microbubbles: Effect of DNA and Microbubble Dose on In Vivo Transfection Efficiency THERANOSTICS Panje, C. M., Wang, D. S., Pysz, M. A., Paulmurugan, R., Ren, Y., Tranquart, F., Tian, L., Willmann, J. K. 2012; 2 (11): 1078-1091

    Abstract

    To assess the effect of varying microbubble (MB) and DNA doses on the overall and comparative efficiencies of ultrasound (US)-mediated gene delivery (UMGD) to murine hindlimb skeletal muscle using cationic versus neutral MBs.Cationic and control neutral MBs were characterized for size, charge, plasmid DNA binding, and ability to protect DNA against endonuclease degradation. UMGD of a codon optimized firefly luciferase (Fluc) reporter plasmid to endothelial cells (1 MHz, 1 W/cm², 20% duty cycle, 1 min) was performed in cell culture using cationic, neutral, or no MBs. In vivo UMGD to mouse hindlimb muscle was performed by insonation (1 MHz, 2 W/cm², 50% duty cycle, 5 min) after intravenous administration of Fluc combined with cationic, neutral, or no MBs. Gene delivery efficiency was assessed by serial in vivo bioluminescence imaging. Efficiency of in vivo UMGD with cationic versus neutral MBs was systematically evaluated by varying plasmid DNA dose (10, 17.5, 25, 37.5, and 50 µg) while maintaining a constant MB dose of 1x10(8) MBs and by changing MB dose (1x10(7), 5x10(7), 1x10(8), or 5x10(8) MBs) while keeping a constant DNA dose of 50 µg.Cationic and size-matched control neutral MBs differed significantly in zeta potential with cationic MBs being able to bind plasmid DNA (binding capacity of 0.03 pg/MB) and partially protect DNA from nuclease degradation while neutral MBs could not. Cationic MBs enhanced UMGD compared to neutral MBs as well as no MB and no US controls both in cell culture (P < 0.001) and in vivo (P < 0.05). Regardless of MB type, in vivo UMGD efficiency increased dose-dependently with DNA dose and showed overall maximum transfection with 50 µg DNA. However, there was an inverse correlation (? = -0.90; P = 0.02) between DNA dose and the degree of enhanced UMGD efficiency observed with using cationic MBs instead of neutral MBs. The delivery efficiency advantage associated with cationic MBs was most prominent at the lowest investigated DNA dose (7.5-fold increase with cationic versus neutral MBs at a DNA dose of 10 µg; P = 0.02) compared to only a 1.4-fold increase at a DNA dose of 50 µg (P < 0.01). With increasing MB dose, overall in vivo UMGD efficiency increased dose-dependently with a maximum reached at a dose of 1x10(8) MBs with no further significant increase with 5x10(8) MBs (P = 0.97). However, compared to neutral MBs, cationic MBs enhanced UMGD efficiency the most at low MB doses. Relative enhancement of UMGD efficiency using cationic over neutral MBs decreased from a factor of 27 for 1x10(7) MBs (P = 0.02) to a factor of 1.4 for 1x10(8) MBs (P < 0.01) and no significant difference for 5x10(8) MBs.Cationic MBs enhance UMGD to mouse skeletal muscle relative to neutral MBs but this is dependent on MB and DNA dose. The enhancement effect of cationic MBs on UMGD efficiency is more evident when lower doses of MBs or DNA are used, whereas the advantage of cationic MBs over neutral MBs is substantially reduced in the presence of excess MBs or DNA.

    View details for DOI 10.7150/thno.4240

    View details for Web of Science ID 000312955800005

    View details for PubMedID 23227124

  • Molecular Imaging: A Primer for Interventionalists and Imagers (Reprinted from J Vasc Interv Radiol, vol 17, pg 1405-1423, 2006) JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Wang, D. S., Dake, M. D., Park, J. M., Kuo, M. D. 2009; 20 (7): S505-S522

    Abstract

    The characterization of human diseases by their underlying molecular and genomic aberrations has been the hallmark of molecular medicine. From this, molecular imaging has emerged as a potentially revolutionary discipline that aims to visually characterize normal and pathologic processes at the cellular and molecular levels within the milieu of living organisms. Molecular imaging holds promise to provide earlier and more precise disease diagnosis, improved disease characterization, and timely assessment of therapeutic response. This primer is intended to provide a broad overview of molecular imaging with specific focus on future clinical applications relevant to interventional radiology.

