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1.  Novel Oncogene Induced Metastatic Prostate Cancer Cell Lines Define Human Prostate Cancer Progression Signatures 
Cancer research  2012;73(2):978-989.
Herein, murine prostate cancer cell lines, generated via selective transduction with a single oncogene (c-Myc, Ha-Ras, and v-Src), demonstrated oncogene-specific prostate cancer molecular signatures that were recapitulated in human prostate cancer, and developed lung metastasis in immune competent mice. Interrogation of two independent retrospective cohorts of patient samples using the oncogene signature demonstrated an ability to distinguish tumor from normal prostate with a predictive value for prostate cancer of 98 – 99%. In a blinded study, the signature algorithm demonstrated independent substratification of reduced recurrence free survival by Kaplan-Meier analysis. The generation of new oncogene-specific prostate cancer cell lines that recapitulate human prostate cancer gene expression, that metastasize in immune-competent mice, are a valuable new resource for testing targeted therapy while the molecular signatures identified herein provides further value over current gene signature markers of prediction and outcome.
PMCID: PMC3561759  PMID: 23204233
2.  A Critical Role for Proinflammatory Behavior of Smooth Muscle Cells in Hemodynamic Initiation of Intracranial Aneurysm 
PLoS ONE  2013;8(9):e74357.
Intracranial aneurysm initiation is poorly understood, although hemodynamic insult is believed to play an important role in triggering the pathology. It has recently been found in a rabbit model that while macrophages are absent during hemodynamic aneurysm initiation, matrix metalloproteinases (MMPs) are elevated and co-localize with smooth muscle cells (SMCs). This study investigates whether SMCs play a mechanistic role in aneurysm initiation triggered by hemodynamics.
Aneurysmal damage was induced at the basilar terminus via bilateral common carotid artery ligation in rabbits (n = 45, plus 7 sham controls). 16 ligated rabbits were treated with doxycycline to inhibit MMPs, 7 received clodronate liposomes to deplete circulating monocytes, and the rest received no drug. Effects of the treatments on aneurysm development were assessed histologically 5 days and 6 months after ligation. MMP production and expression of inflammatory markers by SMCs was monitored by immunohistochemistry and in situ hybridization.
Treatment with doxycycline attenuated aneurysmal development examined at 5 days and 6 months, suggesting that MMPs contribute to aneurysm initiation. However, systemic depletion of macrophages did not decrease MMPs or suppress aneurysmal development. Immunofluorescence showed that during aneurysm initiation MMP-2 and MMP-9 were distributed in SMCs, and in situ hybridization indicated that they were transcribed by SMCs. In regions of early aneurysmal lesion, SMCs exhibited decreased expression of smooth muscle actin and increased NF-κB and MCP-1 expressions.
During aneurysm initiation triggered by hemodynamics, SMCs rather than macrophages are responsible for MMP production that is critical for aneurysmal lesion development. These SMCs exhibit proinflammatory behavior.
PMCID: PMC3759467  PMID: 24023941
3.  Reaching the Limit of the Oculomotor Plant: 3D Kinematics after Abducens Nerve Stimulation during the Torsional Vestibulo-Ocular Reflex 
Accumulating evidence shows that the oculomotor plant is capable of implementing aspects of three-dimensional kinematics such as Listing's law and the half-angle rule. But these studies have only examined the eye under static conditions or with movements that normally obey these rules (e.g., saccades and pursuit). Here we test the capability of the oculomotor plant to rearrange itself as necessary for non-half-angle behavior. Three monkeys (Macaca mulatta) fixated five vertically displaced targets along the midsagittal plane while sitting on a motion platform that rotated sinusoidally about the naso-occipital axis. This activated the torsional, rotational vestibuloocular reflex, which exhibits a zero-angle or negative-angle rule (depending on the visual stimulus). On random sinusoidal cycles, we stimulated the abducens nerve and observed the resultant eye movements. If the plant has rearranged itself to implement this non-half-angle behavior, then stimulation should reveal this behavior. On the other hand, if the plant is only capable of half-angle behavior, then stimulation should reveal a half-angle rule. We find the latter to be true and therefore additional neural signals are likely necessary to implement non-half-angle behavior.
PMCID: PMC3676185  PMID: 22993439
4.  Identification of genes related to agarwood formation: transcriptome analysis of healthy and wounded tissues of Aquilaria sinensis 
BMC Genomics  2013;14:227.
Agarwood is an expensive resinous heartwood derived from Aquilaria plants that is widely used in traditional medicines, incense and perfume. Only wounded trees can produce agarwood, and the huge demand for the agarwood products has led all Aquilaria spp. being endangered and listed in the Appendix II of the CITES ( The major components of agarwood are sesquiterpenes and phenylethyl chromones. Owing to a lack of genomic information, the molecular basis of wound-induced sesquiterpenes biosynthesis and agarwood formation remains unknown.