    View details for DOI 10.1016/j.jvir.2009.04.042

    View details for Web of Science ID 000267613200041

    View details for PubMedID 19560036

  • Identification of noninvasive imaging surrogates for brain tumor gene-expression modules PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Diehn, M., Nardini, C., Wang, D. S., McGovern, S., Jayaraman, M., Liang, Y., Alclape, K., Cha, S., Kuo, M. D. 2008; 105 (13): 5213-5218

    Abstract

    Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. We combined neuroimaging and DNA microarray analysis to create a multidimensional map of gene-expression patterns in GBM that provided clinically relevant insights into tumor biology. Tumor contrast enhancement and mass effect predicted activation of specific hypoxia and proliferation gene-expression programs, respectively. Overexpression of EGFR, a receptor tyrosine kinase and potential therapeutic target, was also directly inferred by neuroimaging and was validated in an independent set of tumors by immunohistochemistry. Furthermore, imaging provided insights into the intratumoral distribution of gene-expression patterns within GBM. Most notably, an "infiltrative" imaging phenotype was identified that predicted patient outcome. Patients with this imaging phenotype had a greater tendency toward having multiple tumor foci and demonstrated significantly shorter survival than their counterparts. Our findings provide an in vivo portrait of genome-wide gene expression in GBM and offer a potential strategy for noninvasively selecting patients who may be candidates for individualized therapies.

    View details for DOI 10.1073/pnas.0801279105

    View details for Web of Science ID 000254723700047

    View details for PubMedID 18362333

  • Monitoring of the biological response to murine Hindlimb ischemia with Cu-64-labeled vascular endothelial growth factor-121 positron emission tomography CIRCULATION Willmann, J. K., Chen, K., Wang, H., Paulmurugan, R., Rollins, M., Cai, W., Wang, D. S., Chen, I. Y., Gheysens, O., Rodriguez-Porcel, M., Chen, X., Gambhir, S. S. 2008; 117 (7): 915-922

    Abstract

    Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training.64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem gamma-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P < 0.001) from a control level of 0.61+/-0.17% ID/g (percentage of injected dose per gram) to 1.62+/-0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59+/-0.14% ID/g at day 29), and correlated with gamma-counting (R2 = 0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P < or = 0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2 = 0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice.64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.

    View details for DOI 10.1161/CIRCULATIONAHA.107.733220

    View details for Web of Science ID 000253428100008

    View details for PubMedID 18250264

  • Comparative evaluation of noninvasive compression adjuncts for hemostasis in percutaneous arterial, venous, and arteriovenous dialysis access procedures JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Wang, D. S., Chu, L. F., Olson, S. E., Miller, F. J., Valji, K., Wong, W. H., Rose, S. C., Austin, M., Kuo, M. D. 2008; 19 (1): 72-79

    Abstract

    To assess the relative efficacy of three compression adjuncts -- D-Stat Dry (D-Stat), QR Powder (QR), and XS Powder (XS) -- for reducing time to hemostasis in patients who underwent diagnostic and interventional percutaneous procedures.D-Stat, QR, or XS was applied in 176 percutaneous diagnostic arterial, therapeutic arterial, venous, and arteriovenous dialysis access (AVDA) procedures in 138 patients. The mean time to hemostasis and application-related complications were retrospectively assessed.Mean time to hemostasis was significantly reduced in all applications of QR (3.1 minutes +/- 1.1) and XS (3.7 minutes +/- 1.1) relative to D-Stat (6.2 minutes +/- 1.1, P < .001 vs both). For therapeutic arterial procedures, mean time to hemostasis for QR and XS was 3.6 minutes +/- 1.1 and 4.8 minutes +/- 1.1, respectively, and this was significantly less than that of D-Stat (10.0 minutes +/- 1.2; P < .001 vs QR, P < .01 vs XS). Mean times to hemostasis for QR and XS were also shorter than that with D-Stat in diagnostic arterial and AVDA procedures (P < .05). For venous procedures, mean time to hemostasis for QR (1.9 minutes +/- 1.2) was significantly shorter than that with both D-Stat (4.0 minutes +/- 1.2, P < .05) and XS (3.7 minutes +/- 1.2, P < .05). Minor immediate complications (hematoma <5 cm) occurred in 2.8% of applications. No access site infections were observed.All three agents effectively reduced time to hemostasis with minimal associated complications. QR was found to be more effective than D-Stat in all four procedure types.