To identify the primary genes that maybe related to agarwood formation, we sequenced 2 cDNA libraries generated from healthy and wounded A. sinensis (Lour.) Gilg. A total of 89,137 unigenes with an average length of 678.65 bp were obtained, and they were annotated in detail at bioinformatics levels. Of those associated with agarwood formation, 30 putatively encoded enzymes in the sesquiterpene biosynthesis pathway, and a handful of transcription factors and protein kinases were related to wound signal transduction. Three full-length cDNAs of sesquiterpene synthases (ASS1-3) were cloned and expressed in Escherichia coli, and enzyme assays revealed that they are active enzymes, with the major products being δ-guaiene. A methyl jasmonate (MJ) induction experiment revealed that the expression of ASS was significantly induced by MJ, and the production of sesquiterpenes was elevated accordingly. The expression of some transcription factors and protein kinases, especially MYB4, WRKY4, MPKK2 and MAPK2, was also induced by MJ and coordinated with ASS expression, suggesting they maybe positive regulators of ASS.
This study provides extensive transcriptome information for Aquilaria spp. and valuable clues for elucidating the mechanism of wound-induced agarwood sesquiterpenes biosynthesis and their regulation.
PMCID: PMC3635961  PMID: 23565705
Agarwood; Aquilaria sinensis; GC-MS; Sesquiterpenes; Transcriptome; Wound signal transduction
5.  Reaching the Limit of the Oculomotor Plant: 3D Kinematics after Abducens Nerve Stimulation during the Torsional Vestibulo-Ocular Reflex 
The Journal of Neuroscience  2012;32(38):13237-13243.
Accumulating evidence shows that the oculomotor plant is capable of implementing aspects of three-dimensional kinematics such as Listing's law and the half-angle rule. But these studies have only examined the eye under static conditions or with movements that normally obey these rules (e.g., saccades and pursuit). Here we test the capability of the oculomotor plant to rearrange itself as necessary for non-half-angle behavior. Three monkeys (Macaca mulatta) fixated five vertically displaced targets along the midsagittal plane while sitting on a motion platform that rotated sinusoidally about the naso-occipital axis. This activated the torsional, rotational vestibulo-ocular reflex, which exhibits a zero-angle or negative-angle rule (depending on the visual stimulus). On random sinusoidal cycles, we stimulated the abducens nerve and observed the resultant eye movements. If the plant has rearranged itself to implement this non-half-angle behavior, then stimulation should reveal this behavior. On the other hand, if the plant is only capable of half-angle behavior, then stimulation should reveal a half-angle rule. We find the latter to be true and therefore additional neural signals are likely necessary to implement non-half-angle behavior.
PMCID: PMC3676185  PMID: 22993439
6.  Probabilistic Identification of Cerebellar Cortical Neurones across Species 
PLoS ONE  2013;8(3):e57669.
Despite our fine-grain anatomical knowledge of the cerebellar cortex, electrophysiological studies of circuit information processing over the last fifty years have been hampered by the difficulty of reliably assigning signals to identified cell types. We approached this problem by assessing the spontaneous activity signatures of identified cerebellar cortical neurones. A range of statistics describing firing frequency and irregularity were then used, individually and in combination, to build Gaussian Process Classifiers (GPC) leading to a probabilistic classification of each neurone type and the computation of equi-probable decision boundaries between cell classes. Firing frequency statistics were useful for separating Purkinje cells from granular layer units, whilst firing irregularity measures proved most useful for distinguishing cells within granular layer cell classes. Considered as single statistics, we achieved classification accuracies of 72.5% and 92.7% for granular layer and molecular layer units respectively. Combining statistics to form twin-variate GPC models substantially improved classification accuracies with the combination of mean spike frequency and log-interval entropy offering classification accuracies of 92.7% and 99.2% for our molecular and granular layer models, respectively. A cross-species comparison was performed, using data drawn from anaesthetised mice and decerebrate cats, where our models offered 80% and 100% classification accuracy. We then used our models to assess non-identified data from awake monkeys and rabbits in order to highlight subsets of neurones with the greatest degree of similarity to identified cell classes. In this way, our GPC-based approach for tentatively identifying neurones from their spontaneous activity signatures, in the absence of an established ground-truth, nonetheless affords the experimenter a statistically robust means of grouping cells with properties matching known cell classes. Our approach therefore may have broad application to a variety of future cerebellar cortical investigations, particularly in awake animals where opportunities for definitive cell identification are limited.
PMCID: PMC3587648  PMID: 23469215
7.  MicroRNA and histopathological characterization of pure mucinous breast carcinoma 
Cancer Biology & Medicine  2013;10(1):22-27.
Pure mucinous breast carcinoma (PMBC) is an uncommon histological type of breast cancer characterized by a large amount of mucin production. MicroRNA (miRNA) is a large class of small noncoding RNA of about 22 nt involved in the regulation of various biological processes. This study aims to identify the miRNA expression profile in PMBC.
MiRNA expression profiles in 11 PMBCs were analyzed by miRNA-microarray and real-time polymerase chain reaction (PCR). Thirty-one PMBCs and 27 invasive ductal carcinoma of no special types (IDC-NSTs) were assessed by immunohistochemistry using antibodies against ER, PR-progesterone receptor, HER2, Ki-67, Bcl-2, p53, PCNA, and CK5 and 6.
We analyzed the miRNA expression in 11 PMBCs and corresponding normal tissues using miRNA-microarray and real-time PCR, and found that miR-143 and miR-224-5p were significantly downregulated in mucinous carcinoma tissue. Compared with IDC-NSTs, PMBC showed a significantly higher ER positive rate, lower HER-2 positive rate, and lower cell proliferation rates.
To our knowledge, this is the first study to demonstrate the miRNA expression profile of PMBC, and our findings may lead to further understanding of this type of breast cancer.
PMCID: PMC3643684  PMID: 23691441
Pure mucinous breast carcinoma; microRNA; real-time PCR
8.  Cellular and Molecular Responses of the Basilar Terminus to Hemodynamics during Intracranial Aneurysm Initiation in a Rabbit Model 
Journal of Vascular Research  2011;48(5):429-442.
Hemodynamics constitute a critical factor in the formation of intracranial aneurysms. However, little is known about how intracranial arteries respond to hemodynamic insult and how that response contributes to aneurysm formation. We examined early cellular responses at rabbit basilar termini exposed to hemodynamic insult that initiates aneurysmal remodeling.
Flow in the basilar artery was increased by bilateral carotid artery ligation. After 2 and 5 days, basilar terminus tissue was examined by immunohistochemistry and quantitative PCR.
Within 2 days of flow increase, internal elastic lamina (IEL) was lost in the periapical region of the bifurcation, which experienced high wall shear stress and positive wall shear stress gradient. Overlying endothelium was still largely present in this region. IEL loss was associated with localized apoptosis and elevated expression of matrix metalloproteinases (MMPs) 2 and 9. A small number of inflammatory cells were sporadically scattered in the bifurcation adventitia and were not concentrated in regions of IEL loss and MMP elevation. Elevated MMP expression colocalized with smooth muscle α-actin in the media.
The initial vascular response to aneurysm-initiating hemodynamic insult includes localized matrix degradation and cell apoptosis. Such destructive remodeling arises from intrinsic mural cells, rather than through inflammatory cell infiltration.
PMCID: PMC3121554  PMID: 21625176
Intracranial aneurysm; Hemodynamic forces; Vascular remodeling; Internal elastic lamina; Matrix metalloproteinase; Apoptosis; Inflammatory cells; Wall shear stress
9.  Homonymous Quadrantanopsia as the First Manifestation of Cerebral Metastasis of Invasive Mole: a case report 
Homonymous quadrantanopsia results from retrochiasmal lesions in the visual pathway. Invasive mole is a benign tumor that arises from myometrial invasion of a hydatidiform mole via direct extension through tissue or venous channels. Cerebral metastasis of invasive mole is rare and there has been no report demonstrating homonymous quadrantanopsia as the first manifestation of metastasis in any trophoblastic neoplasms.
Case presentation
We report the case of a 31-year-old Asian woman who presented with right homonymous inferior quadrantanopsia from the mass effect of a solitary cerebral metastasis from an invasive mole. A magnetic resonance image (MRI) of the brain showed a metastatic tumor in the left occipital lobe. The visual field improved slightly after chemotherapy. There was a reduction in the tumor size and the surrounding edema. This is the first case report demonstrating that homonymous quadrantanopsia should be included in the manifestations of the metastasis of an invasive mole.
The presentation of homonymous quadrantanopsia must alert ophthalmologists to conduct a complete medical history and arrange specialist consultation.
PMCID: PMC3353198  PMID: 22531212
Cerebral metastasis; Homonymous Quadrantanopsia; Invasive mole
10.  Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells 
miR-34a functions as an important tumor suppressor during the process of carcinogenesis. However, the mechanism of miR-34a dysregulation in human malignancies has not been well elucidated. Our study aimed to further investigate the regulation mechanism of miR-34a.
We found that overexpression of NF-kappa B p65 subunit could increase miR-34a levels in EC109, an esophageal squamous cancer cell line, while ectopic expression of DN IkappaB leaded to a significant reduction of miR-34a expression. Bioinformatics analysis suggested three putative KB sites in promoter region of miR-34a gene. Mutation two of these KB sites impaired p65 induced miR-34a transcriptional activity. Chromatin immunoprecipitation and electrophoretic mobility shift assays both showed that NF-kappaB could specifically bind to the third KB site located in miR-34a promoter. In addition, we found that overexpression of NF-kappaB p65 could not successfully induce miR-34a expression in esophageal cancer cell lines with mutant p53 or decreased p53. Reporter assay further showed that NF-kappaB-induced miR-34a transcriptional activity was reduced by p53 impairment. Nevertheless, CHIP analysis suggested binding of NF-kappaB to miR-34a promoter was not affected in cells with mutant p53.