    View details for DOI 10.1016/j.jvir.2007.08.028

    View details for Web of Science ID 000252853200012

    View details for PubMedID 18192470

  • Molecular imaging: A primer for interventionalists and imagers JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Wang, D. S., Dake, M. D., Park, J. M., Kuo, M. D. 2006; 17 (9): 1405-1423

    Abstract

    The characterization of human diseases by their underlying molecular and genomic aberrations has been the hallmark of molecular medicine. From this, molecular imaging has emerged as a potentially revolutionary discipline that aims to visually characterize normal and pathologic processes at the cellular and molecular levels within the milieu of living organisms. Molecular imaging holds promise to provide earlier and more precise disease diagnosis, improved disease characterization, and timely assessment of therapeutic response. This primer is intended to provide a broad overview of molecular imaging with specific focus on future clinical applications relevant to interventional radiology.

    View details for DOI 10.1097/01.RVI.0000235746.86332.DF

    View details for Web of Science ID 000240883100004

    View details for PubMedID 16990461

  • Will stent-graft repair emerge as treatment of choice for acute type B dissection? SEMINARS IN VASCULAR SURGERY Dake, M. D., Wang, D. S. 2006; 19 (1): 40-47

    Abstract

    Endovascular stent grafts are now accepted globally and approved by the US Food and Drug Administration as an alternative to open surgical repair for patients with descending thoracic aortic aneurysm. However, as opposed to the abdominal aorta, application of this technology to manage thoracic aortic disease is not limited to degenerative aneurysms. In fact, international registries and surveys estimate that only 60% of the thoracic cases managed currently with stent-graft placement are aneurysms. The remainder of this experience includes acute dissection, chronic dissection, traumatic aortic injury, penetrating ulcer, intramural hematoma, aortic fistula, anastomotic pseudoaneurysm, and an embolizing lesion. In this regard, it is important to keep in mind that the present devices used in these nonaneurysmal applications are not designed to address the unique anatomical and pathological features that these lesions present. Consequently, in the future, it is possible that we will see stent-graft designs that focus specifically on the challenges of some of the nonaneurysmal thoracic aortic pathologies.

    View details for DOI 10.1053/j.semvascsurg.2005.11.007

    View details for Web of Science ID 000242239900007

    View details for PubMedID 16533691

  • Directed migration of smooth muscle cells to engineer plaque-resistant vein grafts JOURNAL OF ENDOVASCULAR THERAPY Amabile, P. G., Wang, D. S., Kao, E. Y., Lee, J., Elkins, C. J., Yuksel, E., Hilfiker, P. R., Waugh, J. M., Dake, M. D. 2005; 12 (6): 667-675

    Abstract

    To test the hypothesis that controlled perivascular release of tissue plasminogen activator (tPA) can generate cleaved extracellular matrix (ECM) chemotactic gradients to guide the migration of vascular smooth muscle cells (SMCs) away from the lumen, thereby limiting neointima formation.This hypothesis was tested in rabbit models in which the perivascular surface of vein bypass grafts was treated with microspheres releasing tPA (MS-tPA), microspheres containing no drug (MS-blank), or phosphate buffered saline (PBS). Vein graft segments harvested after 7 days were then evaluated for elastin content, proliferating SMCs, intima-to-media (I/M) ratio, and inflammation; late impact on neointima formation was also examined.The 7-day results demonstrated cleaved elastin gradients and proliferating SMCs that assumed a more peripheral distribution in the MS-tPA group than MS-blank and PBS controls (p<0.05). At 28 days, vein grafts treated with MS-tPA showed a mean I/M ratio (0.35+/-0.04) that was 63.5% lower than PBS controls (0.96+/-0.07, p<0.005) and 43.5% lower than MS-blank specimens (0.62+/-0.08, p<0.05).Perivascular release of tPA modifies ECM gradients, directionally guides SMC migration away from the lumen, and limits neointima formation.

    View details for Web of Science ID 000234188800007

    View details for PubMedID 16363896

  • Endovascular repair of abdominal and thoracic aortic aneurysms CIRCULATION Katzen, B. T., Dake, M. D., MaClean, A. A., Wang, D. S. 2005; 112 (11): 1663-1675
  • Local resistance to oxidative stress by overexpression of copper-zinc superoxide dismutase limits neointimal formation after angioplasty JOURNAL OF ENDOVASCULAR THERAPY Kuo, M. D., Bright, I. J., Wang, D. S., Ghafouri, P., Yuksel, E., Hilfiker, P. R., Miniati, D. N., Dake, M. D. 2004; 11 (6): 585-594