Our work indicates a novel mechanism of miR-34a regulation that NF-kappaB could elevate miR-34a expression levels through directly binding to its promoter. And wildtype p53 is responsible for NF-kappaB-mediated miR-34a transcriptional activity but not for NF-kappaB binding. These findings might be helpful in understanding miR-34a abnormality in human malignancies and open new perspectives for the roles of miR-34a and NF-kappaB in tumor progression.
PMCID: PMC3311059  PMID: 22292433
miR-34a; NF-kappa B; p53; gene expression regulation
11.  Hemodynamic-Morphologic Discriminants for Intracranial Aneurysm Rupture 
Background and Purpose
To identify significant morphologic and hemodynamic parameters that discriminate intracranial aneurysm (IA) rupture status using 3D angiography and computational fluid dynamics (CFD).
119 IAs (38 ruptured, 81 unruptured) were analyzed from 3D angiographic images and CFD. Six morphologic and seven hemodynamic parameters were evaluated for significance with respect to rupture. Receiver-operating characteristic (ROC) analysis identified area under the curve (AUC) and optimal thresholds separating ruptured from unruptured aneurysms for each parameter. Significant parameters were examined by multivariate logistic regression analysis in 3 predictive models—morphology only, hemodynamics only, and combined—to identify independent discriminants, and the AUC-ROC of the predicted probability of rupture status was compared among these models.
Morphologic parameters (Size Ratio [SR], Undulation Index, Ellipticity Index, and Nonsphericity Index) and hemodynamic parameters (Average Wall Shear Stress [WSS], Maximum intra-aneurysmal WSS, Low WSS Area, Average Oscillatory Shear Index [OSI], Number of Vortices, and Relative Resident Time) achieved statistical significance (p<0.01). Multivariate logistic regression analysis demonstrated SR to be the only independently significant factor in the morphology model (AUC=0.83, 95% confidence interval [CI] 0.75–0.91), whereas WSS and OSI were the only independently significant variables in the hemodynamics model (AUC=0.85, 95% CI 0.78–0.93). The combined model retained all three variables, SR, WSS, and OSI (AUC=0.89, 95% CI 0.82–0.96).
All three models—morphological (based on SR), hemodynamic (based on WSS and OSI), and combined—discriminate IA rupture status with high AUC values. Hemodynamics is as important as morphology in discriminating aneurysm rupture status.
PMCID: PMC3021316  PMID: 21106956
Hemodynamics; Intracranial aneurysm; Morphology; Rupture
12.  PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b 
Cell Cycle  2011;10(1):73-81.
Cyclin D1 overexpression is a common feature of many human malignancies. Genomic deletion analysis has demonstrated a key role for cyclin D1 in cellular proliferation, angiogenesis and cellular migration. To investigate the mechanisms contributing to cyclin D1 functions, we purified cyclin D1a-associated complexes by affinity chromatography and identified the PACSIN 2 (protein kinase C and casein kinase substrate in neurons 2) protein by mass spectrometry. The PACSIN 2, but not the related PACSIN 1 and 3, directly bound wild-type cyclin D1 (cyclin D1a) at the carboxyl terminus and failed to bind cyclin D1b, the alternative splicing variant of cyclin D1. PACSIN 2 knockdown induced cellular migration and reduced cell spreading in LNCaP cells expressing cyclin D1a. In cyclin D1−/− mouse embryonic fibroblasts (MEFs), cyclin D1a, but not cyclin D1b, reduced the cell spreading to a polarized morphology. siPACSIN 2 had no effect on cellular migration of cyclin D1−/− MEFs. Cyclin D1a restored the migratory ability of cyclin D1−/− MEFs, which was further enhanced by knocking down PACSIN 2 with siRNA. The cyclin D1-associated protein, PACSIN 2, regulates cell spreading and migration, which are dependent on cyclin D1 expression.
PMCID: PMC3048077  PMID: 21200149
PACSIN 2; cyclin D1; polymorphism; cellular migration; cell spreading; cancer
13.  Loss of Sphingosine Kinase 1/S1P Signaling Impairs Cell Growth and Survival of Neurons and Progenitor Cells in the Developing Sensory Ganglia 
PLoS ONE  2011;6(11):e27150.
Lysophospholipids such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are important signaling molecules that can regulate a wide range of cellular responses. We discovered that Sphingosine kinase 1 (Sphk1), a key enzyme that converts sphingosine to S1P, is expressed in neurons and progenitor cells in nascent trigeminal and dorsal root ganglia during mouse embryogenesis.
Methods and Findings
Sphk1 null mouse embryos do not display overt deficits owing to compensation by Sphk2. Thus, we analyzed embryos that are deficient in both Sphk1 and Sphk2 (which essentially eliminates S1P function) in order to investigate the role(s) of Sphk1 during sensory ganglia formation. While animals lacking 1–3 alleles of Sphk1 and Sphk2 had no obvious phenotype, embryos without both genes displayed clear developmental defects. The complete absence of Sphk1 and Sphk2 resulted in trigeminal and dorsal root ganglia with fewer neurons and progenitor cells. The profound loss in cell number could be attributed to a decrease in cell proliferation as well as an increase in apoptosis. Furthermore, Sphk1/2 double mutants displayed an overall reduction in other sphingolipids as well as an imbalance of S1P/sphingosine and S1P/ceramide ratio, thereby favoring cell death and reducing cell growth.
Together, these results provide strong in vivo evidence that sphingosine kinase/S1P signaling plays an important role in regulating early events during development of sensory ganglia.
PMCID: PMC3212543  PMID: 22096531
14.  Characterization of Critical Hemodynamics Contributing to Aneurysmal Remodeling at the Basilar Terminus in a Rabbit Model 
Background and Purpose
Hemodynamic insult by bilateral common carotid artery (CCA) ligation has been shown to induce aneurysmal remodeling at the basilar terminus in a rabbit model. To characterize critical hemodynamics that initiate this remodeling, we applied a novel hemodynamics-histology co-mapping technique.
Eight rabbits received bilateral CCA ligation to increase basilar artery flow. Three underwent sham operations. Hemodynamic insult at the basilar terminus was assessed by computational fluid dynamics. Bifurcation tissue was harvested on day 5; histology was co-mapped with initial postligation hemodynamic fields of wall shear stress (WSS) and WSS gradient (WSSG).
All bifurcations showed internal elastic lamina (IEL) loss in periapical regions exposed to accelerating flow with high WSS and positive WSSG. IEL damage happened 100% of the time at locations where WSS>122 Pa and WSSG>530 Pa/mm. The degree of destructive remodeling accounting for IEL loss, medial thinning, and luminal bulging correlated with the magnitude of the hemodynamic insult.
Aneurysmal remodeling initiates when local hemodynamic forces exceed specific limits at the rabbit basilar terminus. A combination of high WSS and positive WSSG represents “dangerous” hemodynamics likely to induce aneurysmal remodeling.
PMCID: PMC2913882  PMID: 20595660
Destructive remodeling; regional blood flow; hemodynamics; imaging; mapping
15.  Alteration of Intra-Aneurysmal Hemodynamics for Flow Diversion Using Enterprise and Vision Stents 
World neurosurgery  2010;74(2-3):306-315.
Flow diversion is a novel concept for intracranial aneurysm treatment. The recently developed Enterprise Vascular Reconstruction Device (Codman Neurovascular, Raynham MA) provides easy delivery and repositioning. Although designed specifically for restraining coils within an aneurysm, this stent has theoretical effects on modifying flow dynamics, which have not been studied. The goal of this study was to quantify the effect of single and multiple self-expanding Enterprise stents alone or in combination with balloon-mounted stents on aneurysm hemodynamics using computational fluid dynamics (CFD).
The geometry of a wide-necked, saccular, basilar trunk aneurysm was reconstructed from computed tomographic angiography images. Various combinations of 1–3 stents were “virtually” conformed to fit into the vessel lumen and placed across the aneurysm orifice. CFD analysis was performed to calculate hemodynamic parameters considered important in aneurysm pathogenesis and thrombosis for each model.
The complex aneurysmal flow pattern was suppressed by stenting. Stent placement lowered average flow velocity in the aneurysm; further reduction was achieved by additional stent deployment. Aneurysmal flow turnover time, an indicator of stasis, was increased to 114-117% for single-stent, 127-128% for double-stent, and 141% for triple-stent deployment. Furthermore, aneurysmal wall shear stress (WSS) decreased with increasing number of deployed stents.
This is the first study analyzing flow modifications associated with placement of Enterprise stents for aneurysm occlusion. Placement of 2-3 stents significantly reduced intra-aneurysmal hemodynamic activities, thereby increasing the likelihood of inducing aneurysm thrombotic occlusion.