    Abstract

    To examine the effects of oxidative stress on neointimal hyperplasia through local overexpression of human copper-zinc superoxide dismutase (Cu-Zn SOD).The left common femoral arteries (CFA) of 18 New Zealand white rabbits were subjected to balloon overdilation injury. Each dilated CFA was then incubated with either a nonviral (buffer) or viral (adenovirus overexpressing beta-galactosidase) control or an adenovirus overexpressing Cu-Zn SOD. Animals were then sacrificed at 3, 7, or 28 days (3 arteries per group per time point) and the treated CFA segments were harvested for analysis of esterase-positive inflammatory cells and extracellular matrix elements. The intima-to-media ratio (I/M) was measured to assess the degree of neointimal formation.At 3 days, local SOD levels in the Cu-Zn SOD-treated group were significantly elevated relative to both controls (p<0.01). Significant reductions in lipid peroxidation byproducts were also seen in the SOD group relative to viral and nonviral controls (p<0.05). Mean I/M at 28 days was 0.582+/-0.088 for the nonviral control group versus 0.565+/-0.133 for the viral control group. The SOD-treated group had a significant reduction relative to both controls: 0.259+/-0.045 (p<0.05). Statistically significant reductions in I/M were also demonstrated in the SOD group relative to control groups at 7 days (p<0.05). The SOD-treated group demonstrated significant preservation of elastin relative to controls, as well as a significant reduction in esterase-positive granulocytes relative to controls (p<0.05).Direct buffering of oxidative stress in balloon-injured vessels can significantly alter postinjury response and limit neointimal hyperplasia.

    View details for Web of Science ID 000226315200002

    View details for PubMedID 15615548

  • In-stent restenosis limitation with stent-based controlled-release nitric oxide: Initial results in rabbits RADIOLOGY Do, Y. S., Kao, E. Y., Ganaha, F., Minamiguchi, H., Sugimoto, K., Lee, J., Elkins, C. J., Amabile, P. G., Kuo, M. D., Wang, D. S., Waugh, J. M., Dake, M. D. 2004; 230 (2): 377-382

    Abstract

    To evaluate effect of controlled stent-based release of an NO donor to limit in-stent restenosis in rabbits.Bioerodable microspheres containing NO donor or biodegradable polymer (polylactide-co-glycolide-polyethylene glycol) were prepared and loaded in channeled stents. Daily concentrations of NO release from NO-containing microspheres were assayed in vitro. NO- and polymer-containing (control) microsphere-loaded stents were deployed in aortas of New Zealand white rabbits (n = 8). Aortas with stents were harvested at 7 (n = 5) and 28 days (n = 3) and evaluated for cyclic guanosine monophosphate (cGMP) levels (7 days), number of proliferating cell nuclear antigen-positive cells (7 days), and intima-to-media ratio (7 and 28 days), with statistical significance evaluated by using one-way analysis of variance.NO-containing microspheres released NO with an initial bolus in the 1st week, followed by sustained release for the remaining 3 weeks. Significant increase in cGMP levels and decrease in proliferating cell nuclear antigen-positive cells were found at 7 days for the NO-treated group relative to controls (P <.05). Intima-to-media ratio in the NO-treated group was reduced by 46% and 32% relative to controls at 7 and 28 days, respectively (mean, 0.14 +/- 0.01 [standard error] vs 0.26 +/- 0.02 at 7 days, P <.01; 1.34 +/- 0.05 vs 1.98 +/- 0.08 at 28 days, P <.01).Stent-based controlled release of NO donor significantly reduces in-stent restenosis and is associated with increase in vascular cGMP and suppression of proliferation.

    View details for DOI 10.1148/radiol.2302020417

    View details for Web of Science ID 000188463700012

    View details for PubMedID 14699187

  • NOS inhibition accelerates atherogenesis: reversal by exercise AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Niebauer, J., Maxwell, A. J., Lin, P. S., Wang, D., Tsao, P. S., Cooke, J. P. 2003; 285 (2): H535-H540

    Abstract

    In this study, we assessed the effects of chronic exercise training (12 wk) on atherosclerotic lesion formation in hypercholesterolemic apolipoprotein E-deficient mice (n = 31). At the age of 9 wk, mice were assigned to the following groups: sedentary (Sed; n = 9); exercise (Ex; n = 12); sedentary and oral NG-nitro-L-arginine (L-NNA, Sed-NA; n = 4), or exercise and oral L-NNA (Ex-NA; n = 6). Chronic exercise training was performed on a treadmill for 12 wk (6 times/wk and twice for 1 h/day) at a final speed of 22 m/min, and an 8 degrees grade. L-NNA was discontinued 5 days before final treadmill testing. The farthest distance run to exhaustion was observed in Ex-NA mice (Sed: 306 +/- 32 m; Ex: 640 +/- 87; Sed-NA: 451 +/- 109 m; Ex-NA: 820 +/- 49 m; all P < 0.05). Lesion formation was assessed in the proximal ascending aorta by dissection microscopy after oil red O staining. The aortas of Sed-NA mice manifested a threefold increase in lesion formation compared with the other groups. This L-NNA-induced lesion formation was reduced by chronic exercise training (Sed, 786 +/- 144; Ex, 780 +/- 206; Sed-NA, 2,147 +/- 522; Ex-NA, 851 +/- 253; Sed-NA vs. all other groups: P < 0.001). In conclusion, treatment with oral L-NNA (an nitric oxide synthase antagonist) leads to accelerated atherogenesis in genetically determined hypercholesterolemic mice. This adverse effect can be overcome by chronic exercise training.