PMCID: PMC3011938  PMID: 21197155
Aneurysm; computational fluid dynamics; flow diversion; rupture; stent; turnover time
16.  Flow modification in canine intracranial aneurysm model by an asymmetric stent: studies using digital subtraction angiography (DSA) and image-based computational fluid dynamics (CFD) analyses 
An asymmetric stent with low porosity patch across the intracranial aneurysm neck and high porosity elsewhere is designed to modify the flow to result in thrombogenesis and occlusion of the aneurysm and yet to reduce the possibility of also occluding adjacent perforator vessels. The purposes of this study are to evaluate the flow field induced by an asymmetric stent using both numerical and digital subtraction angiography (DSA) methods and to quantify the flow dynamics of an asymmetric stent in an in vivo aneurysm model. We created a vein-pouch aneurysm model on the canine carotid artery. An asymmetric stent was implanted at the aneurysm, with 25% porosity across the aneurysm neck and 80% porosity elsewhere. The aneurysm geometry, before and after stent implantation, was acquired using cone beam CT and reconstructed for computational fluid dynamics (CFD) analysis. Both steady-state and pulsatile flow conditions using the measured waveforms from the aneurysm model were studied. To reduce computational costs, we modeled the asymmetric stent effect by specifying a pressure drop over the layer across the aneurysm orifice where the low porosity patch was located. From the CFD results, we found the asymmetric stent reduced the inflow into the aneurysm by 51%, and appeared to create a stasis-like environment which favors thrombus formation. The DSA sequences also showed substantial flow reduction into the aneurysm. Asymmetric stents may be a viable image guided intervention for treating intracranial aneurysms with desired flow modification features.
PMCID: PMC3111919  PMID: 21666881
Stent; Aneurysm; Digital Subtraction Angiography; Computational Fluid Dynamics; Image guided interventions; CT; image-based finite element models of physiology; image-based biomechanical models; circulation; porosity; wall shear stress
17.  Maize ABP9 enhances tolerance to multiple stresses in transgenic Arabidopsis by modulating ABA signaling and cellular levels of reactive oxygen species 
Plant Molecular Biology  2011;75(4-5):365-378.
The phytohormone abscisic acid (ABA) and reactive oxygen species (ROS) play critical roles in mediating abiotic stress responses in plants. It is well known that ABA is involved in the modulation of ROS levels by regulating ROS-producing and ROS-scavenging genes, but the molecular mechanisms underlying this regulation are poorly understood. Here we show that the expression of maize ABP9 gene, which encodes a bZIP transcription factor capable of binding to the ABRE2 motif in the maize Cat1 promoter, is induced by ABA, H2O2, drought and salt. Constitutive expression of ABP9 in transgenic Arabidopsis leads to remarkably enhanced tolerance to multiple stresses including drought, high salt, freezing temperature and oxidative stresses. ABP9 expressing Arabidopsis plants also exhibit increased sensitivity to exogenously applied ABA during seed germination, root growth and stomatal closure and improved water-conserving capacity. Moreover, constitutive expression of ABP9 causes reduced cellular levels of ROS, alleviated oxidative damage and reduced cell death, accompanied by elevated expression of many stress/ABA responsive genes including those for scavenging and regulating ROS. Taken together, these results suggest that ABP9 may play a pivotal role in plant tolerance to abiotic stresses by fine tuning ABA signaling and control of ROS accumulation.
Electronic supplementary material
The online version of this article (doi:10.1007/s11103-011-9732-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3044229  PMID: 21327835
Transcription factor ABP9; ABA; Reactive oxygen species; Stress tolerance; Gene expression
18.  Evaluation of an asymmetric stent patch design for a patient specific intracranial aneurysm using Computational Fluid Dynamic (CFD) calculations in the Computed Tomography (CT) derived lumen 
Stenting may provide a new, less invasive therapeutic option for cerebral aneurysms. However, a conventional porous stent may be insufficient in modifying the blood flow for clinical aneurysms. We designed an asymmetric stent consisting of a low porosity patch welded onto a porous stent for an anterior cerebral artery aneurysm of a specific patient geometry to block the strong inflow jet. To evaluate the effect of the patch on aneurysmal flow dynamics, we “virtually” implanted it into the patient's aneurysm geometry and performed Computational Fluid Dynamics (CFD) analysis. The patch was computationally deformed to fit into the vessel lumen segmented from the patient CT reconstructions. After the flow calculations, a patch with the same design was fabricated using laser cutting techniques and welded onto a commercial porous stent, creating a patient-specific asymmetric stent. This stent was implanted into a phantom, which was imaged with X-ray angiography. The hemodynamics of untreated and stented aneurysms were compared both computationally and experimentally. It was found from CFD of the patient aneurysm that the asymmetric stent effectively blocked the strong inflow jet into the aneurysm and eliminated the flow impingement on the aneurysm wall at the dome. The impact zone with elevated wall shear stress was eliminated, the aneurysmal flow activity was substantially reduced, and the flow was considerably reduced. Experimental observations corresponded well qualitatively with the CFD results. The demonstrated asymmetric stent could lead to a new minimally invasive image guided intervention to reduce aneurysm growth and rupture.
PMCID: PMC3035358  PMID: 21311732
Stent; Aneurysm; Computational Fluid Dynamics; Image guided interventions; Angiography; Asymmetric stent
19.  1β,10α:4β,5α-Diep­oxy-7αH-germacran-6β-ol monohydrate 
In the title compound, C15H26O3·H2O, a sesquiterpenoid mol­ecule with a germacrene backbone that contains two epoxide groups and one hydroxyl group. Inter­molecular O—H⋯O hydrogen bonds between the ep­oxy groups and solvent water mol­ecules give rise to an infinite three-dimensional supra­molecular structure.
PMCID: PMC3011483  PMID: 21589547
20.  Influence of Intracranial Aneurysm-to-Parent Vessel Size Ratio on Hemodynamics and Implication for Rupture: Results from a Virtual Experimental Study 
Neurosurgery  2009;64(4):622-631.
The effectiveness of intracranial aneurysm (IA) size as a predictor for rupture has been debated. We recently performed a retrospective analysis of IA morphology and found that a new index, namely, aneurysm-to-parent vessel size ratio (SR), was strongly correlated with IA rupture, with 77% of ruptured IAs showing an SR of more than 2, and 83% of unruptured IAs showing an SR of 2 or less. As hemodynamics have been implicated in both IA development and rupture, we examine how varying SR influences intra-aneurysmal hemodynamics.
One sidewall and 1 terminal IA were virtually reconstructed from patient 3-dimensional angiographic images. In 2 independent in silico experiments, the SR was varied from 1.0 to 3.5 by virtually changing either aneurysm size or vessel diameter while keeping the other parameter constant. Pulsatile computational fluid dynamics simulations were performed on each model for hemodynamics analysis.
Low SR (≤2) aneurysm morphology consistently demonstrated simple flow patterns with a single intra-aneurysmal vortex, whereas higher SR (>2) aneurysm morphology presented multiple vortices and complex flow patterns. The aneurysm luminal area that was exposed to low wall shear stress increased with increasing SR. Complex flow, multiple vortices, and low aneurysmal wall shear stress have been associated with ruptured IAs in previous studies.
Higher SR, irrespective of aneurysm type and absolute aneurysm or vessel size, gives rise to flow patterns typically observed in ruptured IAs. These results provide hemodynamic support for the existing correlation of SR with rupture risk.
PMCID: PMC2775481  PMID: 19349824
Intracranial aneurysm; Morphology; Parent vessel diameter; Rupture risk; Size ratio
21.  In vivo assessment of rapid cerebrovascular morphological adaptation following acute blood flow increase 
Journal of neurosurgery  2008;109(6):1141-1147.
Pathological extremes in cerebrovascular remodeling may contribute to basilar artery (BA) dolichoectasia and fusiform aneurysm development. Factors regulating cerebrovascular remodeling are poorly understood. To better understand hemodynamic influences on cerebrovascular remodeling, we examined BA remodeling following common carotid artery (CCA) ligation in an animal model.
Rabbits were subjected to sham surgery (3 animals), unilateral CCA ligation (3 animals), or bilateral CCA ligation (5 animals). Transcranial Doppler ultrasonography and rotational angiography were used to compute BA flow, diameter, wall shear stress (WSS), and a tortuosity index on Days 0, 1, 4, 7, 14, 28, 56, and 84. Basilar artery tissues were stained and analyzed at Day 84. Statistical analysis was performed using orthogonal contrast analysis, repeated measures analysis of variance, or mixed regression analysis of repeated measures. Statistical significance was defined as a probability value < 0.05.
Basilar artery flow and diameter increased significantly after the procedure in both ligation groups, but only the bilateral CCA ligation group demonstrated significant differences between groups. Wall shear stress significantly increased only in animals in the bilateral CCA ligation group and returned to baseline by Day 28, with 52% of WSS correction occurring by Day 7. Only the bilateral CCA ligation group developed significant BA tortuosity, occurring within 7 days postligation. Unlike the animals in the sham and unilateral CCA ligation groups, the animals in the bilateral CCA ligation group had histological staining results showing a substantial internal elastic lamina fragmentation.
Increased BA flow results in adaptive BA remodeling until WSS returns to physiological baseline levels. Morphological changes occur rapidly following flow alteration and do not require chronic insult to affect substantial and significant structural transformation. Additionally, it appears that there exists a flow-increase threshold that, when surpassed, results in significant tortuosity.
PMCID: PMC2775477  PMID: 19035734
basilar artery; carotid artery occlusion; dolichoectasia; rabbit; tortuosity; wall shear stress
Neurosurgery  2007;61(6):1305-1313.
The porous intravascular stents that are currently available may not cause complete aneurysm thrombosis and may therefore fail to provide durable protection against aneurysm rupture when used as a sole treatment modality. The goal of this study was to quantify the effects of porous stents on aneurysm hemodynamics using computational fluid dynamics.