    View details for DOI 10.1152/ajpheart.00360.2001

    View details for Web of Science ID 000184153100011

    View details for PubMedID 12598230

  • Airway management after maxillectomy: Routine tracheostomy is unnecessary LARYNGOSCOPE Lin, H. S., Wang, D., Fee, W. E., Goode, R. L., Terris, D. J. 2003; 113 (6): 929-932

    Abstract

    There is a paucity of data to guide the optimal management of the airway in patients after maxillectomy. The decision on whether a concomitant tracheostomy is needed is often dictated by the surgeon's training and experience. We reviewed our experience with maxillectomy to assess the need for tracheostomy in postoperative airway management.Retrospective analysis at a university hospital.We identified 121 patients who underwent 130 maxillectomies between October 1990 and September 2001. Twenty-four of these were total (all six walls removed), 45 were subtotal (two or more walls removed), and 61 were limited (only one wall removed). Reconstruction ranged from none to microvascular free flap, with split-thickness skin graft being the most common reconstructive option.Only 10 tracheostomies (7.7%) were performed at the time of maxillectomy. These included four tracheostomies in patients who underwent bulky flap reconstruction, two tracheostomies in patients who underwent both flap reconstruction and mandibulectomy, one tracheostomy in a patient who underwent mandibulectomy, one tracheostomy in a patient with mucormycosis in anticipation of prolonged ventilatory support postoperatively, and two tracheostomies at the surgeons' discretion because of concern for upper airway edema. Among the 111 patients who underwent 120 maxillectomies without concomitant tracheostomy, 1 patient (0.9%), a 74 year-old man with oxygen-dependent chronic obstructive pulmonary disease, required repeat intubation on day 3 and again on day 10 after the surgery, because of respiratory failure; fiberoptic examination confirmed the absence of upper airway compromise.The routine performance of tracheostomy in patients undergoing maxillectomy is unnecessary. Selective use of tracheostomy may be indicated in situations in which mandibulectomy or bulky flap reconstruction is performed or a concern for postoperative oropharyngeal airway obstruction because of edema or packing exists.

    View details for Web of Science ID 000183391900002

    View details for PubMedID 12782798

  • Mechanotransduction of endothelial oxidative stress induced by cyclic strain ENDOTHELIUM-JOURNAL OF ENDOTHELIAL CELL RESEARCH Wang, D. S., Proffit, D., Tsao, P. S. 2001; 8 (4): 283-291

    Abstract

    Atherosclerotic lesions display a nonuniform distribution throughout the vascular tree. Mechanical forces produced by local alterations in blood flow may play an important role in the localization of atherosclerosis. One such force, cyclic strain, has been hypothesized to promote atherogenesis by inducing oxidative stress in endothelial cells, resulting in enhanced endothelial adhesiveness for monocytes. To investigate the signal transduction systems involved, human aortic endothelial cells were plated on flexible silicone strips that were either non-coated or adsorbed with poly-L-lysine, vitronectin, fibronectin, or collagen I. Cells were then subjected to uniform sinusoidal stretch (10%) for 6 h. Endothelial superoxide anion production was increased in cells exposed to cyclic strain compared to static conditions. Furthermore, endothelial oxidative response to stretch was matrix protein-dependent, whereas cells grown on fibronectin and collagen I produced significantly more superoxide. The oxidative response to cyclic strain was reduced by coincubation with RGD peptides, blocking antibodies to alpha2- and beta-integrins antibodies, as well as inhibitors of protein kinase C. To investigate the effect of oxidative stress on gene transcription, endothelial cells grown on collagen I were transfected with an NFkappaB-sensitive luciferase construct. Cells that underwent cyclic strain displayed a tenfold induction of NFkappaB activation compared to static controls. Strain-induced luciferase activity was blunted by coincubation with RGD peptides or calphostin C. Thus, exposure of endothelial cells to cyclic strain led to integrin activation of a PKC-sensitive pathway that results in increased superoxide anion production and mobilization of NFkappaB.

    View details for Web of Science ID 000173063400007

    View details for PubMedID 11824481

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