The geometry of a wide-necked saccular basilar trunk aneurysm was reconstructed from a patient′s computed tomographic angiography images. Three commercial stents (Neuroform2; Boston Scientific/Target, San Leandro, CA; Wingspan; Boston Scientific, Fremont, CA; and Vision; Guidant Corp., Santa Clara, CA) were modeled. Various combinations of one to three stents were virtually conformed to fit into the vessel lumen and placed across the aneurysm orifice. An unstented aneurysm served as a control. Computational fluid dynamics analysis was performed to calculate the hemodynamic parameters considered important in aneurysm pathogenesis and thrombosis for each of the models.
The complex flow pattern observed in the unstented aneurysm was suppressed by stenting. Stent placement lowered the wall shear stress in the aneurysm, and this effect was increased by additional stent deployment. Turnover time was moderately increased after single- and double-stent placement and markedly increased after three stents were placed. The influence of stent design on hemodynamic parameters was more significant in double-stented models than in other models.
Aneurysm hemodynamic parameters were significantly modified by placement of multiple stents. Because the associated modifications may be helpful as well as harmful in terms of rupture risk, use of this technique requires careful consideration.
PMCID: PMC2756037  PMID: 18162911
Aneurysm; Endovascular; Hemodynamics; Multiple stenting; Stent
23.  Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling 
Neurological research  2006;28(4):372-380.
Abnormal vascular remodeling mediated by inflammatory cells has been identified as a key pathologic component of various vascular diseases, including abdominal aortic aneurysms, brain arteriovenous malformations and atherosclerosis. Based on findings from observational studies that analysed human intracranial aneurysms and experimental studies that utilized animal models, an emerging concept suggests that a key component of the pathophysiology of intracranial aneurysms is sustained abnormal vascular remodeling coupled with inflammation. This concept may provide a new treatment strategy to utilize agents to inhibit inflammation or cytokines produced by inflammatory cells such as matrix metalloproteinases. Such an approach would aim to stabilize these vascular lesions and prevent future expansion or rupture.
PMCID: PMC2754184  PMID: 16759441
Intracranial aneurysms; inflammation; remodeling; pathophysiology
24.  Validation of CFD Simulations of Cerebral Aneurysms With Implication of Geometric Variations 
Computational fluid dynamics (CFD) simulations using medical-image-based anatomical vascular geometry are now gaining clinical relevance. This study aimed at validating the CFD methodology for studying cerebral aneurysms by using particle image velocimetry (PIV) measurements, with a focus on the effects of small geometric variations in aneurysm models on the flow dynamics obtained with CFD. Method of Approach. An experimental phantom was fabricated out of silicone elastomer to best mimic a spherical aneurysm model. PIV measurements were obtained from the phantom and compared with the CFD results from an ideal spherical aneurysm model (S1). These measurements were also compared with CFD results, based on the geometry reconstructed from three-dimensional images of the experimental phantom. We further performed CFD analysis on two geometric variations, S2 and S3, of the phantom to investigate the effects of small geometric variations on the aneurysmal flow field. Results. We found poor agreement between the CFD results from the ideal spherical aneurysm model and the PIV measurements from the phantom, including inconsistent secondary flow patterns. The CFD results based on the actual phantom geometry, however, matched well with the PIV measurements. CFD of models S2 and S3 produced qualitatively similar flow fields to that of the phantom but quantitatively significant changes in key hemodynamic parameters such as vorticity, positive circulation, and wall shear stress. Conclusion. CFD simulation results can closely match experimental measurements as long as both are performed on the same model geometry. Small geometric variations on the aneurysm model can significantly alter the flow-field and key hemodynamic parameters. Since medical images are subjected to geometric uncertainties, image-based patient-specific CFD results must be carefully scrutinized before providing clinical feedback.
PMCID: PMC2754174  PMID: 17154684
computational fluid dynamics; CFD validations; particle image velocimetry; aneurysm; circulation; hemodynamics; geometric uncertainties
25.  A Model System for Mapping Vascular Responses to Complex Hemodynamics at Arterial Bifurcations In Vivo 
Neurosurgery  2006;59(5):1094-1101.
Cerebral aneurysms are preferentially located at arterial bifurcation apices with complex hemodynamics. To understand disease mechanisms associated with aneurysm initiation, we attempted to establish a causal relationship between local hemodynamics and vascular responses.
Arterial bifurcations were surgically created from native common carotid arteries in two dogs, angiographically imaged 2 weeks and 2 months later, and then excised. We characterized local morphological changes in response to specifically manipulated hemodynamics. Computational fluid dynamics simulations were performed on the in vivo images and results mapped onto histological images.
Local flow conditions, such as high wall shear stress and high wall shear stress gradient, were found to be associated with vascular changes, including an intimal pad in the flow impingement region and a “groove” bearing the characteristics of an early aneurysm.
This novel method of histohemodynamic micromapping reveals a direct correlation between an altered hemodynamic microenvironment and vascular responses consistent with aneurysm development.
PMCID: PMC2754158  PMID: 17143243
Arterial bifurcation; Cerebral aneurysms; Hemodynamics; Vascular remodeling

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